Journal articles on the topic '21 shi ji'

Abstract Background: Surufatinib (S, a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) plus toripalimab (T, an anti-PD-1 antibody) showed encouraging antitumor activity in solid tumors (Cao YS, 2022). Programmed death ligand 1 (PD-L1) expression is the established biomarker for 1L immune checkpoint inhibitors therapy in advanced NSCLC. We conducted an open-label, multi-cohort, single-arm phase 2 study to evaluate the safety and efficacy of S+T in patients (pts) with advanced solid tumors. Here, we reported the results of advanced NSCLC with PD-L1 positive expression cohort. Methods: Eligible pts had histologically confirmed advanced NSCLC with no prior systemic chemotherapy, PD-L1 positive (defined as PD-L1 TPS expression ≥1% [sp263]), and without EGFR, ALK or ROS1 genetic alteration if non-sq-NSCLC. Enrolled pts received 21-day cycles of S (250 mg orally QD) plus T (240 mg IV, Q3W) until disease progression or intolerable toxicity or the maximum duration of treatment with toripalimab is 24 months. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: From July 2020 to September 2021, 55 pts were screened, of whom 23 pts were enrolled and received the treatment of S+T. Median age was 66 years (range: 49-73), 16 (69.6%) were male and 12 (52.2%) had squamous histology. Pts with PD-L1 TPS ≥50% and <50% were 10 and 13 respectively. At the data cutoff (Aug 31, 2022), the median follow-up duration was 13.1 mos. Among 21 pts with at least one post-baseline tumor assessment, the confirmed ORR was 57.1%, the median DOR was 8.31 mos, and DCR was 100%. Median PFS (mPFS) (95% CI) was 9.63 mos (5.49, -), median OS (mOS) (95% CI) was not reached (10.78, -), 12m-OS rate was 64%. According to PD-L1 level, the confirmed ORR were 66.7% and 50% for pts with PD-L1 TPS ≥50% and <50%, respectively; mPFS were 9.66 (0.69, -) and 6.93 mos (1.64, -), respectively; and the 12m-OS rate were 70% and 62%, respectively. mPFS did not differ with histology: 9.66 mos (5.49, -) for squamous cell carcinoma and 9.63 mos (0.69, -) for adenocarcinoma. All pts experienced ≥1 treatment emergent adverse event (TEAE). The most common Gr ≥3 TEAEs (≥5% pts) were aspartate aminotransferase increased (17.4%), malignant neoplasm progression (17.4%), hypokalemia (13.0%), hepatic function abnormal (13.0%), lymphocyte count decreased (8.7%), hypertension (8.7%) and pneumonitis (8.7%). Conclusion: Surufatinib and toripalimab combination showed a promising antitumor activity in 1L therapy for advanced PD-L1 positive NSCLC with manageable toxicity. This study might represent a potential treatment option for these pts. Clinical trial information: NCT04169672. Citation Format: Ying Cheng, Lin Shen, Zhendong Chen, Feng Ye, Xianjun Yu, Xing Zhang, Dongmei Ji, Baorui Liu, Lijie Song, Chunjiao Wu, Ming Lu, Wei Chen, Jingxun Wu, Heli Gao, Desheng Weng, Weina Shen, Rutian Li, Minjie Yang, Jinghong Zhou, Haiyan Shi, Panfeng Tan, Songhua Fan, Michael Shi, Weiguo Su. Surufatinib plus toripalimab for first-line treatment of advanced non-small cell lung cancer (NSCLC) with PD-L1 positive expression: A multicenter, single-arm phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT225.

The presence of water inside a lithium ion (Li-ion) battery causes several interconnected chemical mechanisms that lead to material degradation including transition metal dissolution. [1-4]. As a result, cell performance is reduced, and the cell capacity rapidly fades. To mitigate transition metal dissolution caused by trace water, research groups have proposed various approaches to scavenge and neutralize the water within different components of the cell [4-6]. These methods include using a dehydratable molecular sieve within the cathode active material powder [6], direct dosing of the electrolyte with a water scavenging additive [5], and introducing a metal organic framework with water scavenging properties by mixing it with a polymer binder to create a film for use as a separator. Results from these studies show promise in improving the cycling stability of cells under abuse conditions, such as elevated temperature and high water content in the electrolyte. While these water scavenging techniques show clear benefits to cell capacity retention, they come with the trade-off of higher material cost, more complex production processes, and lower energy density, which have limited their widespread adoption in Li-ion batteries. This study focuses on the use of “cellulose”, a cheap, abundant and naturally dehydrating biopolymer, as a separator material. Cellulose-based separators have been used in Li-ion batteries and shown to be advantageous for capacity retention of the cells. The benefits of the cellulose separators have been attributed to their superior wettability, uniform pore size distribution, high porosity, and low electrical resistance [7-10]. Despite their well-known hydrophilicity, their water scavenging capabilities have not been thoroughly evaluated. In this work, we present new insights into the interaction of water with cellulose-based separator. The water scavenging properties of the cellulose separator are investigated both outside of the battery using the Karl-Fischer Coulometric Titration technique, and inside of the battery through cycling tests. As shown in Figure 1, replacing the conventional polymer-based separator with a cellulose-based nonwoven separator resulted in a significant improvement in cycle life. Furthermore, the water scavenging mechanism of cellulose-based nonwoven separator is studied using surface chemistry characterizations, suggesting water scavenging by the naturally occurring hydrogen bonding sites of cellulose. Additional discussion on drying conditions and the impact of other fiber types are also provided. References: Etacheri, V.; Marom, R.; Elazari, R.; Salitra, G.; Aurbach, D. Challenges in the development of advanced Li-ion batteries: a review. Energy & Environmental Science 2011, 4 (9), 3243-3262. Yoon, T.; Park, S.; Mun, J.; Ryu, J. H.; Choi, W.; Kang, Y.-S.; Park, J.-H.; Oh, S. M. Failure mechanisms of LiNi0. 5Mn1. 5O4 electrode at elevated temperature. Journal of power sources 2012, 215, 312-316. Lux, S.; Lucas, I.; Pollak, E.; Passerini, S.; Winter, M.; Kostecki, R. The mechanism of HF formation in LiPF6 based organic carbonate electrolytes. Electrochemistry Communications 2012, 14 (1), 47-50 Chang, Z.; Qiao, Y.; Deng, H.; Yang, H.; He, P.; Zhou, H. A stable high-voltage lithium-ion battery realized by an in-built water scavenger. Energy & Environmental Science 2020, 13 (4), 1197-1204. Sheha, E.; Refai, H. Water scavenger as effective electrolyte additive and hybrid binder‐free organic/inorganic cathode for Mg battery applications. Electrochimica Acta 2021, 372, 137883. Zhang, H.; Shi, L.; Zhao, Y.; Wang, Z.; Chen, H.; Zhu, J.; Yuan, S. A simple method to enhance the lifetime of Ni-rich cathode by using low-temperature dehydratable molecular sieve as water scavenger. Journal of Power Sources 2019, 435, 226773. Gwon, H.; Park, K.; Chung, S.-C.; Kim, R.-H.; Kang, J. K.; Ji, S. M.; Kim, N.-J.; Lee, S.; Ku, J.-H.; Do, E. C. A safe and sustainable bacterial cellulose nanofiber separator for lithium rechargeable batteries. Proceedings of the National Academy of Sciences 2019, 116 (39), 19288-19293. Jiang, F.; Yin, L.; Yu, Q.; Zhong, C.; Zhang, J. Bacterial cellulose nanofibrous membrane as thermal stable separator for lithium-ion batteries. Journal of Power Sources 2015, 279, 21-27. Wang, Y.; Liu, X.; Sheng, J.; Zhu, H.; Yang, R. Nanoporous regenerated cellulose separator for high-performance lithium ion batteries prepared by nonsolvent-induced phase separation. ACS Sustainable Chemistry & Engineering 2021, 9 (44), 14756-14765. Lv, D.; Chai, J.; Wang, P.; Zhu, L.; Liu, C.; Nie, S.; Li, B.; Cui, G. Pure cellulose lithium-ion battery separator with tunable pore size and improved working stability by cellulose nanofibrils. Carbohydrate polymers 2021, 251, 116975. Figure 1

Background:Systemic lupus erythematosus (SLE) is a chronic disease characterized by periodic flares associated with poor outcomes and subsequent organ damage (1-2). Flare prevention is important for optimal patient management and development of effective therapies.Objectives:To identify patient-level factors associated with flares among patients with moderate/severe SLE.Methods:We conducted a post-hoc analysis of 260 patients with active, autoantibody+ SLE enrolled in a phase II randomized clinical trial (Fenebrutinib) (3). The relationship between baseline demographic (age, gender, ethnicity, BMI), region (US/EU, outside US/EU), disease severity (PGA, SLEDAI-2K, BILAG domain involvement), disease duration, serologic markers (C3, C4, ANA, anti-dsDNA Ab, anti-Smith Ab), treatment arm, standard of care (SOC) and flares (BILAG and SFI) over 48 wks was assessed by survival analysis and multiple Cox Proportional Hazard models. We examined concordance between BILAG and SFI flares using Cohen’s Kappa Index.Results:The overall rate of flare was low (n=37 SFI flare, n=25 BILAG flare). Median time to first flare was 8 wks for SFI flares compared to 12 wks for BILAG flares. There was no difference in flare rate by treatment arm. Cumulative flare hazard increased over time. Concordance between SFI and BILAG flares was 0.14. Multivariable analyses identified a higher flare rate for both SFI and BILAG-defined flares in patients with severe disease at baseline (PGA >1.7, SLEDAI-2K ≥10) and <7 y disease duration.Flares were more common in patients ANA, anti-dsDNA and anti-Smith+ at baseline compared to patients with <3 + markers (p<.001). Furthermore, anti-dsDNA (p = .03) and/or anti-Smith (p = .001) positivity at baseline were better indicators of higher flare rate compared to ANA (p = 0.5). Low baseline complement level (C3 and C4) was associated with a higher flare rate (p = .03 and p = .03 respectively).Patients from non-US/EU regions had a higher flare rate compared to patients from the US/EU, despite receiving more frequent SOC therapy and higher baseline corticosteroid doses (≥10 mg/d). Overall, flare-free probability was comparable at 48 wks regardless of baseline corticosteroid dose but patients receiving <10 mg/d had a median time to flare of 4 vs 24 wks for those receiving ≥10 mg/d (p = .004).Conclusion:In this study, flares were more common among patients with more severe disease, shorter disease duration, multiple serologic markers, were from outside the US/EU, and received lower steroid doses at baseline.References:[1]Fernandez D and Kirou KA. Curr Rheumatol Rep 2016 18:14.[2]Stoll T, et al. Rheum (Oxford) 2004 43(8):1039–44.[3]Isenberg D, et al. Arth Rheum 2019 71 suppl 10.Baseline Factors (%)No Flare n=206FlareBILAG n=25SFI n=37BILAG and SFI n=8Age (mean (SD))41.8 (12)35.2 (9)40.4 (10)34.9 (8)Female199 (97)24 (96)35 (95)7 (88)PGA (mean (SD))1.7 (0.5)1.7 (0.4)1.9 (0.5)1.7 (0.6)BILAG A/B any domain197 (96)23 (92)35 (95)7 (88)SLEDAI 2K >=1087 (42)18 (72)17 (46)4 (50)Disease duration (y) (mean (SD))9.4 (7)5.3 (4)6.6 (6)2.9 (3)ANA +203 (99)24 (96)35 (95)8 (100)anti-dsDNA +102 (50)18 (72)21 (57)5 (63)anti-Smith +45 (22)13 (52)12 (32)4 (50)Low C357 (28)12 (48)13 (35)3 (38)Low C426 (13)7 (28)4 (11)1 (13)Non US/EU157 (76)21 (84)32 (87)8 (100)Corticosteroid130 (63)14 (56)21 (57)5 (63) ≥10 mg/d80 (39)9 (36)14 (38)4 (50)Immunosuppressant74 (36)12 (48)15 (41)3 (38)Antimalarial135 (66)14 (56)21 (57)5 (63)Notes: included patients 18-75 y; 1+ serologic marker of SLE; SLEDAI-2K >=8, PGA>=1; 1+ oral SOC treatmentSFI = SELENA- SLEDAI Flare IndexDisclosure of Interests:Lisa Lindsay Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Huiyan (Ashley) Mao Shareholder of: Employee of Hoffmann-La Roche Limited, Employee of: Employee of Hoffmann-La Roche Limited, Ji (Emmy) Cheng Shareholder of: Employee of Hoffmann-La Roche Limited, Employee of: Employee of Hoffmann-La Roche Limited, Ching-Yi Chuo Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Nicholas Jones Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Matthew D. Cascino Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Katie Tuckwell Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc.

Nanohybrid materials can exhibit the physical properties of their components and be used in various applications. Also, novel chromophores involving synthetically flexible molecules such as pyrazinacenes1 and porphyrins2 can be incorporated into these structures by different means in particular as MOFs or COFs, while other components include simple transition metal salts or oligonuclear metal-oxo clusters. In this work, we discuss nanohybrids materials containing oxoporphyrinogen (OxP), tetrapyrroles or fullerene as the organic component, with hybridization using respectively Ag(I) salt or oxo-Zr(IV) cluster. This yields nanohybrid materials having structures and properties due to their individual components. Highly-colored OxP is a tetrapyrrole macrocycle which can be stimulated to generate reactive singlet oxygen (1O2) under appropriate conditions (1O2 can be used for applications such as photodynamic therapy and environmental remediation). 1O2 generation by OxP undergoes significant enhancement over its unhybridized state when incorporated in nanohybrid structures, either MOFs or COFs, containing respectively oxo-Zr(IV) nodes or electron deficient linkers in porous coordination polymer nanoarchitectures. OxP-oxoZr(IV) nanohybrid can then be applied for oxidation of small molecule substrates to selected products.3 Also, C60 fullerene can be co-crystallized with silver(I) nitrate at the molecular level4 leading to a material that exhibits unique properties during its decomposition so that silver nitrate is released with concurrent deposition of highly nanostructured C60-only crystalline networks. The resulting nanohybrid material has been studied for application as slow-release antibacterial material.4 Other work includes porous materials for sensing applications. The utility of the nanohybrid approaches is demonstrated by using these examples. References: 1) G. J. Richards, J. P. Hill, Acc. Chem. Res., 2021, 54, 3228–3240. 2) M. K. Chahal, A. Liyanage, A. Z. Alsaleh, P. A. Karr, J. P. Hill, F. D'Souza, Chem. Sci., 2021, 12, 4925–4930. 3) J. Hynek, D.T. Payne, M.K. Chahal, F. Sciortino, Y. Matsushita, L.K. Shrestha, K. Ariga, J. Labuta, Y. Yamauchi, J.P. Hill, Mater. Today Chem., 2021, 21, 100534. 4) J. P. Hill, R. G. Shrestha, J. Song, Q. Ji, K. Ariga, L. K. Shrestha, Bull. Chem. Soc. Jpn., 2021, 94, 1347–1354.

Abstract Purpose: The primary role of sentinel lymph node biopsy (SLNB) for early breast cancer (BC) is axillary staging. In terms of clearance of axillary disease or prevention of recurrence, its role may be limited considering the low axillary recurrence rate of less than 2% even though false-negative rates are 5-10% and the 25% additional axillary lymph node (ALN) detection in the ALND arms of the ACOSOG Z0011 and AMAROS trials. The NAUTILUS trial (NCT04303715) randomized cT1-2/N0 BC patients planned for breast-conserving surgery to evaluate the non-inferiority of omitting SLNB regarding 5-year invasive disease-free survival. The secondary endpoints are overall survival, distant metastasis-free survival, axillary recurrence rate, and quality of life of the patients. We aimed to investigate the clinicopathologic characteristics and ALN status of the subjects enrolled in the NAUTILUS trial. Methods: NAUTILUS trial randomized 1,734 subjects into SLNB or no-SLNB arms from September 2020 to October 2022. Axillary ultrasonography was mandatory to determine clinical N0, defined as no suspicious ALN or no tumor on ultrasound-guided biopsy of suspicious ALN. Clinicopathologic variables and the ALN status of the SLNB arm were analyzed. Results: Among 1,734 enrolled subjects, 828 (50.3%) and 818 (49.7%) subjects in the SLNB and no-SLNB arms, respectively, were included for analysis. Clinical and pathologic T stage, hormonal receptor/HER2 status, histologic grade, age, menopausal status, and Ki-67 were evenly distributed between the two groups (p = 0.554, 0.350, 0.056, 0.369, 0.623, 0.725 and 0.214, respectively). Median age was 55.3 (range, 48.0-62.0) years, and 661 (40.2%) were premenopausal. Overall, 30 (1.8%), 1,382 (84.0%), and 229 (13.9%) subjects were pTmic, pT1, and pT2, respectively, and median tumor size was 1.3 cm (range, 0.1-5.0). In the SLNB group, 94 (11.4%) had ALN metastasis, of which 9 (1.1%), 78 (9.4%), and 5 (0.6%) were pN1mic, pN1, and pN2-3, respectively (Table 1). According to pathologic tumor size, 5.8% (16/279), 11.4% (48/421), and 23.8% (30/126) were ALN positive for ≤ 1.0 cm, &gt;1.0cm & ≤ 2.0 cm, and &gt; 2.0 & ≤ 5.0 cm, respectively. The clinical and pathologic tumor size distribution among subjects with ALN metastasis were 23 (24.5%), 43 (45.7%), 9 (9.6%) and 16 (17.0%), 48 (51.1%), 30 (31.9%), respectively, for ≤ 1.0 cm, &gt;1.0cm & ≤ 2.0 cm, and &gt; 2.0 & ≤ 5.0 cm (Table 2). Among them, 12 (12.8%) received subsequent ALND. There was no difference in ALN metastasis rate according to molecular subtype, histologic grade, age, menopausal status, and Ki-67 (p= 0.812, 0.204, 0.671, and 0.101, respectively). Conclusions: The NAUTILUS trial completed enrollment of 1,734 subjects, among which 1,646 are available to analyze basic clinicopathologic characteristics. The trial included 229 (13.9%) pT2 and 661 (40.2%) premenopausal subjects and is expected to show the impact of SLNB omission in these subgroups. Data lock is expected in October 2027. Patients characteristics SLNB, sentinel lymph node biopsy; LVI, lymphovascular invasion; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; HER2, anti-human epidermal growth factor-2; BCS, breast conserving surgery; TM, total mastectomy; ALND, axillary lymph node dissection Basic characteristics for sentinel lymph node biopsy group a revealed no lymph node metastasis by fine needle aspiration or gun biopsy ALN, axillary lymph node; LN, lymph node Citation Format: Jai Min Ryu, Han-Byoel Lee, Sei Hyun Ahn, Il-Yong Chung, Seeyoun Lee, Seho Park, Woosung Lim, Joon Jeong, Jeong Eon Lee, Eunhye Kang, Ji Hyun Chang, Jung Min Chang, Woo Kyung Moon, Wonshik Han, Eun-Kyu Kim. What to expect from the No axillary surgical treatment for lymph node-negative patients after ultra-sonography [NAUTILUS] trial (KBCSG-21): Clinicopathologic characteristics and axillary lymph node status of enrolled patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS01-03.

Background:Systemic lupus erythematosus (SLE) is an autoimmune disorder more prevalent in the Asian population vs Caucasians. Belimumab (BEL), a monoclonal antibody targeting B-lymphocyte stimulator, is approved in patients (pts) ≥5 years with active, autoantibody-positive SLE.Objectives:Evaluate long-term safety and efficacy of intravenous (IV) BEL + standard SLE therapy (SST) in pts with SLE in Japan/Korea.Methods:In this Phase 3, multicentre, open-label (OL) study (BEL114333;NCT01597622), eligible (≥18 years of age) completers of the double-blind phase of GSK study BEL113750 in Japan and South Korea or the subcutaneous OL phase of GSK Study BEL112341 in Japan, received monthly BEL 10 mg/kg IV plus SST. Primary endpoints: safety assessments. Key secondary endpoints: SRI4 response rate at each scheduled visit (observed data), defined as a ≥4-point reduction from baseline in SELENA-SLEDAI score, no worsening in PGA (<0.3-point increase from baseline) and no new BILAG 1A/2B organ domain scores; time to first severe SFI flare over time. Endpoints were analysed relative to first BEL dose (parent or current study). No follow-up data were collected after study withdrawal.Results:Overall, 142 pts were enrolled (Japan n=72; Korea n=70), 104 (73.2%) completed the study, 1 (0.7%) died and 37 (26.1%) withdrew.Overall, 139 (97.9%) pts had ≥1 adverse event (AE) (Table). Most frequent AEs included: nasopharyngitis (60.6%); headache (28.2%); cough, herpes zoster and viral upper respiratory tract infection (18.3% each). Serious AEs (SAEs) occurred in 48 (33.8%) pts. Most common SAEs were infections and infestations, reported in 24 (16.9%) pts (Table). During this study, the annual incidence of AEs, including SAEs and AESI, remained stable or declined, with no trends of clinical concerns regarding the incidence of Grade 3 or 4 values for laboratory parameters. There was 1 transient positive immunogenicity result of no clinical concern.Table.The proportion of SRI4 responders was 47.8% at Year 1 (Week 24) and tended to increase numerically up to 84.6% at Year 7 (Week 48). The proportion of pts with a ≥4-point decrease from baseline in SELENA-SLEDAI score numerically increased from 51.5% at Year 1 (Week 24) to 84.6% at Year 7 (Week 48). Proportion of pts with no PGA worsening was 91.3-100% and the proportion with no new BILAG 1A/2B organ domain scores was 93.3-100% up to Year 7 (Week 48). A total of 21 (14.8%) pts had 24 severe SFI flares.Conclusion:BEL was well tolerated as add-on therapy to SST for ≤7 years in pts with SLE from Japan/Korea. Safety results were consistent with the known BEL safety profile.Study funding: GSK.Disclosure of Interests:Yoshiya Tanaka Grant/research support from: Received research grants from Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Ono, Speakers bureau: Received speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Teijin, Sang-Cheol Bae: None declared, Damon Bass Shareholder of: GSK, Employee of: GSK, Myron Chu Shareholder of: GSK, Employee of: GSK, Paula Curtis Shareholder of: GSK, Employee of: GSK, Kathleen DeRose Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Regina Kurrasch Shareholder of: GSK, Employee of: GSK, Jenny Lowe Shareholder of: GSK, Employee of: GSK, Paige Meizlik Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK

Abstract Background RMC-6291 is a potent, covalent, orally bioavailable KRASG12C(ON) inhibitor that uses a novel tri-complex mechanism to selectively target the active, GTP-bound state of the oncogenic KRASG12C. In preclinical models, RMC-6291 achieved a superior response rate, deeper regressions and longer duration of response compared to the KRASG12C(OFF) inhibitor, adagrasib. Receptor tyrosine kinase (RTK) overexpression and/or hyperactivating alterations and new synthesis of KRASG12C(ON) have been identified as potential resistance mechanisms to KRASG12C(OFF) inhibitors. Preclinical modeling shows KRASG12C(ON) inhibitors retain potency in cells with RTK activation and further are expected to rapidly extinguish newly synthesized KRASG12C(ON). Methods Patients with previously treated, advanced KRASG12C-mutated solid tumors received escalating doses of RMC-6291. Doses included 50, 100, and 200mg once daily (QD) and 100, 200, 300, and 400mg twice daily (BID). Each cycle had 21 days, with efficacy assessed every 6 weeks. Additional patients were enrolled to backfill cohorts at dose levels that cleared dose-limiting toxicity evaluation to further characterize PK, safety, and anti-tumor activity of RMC-6291. Results As of August 8, 2023, 47 patients with KRASG12C mutated solid tumors were treated, and 35 remained on treatment. The median number of prior therapies was 3 (range, 1-7). RMC-6291 exhibited dose-dependent exposure with a median Tmax of 1.0 hour and terminal half-life of 1.8 hours. Modeling projected average target occupancy of ≥~90% at 100mg BID and above. Treatment-related adverse events (TRAEs) occurring in ≥10% of patients were nausea (34%), diarrhea (30%), QTc prolongation (21%), vomiting and fatigue (15% each). The most common Gr3 TRAEs were QTc prolongation reported in 5 patients (3 at 400mg BID, 1 at 300mg, 1 at 200mg BID). Only one out of these 5 patients had an average QTc interval &gt;501ms. Most events of Gr3 QTc prolongation resolved to Gr1 or normal following dose interruption and/or reduction, and all 5 patients were asymptomatic and remained on treatment at a reduced dose. No treatment-related ≥Gr3 hepatotoxicity was observed. No patients experienced a treatment-related Gr4 or 5 AE, or a treatment-emergent AE that led to treatment discontinuation. Efficacy analysis was conducted in two dominant subgroups and included patients enrolled ≥8 weeks before data cutoff across all dose levels. The objective response rate was 57% (4/7; 3 confirmed) in NSCLC patients with recent prior KRASG12C(OFF) inhibitor treatment, and 44% (4/9; 3 confirmed) in CRC patients naive to KRASG12C(OFF) inhibitor treatment. Conclusions This preliminary data set shows promising anti-tumor activity of RMC-6291 in KRASG12C-mutated NSCLC with recent prior KRASG12C(OFF) inhibitor treatment, and in KRASG12C-mutated CRC naive to KRASG12C(OFF) inhibitor treatment. Tolerability was acceptable below 400mg BID, suggesting the potential for combination with standard therapy, including immunologic agents. Dose optimization is ongoing. Citation Format: Pasi A. Jänne, Frédéric Bigot, Kyriakos Papadopoulos, Lauriane Eberst, David Sommerhalder, Loic Lebellec, Pei Jye Voon, Bruna Pellini, Ewa Kalinka, Kathryn Arbour, Benjamin Herzberg, Valentina Boni, Stephanie Bordenave, Hyun Woo Lee, Sai I. Ou, Jonathan Wesley Riess, Joseph T. Beck, Mariano Ponz-Sarvise, Paolo Antonio Ascierto, Yoon Ji Choi, Michelle Yang, Lei Bao, Rakesh Raman, Luxi Yang, Yunming Mu, Sofia Wong, Richa Dua, Melissa Johnson. Preliminary safety and anti-tumor activity of RMC-6291, a first-in-class, tri-complex KRASG12C(ON) inhibitor, in patients with or without prior KRASG12C(OFF) inhibitor treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR014.

The development of Sodium-ion battery technologies and materials is moving rapidly forward, and several companies are on the verge of commercialising their products. An important question is what knowledge and synergies that can be drawn from Lithium-ion batteries. This work has investigated whether the Doyle-Fuller-Newman model (DFN model) [1] can be used for simulating the insertion and extraction of mobile sodium ion in hard carbon. Previous work indicates that this should be the case [2]–[4]. It has been shown that the insertion process of sodium in hard carbon does not follow the same process as for lithium in hard carbon [5]. The sodium insertion in hard carbon is suggested to be a combination of capacitive adsorption, intercalation and nanopore filling [6]–[8]. Hence, the question is if capacitive adsorption and nanopore filling can be simulated as an intercalation process. In addition, the sodium-ion has a lower charge density than lithium-ion, leading to different properties for the electrolyte and the interfacial species [9], [10]. One of the issues with the DFN model is to measure, calculate or estimate the material and electrode properties needed. As a first step in investigating the above assumption, an additional assumption made is that the needed parameters can be extracted using similar methods as for Li-ion batteries. With this starting point, a parameter sensitivity analysis is made for simulating mobile sodium in hard carbon with the DFN model. References [1] M. Doyle, T. Fuller, and J. Newman, “Modeling of galvanostatic charge and discharge of the lithium/ polymer/insertion cell,” J. Electrochem. Soc., vol. 140, no. 6, pp. 1526–1533, 1993, doi: 10.1149/1.2221597. [2] K. Chayambuka, M. Jiang, G. Mulder, D. L. Danilov, and P. H. L. Notten, “Physics-based modeling of sodium-ion batteries part I: Experimental parameter determination,” Electrochim. Acta, vol. 404, p. 139726, Feb. 2022, doi: 10.1016/J.ELECTACTA.2021.139726. [3] K. Chayambuka, G. Mulder, D. L. Danilov, and P. H. L. Notten, “Physics-based modeling of sodium-ion batteries part II. Model and validation,” Electrochim. Acta, vol. 404, p. 139764, Feb. 2022, doi: 10.1016/J.ELECTACTA.2021.139764. [4] C. M. Doyle, “Peer Reviewed Title: Design and Simulation of Lithium Rechargeable Batteries,” 2010. Accessed: Feb. 01, 2021. [Online]. Available: http://www.escholarship.org/uc/item/6j87z0sp [5] H. D. Asfaw, C. W. Tai, M. Valvo, and R. Younesi, “Facile synthesis of hard carbon microspheres from polyphenols for sodium-ion batteries: insight into local structure and interfacial kinetics,” Mater. Today Energy, vol. 18, p. 100505, Dec. 2020, doi: 10.1016/j.mtener.2020.100505. [6] J. Y. Hwang, S. T. Myung, and Y. K. Sun, “Sodium-ion batteries: Present and future,” Chemical Society Reviews, vol. 46, no. 12. Royal Society of Chemistry, pp. 3529–3614, Jun. 21, 2017. doi: 10.1039/c6cs00776g. [7] D. Chen et al., “Hard carbon for sodium storage: mechanism and optimization strategies toward commercialization,” Energy Environ. Sci., vol. 14, no. 4, pp. 2244–2262, Apr. 2021, doi: 10.1039/D0EE03916K. [8] C. Bommier, T. W. Surta, M. Dolgos, and X. Ji, “New Mechanistic Insights on Na-Ion Storage in Nongraphitizable Carbon,” Nano Lett., vol. 15, no. 9, pp. 5888–5892, Sep. 2015, doi: 10.1021/ACS.NANOLETT.5B01969/ASSET/IMAGES/LARGE/NL-2015-01969W_0002.JPEG. [9] R. Mogensen, S. Colbin, and R. Younesi, “An attempt to formulate non‐carbonate electrolytes for sodium‐ion batteries,” Batter. Supercaps, p. batt.202000252, Dec. 2020, doi: 10.1002/batt.202000252. [10] L. A. Ma, A. J. Naylor, L. Nyholm, and R. Younesi, “Strategies for Mitigating Dissolution of Solid Electrolyte Interphases in Sodium-Ion Batteries,” Angew. Chemie - Int. Ed., 2020, doi: 10.1002/anie.202013803.

Heavy metals contamination is a serious threat to all life forms. Long term exposure of heavy metals can lead to different life-threatening medical conditions including cancers of different body parts. Phytoremediation and bioremediation offer a potential eco-friendly solution to such problems. Different microbes can interact with heavy metals in a variety of ways such as biotransformation, oxidation/reduction, and biosorption. Phytoremediation of the heavy metals using plants mostly involves rhizofilteration, phytoextraction, phytovolatization, and Phyto stabilization. A synergistic approach using both plants and microbes has proven much more efficient as compared to the individual applications of microbes or plants. This article aims to highlight the synergistic methods used in bioremediation, emphasizing the potent collaboration between bacteria and plants for environmental cleaning, along with the discussion of the importance of site-specific variables and potential constraints. While identifying the necessity for all-encompassing solutions, this review places emphasis on the combination of methodologies as a multifarious rehabilitation approach. This discussion offers insightful suggestions for scholars, scientists and decision-makers about the sustainable recovery of heavy metal-contaminated environments using a comprehensive strategy. REFERENCES Ankit, Bauddh K, Korstad J (2022). Phycoremediation: Use of algae to sequester heavy metals. Hydrobiol. 1(3): 288-303. Arantza SJ, Hiram MR, Erika K, Chávez-Avilés MN, Valiente-Banuet JI, Fierros-Romero G (2022). Bio-and phytoremediation: Plants and microbes to the rescue of heavy metal polluted soils. SN Appl. Sci. 4(2): 59. Azubuike CC, Chikere CB, Okpokwasili GC (2016). Bioremediation techniques–classification based on site of application: principles, advantages, limitations and prospects. World J. Microbiol. Biotechnol. 32: 1-18. Berti WR, Cunningham SD (2000). Phytostabilization of metals. Phytoremediation of toxic metals: Using plants to clean up the environment. Wiley, New York. 71-88. Bingöl NA, Özmal F, Akın B (2017). Phytoremediation and biosorption potential of Lythrum salicaria for nickel removal from aqueous solutions. Pol. J. Environ. Stud. 26(6): 2479-2485. Chandra R, Saxena G, Kumar V (2015). Phytoremediation of environmental pollutants: an eco-sustainable green technology to environmental management, In Advances in biodegradation and bioremediation of industrial waste. 1-29. Chaudhary K, Agarwal S, Khan S (2018). Role of phytochelatins (PCs), metallothioneins (MTs), and heavy metal ATPase (HMA) genes in heavy metal tolerance, In Mycoremediation and Environmental Sustainability. Volume 2: 39-60. Choudhary M, Kumar R, Datta A, Nehra V, Garg N (2017). Bioremediation of heavy metals by microbes, In Bioremediation of salt affected soils: an Indian perspective. 233-255. Chugh M, Kumar L, Shah MP, Bharadvaja N (2022). Algal bioremediation of heavy metals: An insight into removal mechanisms, recovery of by-products, challenges, and future opportunities. Energy Nexus. 7:100129. Congeevaram S, Dhanarani S, Park J, Dexilin M, Thamaraiselvi K (2007). Biosorption of chromium and nickel by heavy metal resistant fungal and bacterial isolates. J. Hazard. Mat. 146(1-2): 270-277. Cristaldi A, Conti GO, Jho EH, Zuccarello P, Grasso A, Copat C, Ferrante M (2017). Phytoremediation of contaminated soils by heavy metals and PAHs. A brief review. Environ. Technol. Inno. 8: 309-326. Crusberg T, Mark S. (2000). Heavy metal remediation of wastewaters by microbial biotraps, In Springer. 123-137. Emenike CU, Jayanthi B, Agamuthu P, Fauziah S (2018). Biotransformation and removal of heavy metals: a review of phytoremediation and microbial remediation assessment on contaminated soil. Environ. Rev. 26(2): 156-168. Ghosh M, Singh S (2005). A review on phytoremediation of heavy metals and utilization of it’s by products. Asian J. Energy Environ. 6(4): 18. Guignardi Z, Schiavon M (2017). Biochemistry of plant selenium uptake and metabolism, In Selenium in plants: molecular, physiological, ecological and evolutionary aspects. 21-34. Hong-Bo S, Li-Ye C, Cheng-Jiang R, Hua L, Dong-Gang G, Wei-Xiang L (2010). Understanding molecular mechanisms for improving phytoremediation of heavy metal-contaminated soils. Crit. Rev. Biotechnol. 30(1): 23-30. Igiri BE, Okoduwa SI, Idoko GO, Akabuogu EP, Adeyi AO, Ejiogu IK (2018). Toxicity and bioremediation of heavy metals contaminated ecosystem from tannery wastewater: a review. J. Toxicol. 2018. Jabeen R, Ahmad A, Iqbal M (2009). Phytoremediation of heavy metals: physiological and molecular mechanisms. Bot. Rev. 75: 339-364. Joshi P, Swarup A, Maheshwari S, Kumar R, Singh N (2011). Bioremediation of heavy metals in liquid media through fungi isolated from contaminated sources. Indian J. Microbiol. 51: 482-487. Junaid M, Hashmi MZ, Tang YM, Malik RN, Pei,DS (2017). Potential health risk of heavy metals in the leather manufacturing industries in Sialkot, Pakistan. Sci. Rep. 7(1): 8848. Kapahi M, Sachdeva S (2019). Bioremediation options for heavy metal pollution. J. Health Pollut. 9(24): 191203. Lebeau T, Jézéquel K, Braud A (2011). Bioaugmentation-assisted phytoextraction applied to metal-contaminated soils: state of the art and future prospects, In Microbes and Microbial Technology: Agricultural and Environmental Applications. 229-266. Leong YK, Chang JS (2020). Bioremediation of heavy metals using microalgae: Recent advances and mechanisms. Bioresour.Technol. 303: 122886. Limmer M, Burken J (2016). Phytovolatilization of organic contaminants. Environ. Sci. Technol. 50(13): 6632-6643. Ma Y, Oliveira RS, Freitas H, Zhang C (2016). Biochemical and molecular mechanisms of plant-microbe-metal interactions: relevance for phytoremediation. Front. Plant Sci. 7: 918. Manzoor M, Gul I, Ahmed I, Zeeshan M, Hashmi I, Amin BAZ, Kallerhoff J, Arshad M (2019). Metal tolerant bacteria enhanced phytoextraction of lead by two accumulator ornamental species. Chemosphere. 227: 561-569. Mueller B, Rock S, Gowswami D, Ensley D (1999). Phytoremediation decision tree. Prepared by-Interstate Technology and Regulatory Cooperation Work Group. 1-36. Nies DH (1999). Microbial heavy-metal resistance. Appl. Microbiol. Biotechnol. 51: 730-750. Nies DH, Silver S (1995). Ion efflux systems involved in bacterial metal resistances. J. Ind. 14: 186-199. Pande V, Pandey SC, Sati D, Bhatt P, Samant M (2022). Microbial interventions in bioremediation of heavy metal contaminants in agroecosystem. Front. Microbiol. 13: 824084. Pandey VC, Bajpai O (2019). Phytoremediation: from theory toward practice, In Phytomanagement of polluted sites. 1-49. Robinson BH, Leblanc M, Petit D, Brooks RR, Kirkman JH, Gregg PE (1998). The potential of Thlaspi caerulescens for phytoremediation of contaminated soils. Plant Soil. 203: 47-56. Romantschuk M, Lahti-Leikas K, Kontro M, Allen JA, Sinkkonen A (2023). Bioremediation of contaminated soil and groundwater by in situ Front. Microbiol. 14: 1258148. Sabreena, Hassan S, Bhat SA, Kumar V, Ganai BA, Ameen F (2022). Phytoremediation of heavy metals: An indispensable contrivance in green remediation technology. Plants. 11(9): 1255. Saha L, Tiwari J, Bauddh K, Ma Y (2021). Recent developments in microbe–plant-based bioremediation for tackling heavy metal-polluted soils. Front. Microbiol. 12: 731723. Sharma I. (2020). Bioremediation techniques for polluted environment: concept, advantages, limitations, and prospects, In Trace metals in the environment-new approaches and recent advances. IntechOpen. Sharma JK, Kumar N, Singh NP, Santal, AR (2023). Phytoremediation technologies and their mechanism for removal of heavy metal from contaminated soil: An approach for a sustainable environment. Front. Plant Sci. 14: 1076876. Shen X, Dai M, Yang J, Sun L, Tan X, Peng C, Ali I, and Naz I (2022). A critical review on the phytoremediation of heavy metals from environment: Performance and challenges. Chemosphere. 291: 132979. Silver S (2011). BioMetals: a historical and personal perspective. Biometals. 24(3): 379-390. Silver S, Phung LT (2005). A bacterial view of the periodic table: genes and proteins for toxic inorganic ions. J. Ind. Microbiol. Biotechnol. 32: 587-605. Singh N, Santal AR (2015). Phytoremediation of heavy metals: the use of green approaches to clean the environment, In Phytoremediation: Management of Environmental Contaminants. Volume 2: 115-129. Strong PJ, Burgess JE (2008). Treatment methods for wine-related and distillery wastewaters: a review. Bioremediation J. 12(2): 70-87. Syranidou E, Christofilopoulos S, Gkavrou G, Thijs S, Weyens N, Vangronsveld J, Kalogerakis N (2016). Exploitation of endophytic bacteria to enhance the phytoremediation potential of the wetland helophyte Juncus acutus. Front. Microbiol. 7: 1016. Umrania VV (2006). Bioremediation of toxic heavy metals using acidothermophilic autotrophes. Bioresour. Technol. 97(10): 1237-1242. Valls M, De Lorenzo V (2002). Exploiting the genetic and biochemical capacities of bacteria for the remediation of heavy metal pollution. FEMS Microbiol. Rev. 26(4): 327-338. Verma P, George K, Singh H, Singh S, Juwarkar A, Singh R (2006). Modeling rhizofiltration: heavy-metal uptake by plant roots. Environ. Model. Assess. 11: 387-394. Wu Y, Li Z, Yang Y, Purchase D, Lu Y, Dai Z (2021). Extracellular polymeric substances facilitate the adsorption and migration of Cu2+ and Cd2+ in saturated porous media. Biomolecules. 11(11): 1715. Wuana RA, Okieimen FE (2011). Heavy metals in contaminated soils: a review of sources, chemistry, risks and best available strategies for remediation. International Scholarly Research Notices. Yan A, Wang Y, Tan SN, Mohd Yusof ML, Ghosh S, Chen Z (2020). Phytoremediation: a promising approach for revegetation of heavy metal-polluted land. Front. Plant Sci. 11: 359. Zhang Y, Hu J, Bai J, Wang J, Yin R, Wang J, and Lin X (2018). Arbuscular mycorrhizal fungi alleviate the heavy metal toxicity on sunflower (Helianthus annuus) plants cultivated on a heavily contaminated field soil at a WEEE-recycling site. Sci. Total Environ. 628: 282-290.

Liquid crystal on silicon (LCOS) spatial light modulator (SLM) is the most widely used optical engine for digital holography. This paper aims to provide an overview of the applications of phase-only LCOS in two-dimensional (2D) holography. It begins with a brief introduction to the holography theory along with its development trajectory, followed by the fundamental operating principle of phase-only LCOS SLMs. Hardware performance of LCOS SLMs (in terms of frame rate, phase linearity and flicker) and related experimental results are presented. Finally, potential improvements and applications are discussed for futuristic holographic displays. Full Text: PDF ReferencesM. Wolfke, Physikalische Zeitschrift 21, 495 (1920). DirectLink D. Gabor, "A New Microscopic Principle", Nature 161, 777 (1948). CrossRef H. Haken, "Laser Theory", Light and Matter 5, 14 (1970). CrossRef S. Benton, "Selected Papers on Three-dimensional displays", SPIE Press (2001). DirectLink X. Liang et al, "3D holographic display with optically addressed spatial light modulator", 3DTV-CON 2009 - 3rd 3DTV-Conference (2009). CrossRef J. Chen, W. Cranton, M. Fihn, "Handbook of Visual Display Technology", Springer (2012). CrossRef D. Rogers, "The chemistry of photography: From classical to digital technologies", Royal Society of Chemistry (2007). CrossRef S. Reichelt et al, "Depth cues in human visual perception and their realization in 3D displays", Proc. SPIE 7690, 76900B (2010). CrossRef A.W. Lohmann, D. Paris, "Binary Fraunhofer Holograms, Generated by Computer", Appl. Opt. 6, 1739 (1967). CrossRef J.W. Goodman, R.W. Lawrence, "Digital Image Formation from Electronically Detected Hologtrams", Appl. Phys. Lett 17, 77 (1967). CrossRef D.C. O'Brien, R.J. Mears, and W.A. Crossland, "Dynamic holographic interconnects that use ferroelectric liquid-crystal spatial light modulators", Appl. Opt. 33, 2795, (1994). CrossRef R.W. Gerchberg, and W.O. Saxton, "A practical algorithm for the determination of phase from image and diffraction plane pictures", Optik 35, 237 (1972). DirectLink M. Ernstoff, A. Leupp, M. Little, and H. Peterson, "Liquid crystal pictorial display", Proceedings of the 1973 International Electron Devices Meeting, IEEE, 548 (1973). CrossRef W.A. Crossland, P.J. Ayliffe, and P.W. Ross, "A dyed-phase-change liquid crystal display over a MOSFET switching array", Proc SID 23, 15 (1982). DirectLink M. Tang, and J. Wu, "Optical Correlation recoginition based on LCOS", Internation Symposium on Photoelectronic Detection and Imaging 2013, Optical Storage and Display Tech., 8913 (2013). CrossRef A. Hermerschmidt, et al. Holographic optical tweezers with real-time hologram calculation using a phase-only modulating LCOS-based SLM at 1064 nm, Complex Light and Optical Forces II, International Society for Optics and Photonics, 30282 (2008). CrossRef M. Wang, et al. "LCoS SLM Study and Its Application in Wavelength Selective Switch", Photonics 4, 22 (2017). CrossRef Z. Zhang, Z. You, and D. Chu, "Fundamentals of phase-only liquid crystal on silicon (LCOS) devices", Light Sci. & Appls. 3, e213 (2014). CrossRef D. Yang, and S. Wu, Fundamentals of liquid crystal devices, 2nd edition (Wiley 2015). CrossRef B. Prince, Semiconductor memories: A handbook of design, manufacture, and application, 2nd ed. (John Wiley & Sons 1996). DirectLink J.C. Jones, Liquid crystal displays, Handbook of optoelectronics: Enabling Technologies, 2nd ed. (CRC Press 2018). DirectLink A. Ayriyan, et al. "Simulation of the Static Electric Field Effect on the Director Orientation of Nematic Liquid Crystal in the Transition State", Phys. Wave Phenom. 27, 67 (2019). CrossRef S.M. Kelly, and M. O'Neil, Liquid crystal for electro-optic applications, Handbook of advanced electronics and photonic materials and devices 7, 15 (2000). DirectLink Y. Ji, et al., "Suspected Intraoperative Anaphylaxis to Gelatin Absorbable Hemostatic Sponge", J. SID 22, 4652 (2015). CrossRef X. Chang, Solution-processed ZnO nanoparticles for optically addressed spatial light modulator and other applications, Ph.D. thesis, (University of Cambridge, Cambridge 2019) CrossRef E. Moon, et al. "Holographic head-mounted display with RGB light emitting diode light source", Opt. Express 22, 6526 (2014). CrossRef G. Aad, et al. "Study of jet shapes in inclusive jet production in pp collisions at √s=7 TeV using the ATLAS detector", Phys Rev. D 83, 052003 (2011). CrossRef M. Pivnenko, K. Li, and D. Chu, "Sub-millisecond switching of multi-level liquid crystal on silicon spatial light modulators for increased information bandwidth", Opt. Express 29, 24614 (2021). CrossRef H. Yang, and D.P. Chu, "Phase flicker optimisation in digital liquid crystal on silicon devices", Opt. Express 27, 24556 (2019). CrossRef P. Bach-Y-Rita, et al. "Seeing with the Brain", Int. J. Hum. -Comput. Interact 15, 285 (2003). CrossRef Y. Tong, M. Pivnenko, and D. Chu, "Improvements of phase linearity and phase flicker of phase-only LCoS devices for holographic applications", Appl. Opt. 58, G248 (2019). CrossRef Y. Tong, M. Pivnenko, and D. Chu, "Implementation of 10-Bit Phase Modulation for Phase-Only LCOS Devices Using Deep Learning", Adv. Dev. & Instr. 1, 10 (2020). CrossRef H. Yang, and D. Chu, "Phase flicker optimisation in digital liquid crystal on silicon devices", Opt. Express 27, 24556 (2019). CrossRef J. García-Márquez, et al. "Mueller-Stokes characterization and optimization of a liquid crystal on silicon display showing depolarization", Opt.Express 16, 8431 (2008). CrossRef

Nitrogen is a paramount important essential element for all living organisms. It has been found to bea crucial structural component of proteins, nucleic acids, enzymes and other cellular constituents which are inevitable for all forms of life. In the atmosphere, the percentage of nitrogen is very high (N2, 78%) compared to other inorganic gases. However, most organisms have practically no direct access to this nitrogen. While plants can not directly uptake nitrogen from atmosphere, they are capable of assimilating other forms of nitrogen, for example ammonium (NH4+) and nitrate (NO3-). For agricultural crop production, artificial fixation of nitrogen is heavily utilized and it is an expensive process that requires high temperatures (at least 400 °C) and pressures (around 200 atm). It has been conspicuously demonstrated that indiscriminate use of fertilizer hampers soil physical, chemical and micro biological properties and also a potential risk to environment e.g. water quality. Besides, chemically manufactured fertilizers are depleted from soils in various ways, for instance; denitrifying bacteria, volatilization, and leaching. Consequently, it results relatively poor availability of nitrogen to get into plants. On the flipside, only 1-2% of the nitrogen fixation in the world occurs through the natural process of lightening. Notably, microbial fixation is well characterized in diazotrophs for example; Rhizobia and Frankia, and blue-green algae. Against the backdrop, we are accentuated on an environmentally friendlyand themost sustainable approach to increase productivity for legume and non-legume crops. Till today, the term biological nitrogen fixation (BNF) has received much attention as a sustainable alternative; this process facilitates atmospheric nitrogen to convert into ammonia by rhizobia in specialized plan organs termed “root nodules”. This review article seeks to better understand plant mechanisms involved in the development of root nodules in soybean. Soybean (Glycine max) is one of the most important oil crops and a source of animal feed protein in the world. It has a salient feature to fix atmospheric nitrogen through symbioses with compatible rhizobia that yields to determinate type nodule (Oldroyd, Murray et al. 2011). Biological nitrogen fixation in soybean nodules reduces the use of chemical nitrogen fertilizers resulting in cost-savings to producers and minimizes environmental damage due to nitrogen run-off. A better understanding of how nodules form and function is important for selection or generation of soybean genotypes with better nitrogen fixation capacity. Soybean nodules originate from root cortex via de novo cell differentiation (Oldroyd 2013). Consequently, two major nodule development zones are formed for instance; the nodule primordium (Npr) in the middle and it is encircled by nodule parenchyma (Npa). At later time point, the Npr gives rise to N-fixation zone and the Npa holds vascular bundles. It is not clear what early signaling pathways driving the conspicuous development of the nodule zones. My research is aimed at filling this knowledge gap by illustrating the molecular signatures that paves the way to cellular differentiation in root nodule development in soybean. Based on initial evidence obtained by the Subramanian lab, we hypothesize that microRNAs (miRNAs) play important regulatory roles in spatio-temporal expression of their target genes during nodule developmental in soybean. For instance, the regulation of auxin sensitivity by miR160 has been found to be crucial for formation of nodule primordia and vasculature in the parenchyma (Marie Turner 2013). Against this backdrop, this review article focused on nuclear and cytoplasmic transcriptome as well as miRNA profiles of parenchyma and primordial tissues and determine the relative abundance and differentially expressed mRNAs and regulatory role of miRNAs in cell differentiation and nodule development. Root nodule a sustainable alternative to fix atmospheric nitrogen Atmospheric nitrogen percentage is very high (N2, 78%) compared to other inorganic gases (Mary Elvira 1932). However, most of the organisms have practically no direct access to this nitrogen. Nevertheless, plants can not directly uptake nitrogen from atmosphere but they are capable of assimilating only very specific forms of nitrogen, for example ammonium (NH4+) and nitrate (NO3-) (Bytnerowicz and Fenn 1996, Peter M. Vitousek 1997) (Sponseller, Gundale et al. 2016). Virtually, nitrogen has been found to be a crucial structural component of proteins, nucleic acids, enzymes, and other cellular constituents which are inevitable for all forms of life (O'Brien, Vega et al. 2016). For agricultural crop production, artificial fixation of nitrogen is heavily utilized. It is an expensive process that requires high temperatures (approx. 400 °C) and pressures (approx. 200 atm) (Witschi 2000). It has been conspicuously demonstrated that indiscriminate use of N fertilizer hampers the diversity of the bacterial community and decreases soil C and N concentrations (Verzeaux, Alahmad et al. 2016). Notably, it has been demonstrated as a potential risk to environment e.g. water quality (Zhao, Sha et al. 2016) (Sponseller, Gundale et al. 2016). Besides, chemically manufactured fertilizers are depleted from soils in various ways, for instance; denitrifying bacteria, volatilization, and leaching (Johnson 1996, Peter M. Vitousek 1997). Consequently, it results relatively poor availability of nitrogen to get into plants. On the flipside, over 90 % of the nitrogen fixation in the world occurs through the natural process of lightening and microorganisms. Furthermore, microbial fixation is well characterized in diazotrophs for example; Rhizobia and Frankia, and blue-green algae (Cheng 2008). It has been demonstrated that Bradyrhizobium strains substantially escalated soybean grain yield, and protein content up to 57% and 26%, respectively (Zimmer, Messmer et al. 2016). Against the backdrop, we are accentuated on an environmentally friendly and a sustainable approach to increase the productivity for legume and non-legume crops. Literature mining depicted that biological nitrogen fixation in soybean nodules reduces the use of chemical nitrogen fertilizers resulting in cost-savings to producers and minimizes environmental damage due to nitrogen run-off. Rhizobia infection leads to the root nodule development In the natural environment, plants are continuously confronted with pathogenic and symbiotic microbes. Symbioses involves mutual exchange of diffusible signal molecules, first endophytic bacteria (rhizobia) are attracted by the plant root exudates flavonoids which are perceived and triggered the bacterial nodulation (nod) genes. Consequently, the bacteria synthesize specific lipochito-oligosaccharides, called nodulation (Nod) factors. This signal is perceived by the LysM receptor like kinase of host plant, it induces the root hair curling, and bacteria get access into the host epidermis through infection threads (ITs) and initiate cell division within the root cortex, leading to the progression of the root nodule meristem. In later stages of the interaction, bacteria are released from the infection threads into the plant cells, surrounded by membrane of plant origin. These bacteria multiply within the host cells and differentiate into the nitrogen fixing bacteroids (Udvardi and Day 1997) (Oldroyd 2013). Till now, integration of genetic and genomic approaches has revealed twenty-six genes to be involved in nodule development of Medicago truncatualaand Lotus japonicum (Kouchi, Imaizumi-Anraku et al. 2010). In addition, deep sequencing of the Medicago truncatularoot transcriptome has uncovered thousands of genes to be induced during Nod factor signaling and its resulting ethylene (ET) biosynthesis throughout the multiple development stages of indeterminate nodule (Larrainzar, Riely et al. 2015). Albeit the molecular mechanism of such regulation is not well understood. There has been a large-scale transcriptome analysis of B. japonicum-inoculated and mock-inoculated soybean root hairs. It has showed that a total of 1,973 soybean genes differentially expressed during root hair infection, particularly NFR5 and NIN genes (Libault, Farmer et al. 2010). Nevertheless, the signaling mechanisms directing the cellular differentiation of nodule are not known. Soybean root nodule organogenesis Soybean (Glycine max) has a genome size of 1.1 to1.5 Gb, it is partially diploidized tetraploid. It is one of the most important oil crops and a source of animal feed protein in the world (soybase.org/sb_about.php). It has a salient feature to fix atmospheric nitrogen through symbioses with compatible rhizobia that yields to determinate type nodule (Udvardi and Day 1997) (Oldroyd, Murray et al. 2011). Notwithstanding of the economic and environmental importance, there has been very few studies about quantitative trait loci (QTL) that controlling BNF traits, for instance nodule number, ration of nodule dry weight with nodule number, and shoot dry weight (SDW). It has been reported via composite interval mapping that approximately six QTLs bears very small effect on BNF traits (Santos, Geraldi et al. 2013). Besides, it has been demonstrated in earlier studies that nodules originate from root cortex via de novo cell differentiation into two different cell types, parenchymal and primordium (Celine Charon 1997) (Oldroyd&Downie 2008; Oldroyd 2013). In addition, early nodulin genes in legume for instance; Enod 40 gene reported to be expressed in root pericycle during the rhizobia infection and later it occupied in the dividing cortical cells (H. Kouchi and S. Hata 1993). Among the two major nodule development zones, the nodule primordium (Npr) in the middle which is encircled by nodule parenchyma (Npa). At later time point, the Npr gives rise to N-fixation zone and the Npa holds vascular bundles. Lately, a β- expansin gene, GmEXPB2 fused with GUS reporter gene which was observed to be preferentially expressed in nodule vascular trace and nodule vascular bundles. It indicated that GmEXPB2 might be crucial for nodule organogenesis. Over expression of GmEXPB2 contrast to suppressed GmEXPB2 transgenic lines found to be escalated nodule number, nodule mass and nitrogenase activity. It further suggested that GmEXPB2 might have influenced over root architecture, nodule formation and development, and profoundly yielding to biological N2 fixation (Li, Zhao et al. 2015). Even though, it is not clear what early signaling pathways driving the conspicuous development of the nodule zones. Against the back drop, to understand the regulation of auxin sensitivity by miR160 which is believed to be crucial for the formation of nodule primordia (Marie Turner 2013). Figure 1 a. Illustrating the progression of root nodule development through Rhizobial bacterial infection in the plant root leading to the determinate nodule (Oldroyd 2013). b. Nodule development zones A. Nodule primordial zone (Enod 40 gene) in the middle B. surrounding parenchyma (Enod 2 gene), differentiated from cortex (collected from Sen Subramanian lab). Regulatory small RNAs biogenesis and its molecular functions Regulatory small RNAs are ranged between 20 to 24 nucleotides which are ubiquitous elements of endogenous plant transcriptomics, a common response to exogenous viral infections and introduced double-stranded RNA (Axtell 2013). Three core enzymes families, for instance; RNAdependent RNA polymerase (RDR), Dicer like (DCL), and Argonaute (AGO) proteins paves the way of small RNA biogenesis and function in plants. Firstly, ribonuclease type III or DICERLIKE1 involves in the yield of a fold-back precursor RNA or primary miRNA (primiRNA) transcripts using an RNA templates in the nuclei. Later, the resulting miRNA-miRNA duplex which is originated in nucleus then translocated into cytoplasm. The guided miRNAmolecule is incorporated into ARGONAUTE (AGO) to form an active RISC complex to specific target RNAs that are complementary to the miRNA, and this process eventually follows up mRNA cleavage, represses the translation of the mRNAs or Chromatin modification. This phenomenon accentuated as an inhibition or silencing of the gene expression, which play a crucial role in the developmental process in plant and animal (Chapman and Carrington 2007) (Axtell 2013). Fig. 2 Regulation of gene expression events via RISC complex (modified from https://www.google.com/?gws_rd=ssl#q=mirna+picture+in+plants accessed on 7th February, 2016) Fig. 3 Gene expression events occurring in typical plant cell (modified https://www.google.com/search?q=transcription+and+translation accessed on 7th February, 2016) It has been found in several studies that most plant miRNAs are non-coding RNA, and small 21-24 nucleotide long (Cuperus, Fahlgren et al. 2011). It requires DCL1-clade DCL for their biogenesis and AGO1-clade AGO for their function (Wu, Zhou et al. 2010, Manavella, Koenig et al. 2012). In rice (Oryza sativa), DCL3 has been reported in the biogenesis of 24nt long miRNA that incorporated in AGO4 to regulate the target gene expression primarily through mRNA cleavage (Wu, Zhou et al. 2010). Argonaute proteins (AGO) form RNA inducing silencing complexes (RISC) with small RNAswhich is known as post-transcriptional gene silencing. It has typically four domains, for instance:N-terminal, PAZ, MID and PIWI domains. The MID-PIWI lobes are belongs to the C-terminus. It has been studied that MID-domains contains the specificity loop to recognize and bind to the 5’-phosphate of smRNAs. The PIWI domains contained the catalytic active site D-E-D-H/D. PAZ domain anchored the 2-nt overhang at the 3’ end of miRNAs. The N-terminal domain involved in the separation of miRNA-miRNA duplex and the slicer activity of the mRNA (Song, Smith et al.2004). There has been an expansion and duplications of AGO family members during plantevolution (Singh, Gase et al. 2015). The functional diversification of AGOs is indicating sRNAdirected regulatory pathways. The binding preference of AGO and sRNA is mainly assigned by the sequence of sRNA. In Arabidopsis, 10 AGO have been extensively studied (Liu et al. 2014). It has been demonstrated that AtAGO10 like AtAGO1, it recognized distinct structural features in miR165/miR166 duplex than involved by AtGO1. AtAGO10 found to regulate shoot apical meristem by decoying miR165/miR166 and subsequent repression of homeodomain-leucinezipper (HD-ZIP) gene expression (Zhu, Hu et al. 2011). Notably, 22 AGO proteins have been reported in Soybean (Glycine max). It has been found that genome duplication in Soybean resulted such a proliferation of AGOs. For example: its genome encodes two copies of AGO1, AGO2, AGO5, AGO4/9, AGO6 and AGO7 (Xiang Liu 2014). However, the molecular function of the plant AGO genes yet not very clear. There are several miRNA families that are conserved across the vast evolutionary distances from flowering plants to mosses (Cuperus, Fahlgren et al. 2011). It has been observed in another study that miRNA, and its target pairing found to be stable for a prolonged periods of plant evolution. On the flip side, another group demonstrated that conserved plant miRNAs and their targets are to somehow flexible. For instance; miR159 is a highly conserved miRNA that targets not only a subset of MYB mRNAs but also observed to target a non MYB mRNA, SGN-U567133 (Buxdorf, Hendelman et al. 2010). A mutant tomato transgenic line (miR159-resistant line) showed higher level of the SGN-U567133 transcript and exhibited defects in leaf and flower development. This result suggests that miR159 involves in a post-transcriptional regulation. Additionally, it is found to be crucial for the normal tomato development. Recently, the identification of miRNAs in the regulation of photoperiodic pathways in soybean have been reported through high throughput sequencing and qRT-PCR. Six libraries were constructed using Illumina Solexa, for instance; 0, 8, and 16 h under short day treatment, similar time points considered for the long the long day treatment. A total of 163 miRNAs families were reported which covered 318 plant miRNAs, and unclassified 81 novel predicted miRNAs. As expected, significant differences in abundance between short day and long day treatment was observed (Wenbin Li 2015). These findings provided evidence of miRNA in the regulation of flowering time that ultimately affects the seed yield and quality of soybean. The complex regulatory network of miRNA-mRNA interactions during viral infection has been revealed via small RNA seq (sRNA), degradome seq, and genome-wide transcriptome analysis. There has been a total of 253 soybean miRNAs found to be two-folds abundance compared with mock-inoculated control demonstrated through sRNA seq analysis. Among them 105 miRNAs were identified as potential targets of 125 transcripts that has been validated by degradome seq analyses. In addition, 2679 genes were detected via genome wide transcriptomic analysis. These genes have been differentially expressed during infection of soybean mosaic virus and among them 71 genes projected to induce in defense response (Hui Chen 2016). These findings suggested the regulatory role miRNA that governed the target gene expression during viral infection. Furthermore, the regulatory role of microRNAs (miRNAs) during Soybean- Bradyrhizobium japonicum mutualistic association was studied first by Subramanian et al. 2008. They sequenced approximately 350000 small RNAs of soybean root sample which were inoculated with B. japonicum. It helps to detect 20 conserved miRNAs loci based on the similarity to miRNAs in another plant species. In addition, 35 novel miRNAs were identified based on potential hairpin forming precursors in Soybean EST as well as shotgun genomic sequences (Subramanian, Fu et al. 2008). These findings advocated the potential role of miRNAs in the regulation of legumerhizobiumsymbiosis. In another study, 120 hairpin-forming precursor genes have been identified in soybean by Turner et al. In addition, they reported three novel miRNAs for instance; miR160, miR164 and miR393 found to be involved in auxin signaling (Turner, Yu et al. 2012). Moreover, the plant hormone auxin is thought to have a pivotal role in nodule organogenesis in determinate and indeterminate type of nodule. It indicates a redundancy and diversity of miRNAs family members that governs the formation of root nodule. It has been illustrated that auxin receptor gene family hushed by over expressed microRNA393. These plant roots found to be hypersensitive to auxin and yielded normal nodule. This observation advocated that only minimal/reduced auxin signaling is required for determinate nodule development. Likewise, overexpressed microRNA160 hushed a set of repressor auxin response transcription factor. These plant roots were hypersensitive to auxin and observed not to be reluctant in epidermal responses to rhizobia. Notably, it yielded to lower sized nodule primordium (Marie Turner 2013). This observation indicated that auxin hypersensitivity inhibits nodule organogenesis Organ specific expression of profile of miRNA and the potential targets were also studied. Two genes (Glyma10g10240 and Glyma17g05920) which were the target of miR169 but detected to be highly expressed in soybean nodule. Likewise, three potential targets of gma-new-miR13587 demonstrated to be highly expressed in the nodules than in the roots. As expected, gma-newmiR13587 found to be poorly expressed in the nodules than in the roots (Turner, Yu et al. 2012). There was an inverse expression pattern observed in between roots and nodules. Li et al., studied the transgene expression of three novel miRNAs namely, miR482, miR1512, and miR1515 in Soybean. They noticed a significant increase of nodule numbers while root length and later root density were normal in all tested miRNA lines. As expected, there were differential expression of these miRNAs in supernodulating and nonnodulating soybean mutants. They reported that 6 novel miRNAs decoyed 22 predicted target genes. And it was estimated via real time polymerase chain reaction and qRT-PCR (Li, Deng et al. 2010). It advocates that miRNAs have the signatory roles in soybean nodule development. Sequencing of small RNAs and Parallel analysis of RNA ends (PARE) libraries revealed to identify 284 nodule miRNAs, more than 500 target genes, and including 178 novel soybean miRNAs. It has been reported that ENOD93 only found to be expressed in nodule tissue not in other plant parts of Soybean. Ectopic expression of miR393j-3p and RNAi silencing approach to ENOD93 expression showed a significant reduction in nodule formation (Zhe Yan 2015). Therefore, this study showed a list of miRNAs and their potential target of nodulation genes. In the model legume (Medicago truncatula), 25 conserved miRNA families and 100 novel miRNA reads were detected by high-throughput sequencing. The expression of MtHAP2-1 (encodes a CCAAT binding transcription factor) to meristematic zones was restricted by miR169a which is found to be critical for the development of indeterminate type of nodule (Combier, Frugier et al. 2006). In another study, HDZIPIII transcripts were inhibited by overexpression of miR166, it dropped the number of symbiotic nodule and lateral root (Boualem, Laporte et al. 2008). To get insights into key genes of nodule zones, transcript profiles of specific cells/tissues were investigated at different time points from indeterminate nodules of M. truncatulausing laser capture micro dissection. It has been demonstrated from the comprehensive gene expression map that selected genes enriched in different cell/tissue types (Limpens, Moling et al. 2013). These findings indicated that organ specific gene expression could be controlled by the presence or absence of miRNAs. Recently, Agrobacterium rhizogenesmediated hairy root transformation has been applied as tool for exploring cell type specific gene expression in tomato. Cell type or tissue specific promoter introduced into INTACT and TRAP constructs via gateway cloning technology to develop binary vectors. INTACT method used to capture biotin tagged nuceli from specific cell types and TRAP method used for profiling of mRNAs or foot printing of individual ribosomes (Ron 2014). TRAP methodology is not required tissue fixation or single cell suspension. It has been successfully used to date in organisms ranging from D. melanogaster to mice and human cultured cells. Multiple ribosomes or Polyribosomes (polysomes) are engaged in translation on a single mRNA. To evaluate the translation state of an mRNA, ribosomal subunits, ribosomes, and polysomes can be isolated from detergent-treated cell extracts (Heiman, Kulicke et al. 2014). In this study, we would perform polysome isolation deploying gene cassettes ENOD40p:HF-GFP-RPL18 for primordial tissues, and ENOD2p:HF-GFP-RPL18 for parenchymal tissues in Glycine max root nodules that express an epitope tagged version of ribosomal protein L18. Over the last one decade, there has been several microarrays-based studies which characterized transcriptional variations deployed in nodule formation. It has been embedded with couple of shortcomings, for instance; relative late time points study, incomplete representation of plant genes,discrimination of close paralogs, and reduced sensitivity. Lately, next generation sequencingtechnology have widened the horizon of transcription analyses in different legume species to detectsymbiosis induced changes in late nodule developmental stages. Against this backdrop, we areaccentuated to reveal early transcriptional changes induced in determinate type of soybean noduleby Bradyrhizobium japonicum. In determinate type of nodule, two major nodule development zones are formed for instance, the nodule primordium (Npr) in the middle and it is encircled by nodule parenchyma (Npa). At later time point, the Npr converted to N-fixation zone and the Npa contained vascular bundles. Of these facts, it is not clear what early signaling pathways driving the conspicuous development of thenodule zones. In this context, mechanisms regulate the distinct gene expression profiles in Npr andNpa cell types has not understood clearly. The proposed research study is aimed at filling this knowledge gap byillustrating the molecular signatures that paves the way to cellular differentiation in root noduledevelopment in soybean considering four different time points (5 dai, 7 dai, 10 dai& 14 dai). The hypothesisis microRNAs(miRNAs) play important regulatory roles in spatio-temporal expression of their target genesduring nodule developmental in soybean. For example, a gradient of microRNA localizationbetween nodule primordium and parenchyma cells could result in distinct differentiation of thesecell types. To test this hypothesis, one has to obtain both cell type-specific miRNA andtranscriptome (miRNA target) profiles. Since, the majority of miRNA regulation occurs in thecytoplasm, we reasoned that comparison of nuclear and ribosomal transcriptome profiles wouldreveal genes whose expression is potentially regulated by post transcriptional mechanisms such asmiRNA cleavage. Combining this information with cell type-specific miRNA profiles, andto test the above hypothesis and identify key miRNA-target pairs important for nodule celldifferentiation. The use of translating ribosome affinity purification (TRAP) of nodule zonecells, namely from parenchyma and primordial tissues, to obtain cytoplasmic transcriptomes data. Techniques to determine cell type specific expression profiles: TRAP methods TRAP is termed translating ribosome affinity purification, combines cell-type-specific transgene expression with affinity purification of translating ribosomes. It supersedes the need for tissue fixation, and facilitates to study the cell type-specific mRNA profiles of any genetically defined cell type. It has been successfully used to date in organisms ranging from D. melanogaster to mice, and human cultured cells. Multiple ribosomes or Polyribosomes (polysomes) are engaged in translation on a single mRNA. To evaluate the translation state of an mRNA, ribosomal subunits, ribosomes, and polysomes can be isolated from detergent-treated cell extracts. In this study, the polysome isolation using gene cassettes ENOD40p:HF-GFP-RPL18 for primordial tissues, and ENOD2p:HF-GFP-RPL18 for parenchymal tissues in Glycine max root nodules that express an epitope tagged version of ribosomal protein L18 RPL18(Heiman, Kulicke et al. 2014, Ron 2014). Relative abundance and differentially expressed mRNAs profile in two different tissue specific zones would help to understand the effect of regulatory role of miRNAs in cell differentiation and nodule development. References: Axtell, M. J. (2013). "Classification and comparison of small RNAs from plants." Annu Rev PlantBiol 64: 137-159. Boualem, A., et al. (2008). "MicroRNA166 controls root and nodule development in Medicago truncatula." Plant J 54(5): 876-887. Buxdorf, K., et al. (2010). "Identification and characterization of a novel miR159 target not relatedto MYB in tomato." Planta 232(5): 1009-1022. Celine Charon, C. J., Eva Kondorosi, Adam Kondorosi and Martin Crespi (1997). "enod40 inducesdedifferentiation and division of root cortical cells in legumes." Proc. Natl Acad. Sci. USA. 94:8901-8906. Chapman, E. J. and J. C. Carrington (2007). "Specialization and evolution of endogenous small RNA pathways." Nat Rev Genet 8(11): 884-896. Cheng, Q. (2008). "Perspectives in biological nitrogen fixation research." J Integr Plant Biol 50(7):786-798. Combier, J. P., et al. (2006). "MtHAP2-1 is a key transcriptional regulator of symbiotic nodule development regulated by microRNA169 in Medicago truncatula." Genes Dev 20(22): 3084-3088. Cuperus, J. T., et al. (2011). "Evolution and functional diversification of MIRNA genes." Plant Cell 23(2): 431-442. Hiroshi Kouchi1, K.-i. T., Rollando B. So2, Jagdish K. Ladha2 and Pallavolu M. Reddy2 (1999). "Rice ENOD40: isolation and expression analysis in rice and transgenic soybean root nodules." The Plant Journal 18(2): 121-129. Johnson, D. S. O. a. G. V. (1996). "Fertilizer Nutrient Leaching and Nutrient Mobility: A Simple Laboratory Exercise." Nat. Resour. L. ife Sci. Educ 25(2): 128-131. Kouchi, H. and Hata, S. (1993) Isolation and characterization of novel nodulin cDNAs representing genes expressed at early stages of soybean nodule development. Gen. Genet. 238, 106–119. Li, H., et al. (2010). "Misexpression of miR482, miR1512, and miR1515 increases soybean nodulation." Plant Physiol 153(4): 1759-1770. Manavella, P. A., et al. (2012). "Plant secondary siRNA production determined by microRNAduplexstructure." Proc Natl Acad Sci U S A 109(7): 2461-2466. Marie Turner, e. a. (2013). "Ectopic Expression of miR160 Results in Auxin Hypersensitivity, Cytokinin Hyposensitivity, and Inhibition of Symbiotic Nodule Development in Soybean." Plant Physiology 162(2013): 2042–2055. Oldroyd GE, Downie JA. (2008). “Coordinating nodule morphogenesis with rhizobial infection inlegume. Annual Review of Plant Biology 59:519-546. Singh, R. K., et al. (2015). "Molecular evolution and diversification of the Argonaute family of proteins in plants." BMC Plant Biol 15: 23. Song, J. J., et al. (2004). "Crystal structure of Argonaute and its implications for RISC slicer activity." Science 305(5689): 1434-1437. Sponseller, R. A., et al. (2016). "Nitrogen dynamics in managed boreal forests: Recent advances and future research directions." Ambio 45 Suppl 2: 175-187. Subramanian, S., et al. (2008). "Novel and nodulation-regulated (2012). microRNAs in soybean roots." BMC Genomics 9: 160. Turner, M., et al. "Genome organization and characteristics of soybean microRNAs." BMCGenomics 13: 169. Udvardi and Day (1997). "Metabolite transport across symbiotic membranes of legume nodules." Annual Review of Plant Physiology and Plant Molecular Biology 48: 493-523. Weeks, Marry Elvira (1932). “The discovery of the elements. IV. Three impotant gases”. Journal of Chemical Education. 9 (2): 215 Wu, L., et al. (2010). "DNA methylation mediated by a microRNA pathway." Mol Cell 38(3): 465-475. Xiang Liu, T. L., Yongchao Dou, Bin Yu, and Chi Zhang (2014). "Identification of RNA silencingcomponents in soybean and sorghum." BMC Bioinform 15: 4. Zhe Yan, M. S. H., SiwaretArikit, Oswaldo Valdes-Lopez, JixianZhai, Jun Wang1,Marc Libault1, Tieming Ji, LijuanQiu, Blake C. Meyers and Gary Stacey (2015). "Identification of microRNAs and their mRNA targets during soybean nodule development: functional analysis of the role of miR393j-3p in soybean nodulation." New Phytologist 207: 748–759. Zhu, H., et al. (2011). "Arabidopsis Argonaute10 specifically sequesters miR166/165 to regulate shoot apical meristem development." Cell 145(2): 242-256.

Introducción: La enfermedad renal crónica asociada a la obesidad (ERC-AO) es una enfermedad con aumento en la prevalencia en las últimas décadas. Se caracteriza por un exceso de desequilibrios hormonales adipocíticos (adipoquinas), desregulación del sistema de equilibrio energético y desequilibrios en la homeostasis metabólica. Propósito de la revisión: El objetivo de la revisión es delinear el papel de los diferentes mecanismos fisiopatológicos para el desarrollo de enfermedad renal funcional o anatómica en pacientes con obesidad. Buscamos reportes actualizados en donde se incluye los resultados de mejor supervivencia para los pacientes con ERC-AO. Recientes hallazgos: Actualmente sabemos la ERC-AO tiene un comportamiento pro inflamatorio crónico. La obesidad y sobrepeso se asocian alteraciones hemodinámicas, estructurales e histopatológicas en el riñón, así como alteraciones metabólicas y bioquímicas que predisponen a la enfermedad renal, aun cuando la función renal y las pruebas convencionales sean normales. Conclusiones: Clasificamos a la ERC-AO en Tipo 1: Obesidad y alteraciones funcionales potencialmente reversibles. Tipo 2: Obesidad y alteraciones estructurales histopatológicas potencialmente no reversibles (Incluye la Glomerulopatía asociada a obesidad y glomeruloesclerosis focal y segmentaria). Tipo 3: Obesidad en relacionada con enfermedades crónicas (Diabetes, Hipertensión, Hipertensión pulmonar. Insuficiencia Cardíaca). Tipo 4: Obesidad en el paciente con terapia sustitutiva de la función renal. Recibido: Agosto 03, 2022 Aceptado: Septiembre 30, 2022 Publicado: Septiembre 30, 2022 Editor: Dr. Franklin Mora Bravo. Introducción La obesidad es una enfermedad en crecimiento con un aumento en su prevalencia en las últimas décadas, asociándose a un elevada carga asistencial y económica para los sistemas sanitaros derivado de su relación con enfermedades cardiovasculares, endocrinas, psicológicas, renales entre otras [1, 2]. El incremento en las tasas de obesidad en distintos grupos etarios, desde niños hasta adultos jóvenes conlleva a asumir que en el futuro veremos más enfermedad renal relacionada con la obesidad (ERC-AO) en la población general, con implicaciones relevantes para los sistemas de atención [3]. Por ello el conocimiento y comprensión de esta interacción podría tener implicaciones en la prevención y tratamiento de las enfermedades renales. Dentro de la población general la obesidad se asocia a incremento en el riesgo de diversas condiciones patológicas, como la hipertensión arterial crónica (HTA), enfermedad renal crónica (ERC), artrosis, infecciones, síndrome de apnea hipopnea obstructiva del sueño (SAHOS) y diabetes mellitus (DM) entre otras [3]. No obstante, en el escenario de la ERC, la obesidad juega un rol dual y paralelo en el desarrollo de la enfermedad, tradicionalmente se ha denominado “paradoja de la obesidad”, donde por un lado actúa como un factor de riesgo modificable para el desarrollo de la enfermedad renal crónica (ERC) y por otro se ha asocia de manera consistente con mejores resultados de supervivencia en pacientes con enfermedad renal terminal [1]. Por lo anterior, en las próximas páginas describimos aspectos fisiopatológicos que involucran la obesidad en el desarrollo de la ERC. Definición y epidemiología La obesidad es una condición que se caracteriza por la acumulación anormal o excesiva de tejido adiposo con consecuencias patológicas adversas e incremento del riesgo cardiovascular [4]. Utilizando para su definición y diagnostico un indicador simple como es la relación entre el peso y la talla denominado índice de masa corporal (IMC), se calcula dividiendo el peso de una persona en kilos por el cuadrado de su talla en metros (kg/m2). Un IMC entre 18.5 y 25 kg/m2 es considerado por la Organización Mundial de la Salud (OMS) como peso normal, un IMC entre 25 y 30 kg/m2 como sobrepeso y un IMC > 30 kg/m2, como obesidad [5-7]. Además, la obesidad puede ser clasificada en tres niveles de severidad: clase I (IMC 30.0 – 34.9), clase II (IMC 35.0 – 39.9) y clase III (IMC > 40) [8]. Durante las últimas tres décadas, la prevalencia de adultos con sobrepeso y obesidad (IMC ≥ 25 kg/m2) en todo el mundo ha aumentado sustancialmente, convirtiendo a la obesidad en una epidemia y se prevé que su prevalencia crezca un 40% en la próxima década [6]. Actualmente, el problema de obesidad se ha visto en mayor aumento debido al incremento en la afectación en niños, lo que ocasiona una mayor prevalencia de patologías a edad temprana. En 2016, según las estimaciones de la OMS unos 41 millones de niños menores de cinco años tenían sobrepeso o eran obesos [7]. Esto afectando a todos los países, independiente de su nivel de ingresos [7]. La prevalencia del sobrepeso y la obesidad en niños y adolescentes (de 5 a 19 años) ha aumentado de forma espectacular, del 4% en 1975 a más del 18% en 2016. Este aumento ha sido similar en ambos sexos: un 18% de niñas y un 19% de niños con sobrepeso en 2016. Mientras que en 1975 había menos de un 1% de niños y adolescentes de 5 a 19 años con obesidad, en 2016 eran 124 millones (un 6% de las niñas y un 8% de los niños) [7]. La creciente prevalencia de la obesidad tiene implicaciones para las enfermedades cardiovasculares (ECV) y también para la ERC. Un IMC alto es uno de los factores de riesgo más fuertes para la ERC de nueva aparición [6]. Epidemiología de la enfermedad renal crónica asociada a obesidad (ERC-AO) La enfermedad renal crónica (ERC) es una condición de interés en salud pública, asociada a una elevada morbilidad y mortalidad a nivel mundial. Las guías KDIGO (Kidney Disease: Improving Global Outcomes), definen la ERC como la presencia de alteraciones en la estructura o función renal durante al menos tres meses y con implicaciones para la salud [9, 10]. Los principales elementos clasificatorios para definir la presencia de ERC son la tasa de filtración glomerular (TFG) estimada (G1 a G5) utilizando como umbral definitorio una TFG 60 ml/min/1,73m2 y la tasa de excreción de albúmina en orina (A1 a A3) según el cociente albúmina/creatinina en una muestra aislada de orina sea < 30, 30-300 o > 300 mg/g, respectivamente [9, 10]. Si bien inicialmente existía cierta controversia sobre el uso de la TFG para el diagnóstico de la ERC en fases iniciales, trabajos recientes han puesto en evidencia que tanto una TFG< 60 ml/min/1.73 m2 como un cociente albúmina/creatinina (CAC) ≥ 1.1 mg/mmol (10 mg/g) son predictores independientes del riesgo de mortalidad e insuficiencia renal terminal (IRT) en población general [11, 12]. En consecuencia, debido a estas categorías podemos determinar el pronóstico de cada paciente. Los datos globales sugieren que la prevalencia de la ERC se encuentra entre el 10 y el 16 %, pero la información sobre la prevalencia de la población por categoría de TFG y ACR es escasa [13]. La ERC es una afección asociada a una elevada carga de morbilidad, mortalidad y enfermedad cardiovascular (ECV). A medida que disminuye la función renal, surgen trastornos metabólicos y hemodinámicos que aumentan las tasas de hospitalización, ECV y muerte [4]. El conjunto de factores de riesgo conocidos para la progresión de la ERC es relativamente pequeño, y las terapias y estrategias efectivas para retrasar la progresión de la ERC son limitadas [14]. Por lo cual resulta necesario conocer y entender los diferentes factores de riesgo y su impacto en el daño renal, en aras de lograr minimizar la progresión del mismo, sobre todo en aquellos en los cuales se puede realizar intervenciones activas, evaluables, controlables y con seguimiento continuo como es la obesidad. A la fecha existe suficiente evidencia para asociar la obesidad con el desarrollo y progresión de la enfermedad renal crónica. Los datos granulares sobre la prevalencia de la obesidad en personas con ERC son limitados pero consistentes en todo el espectro de la enfermedad renal. En la Encuesta Nacional de Examen de Salud y Nutrición de 2011–2014, el 44.1 % de los pacientes con ERC en los Estados Unidos también tenían obesidad (21.9 % con obesidad de clase 1 y 11.1 % con clase 2 y obesidad clase 3, habiéndose incrementado el porcentaje global un 5% en los últimos 12 años [15]. La glomeruloesclerosis focal y segmentaria (GEFS) es el tipo de glomerulonefritis que se asocia con mayor frecuencia a la obesidad [16]. La enfermedad glomerular habitualmente asociada a la obesidad se denomina glomerulopatía relacionada con la obesidad (GRO). Esta condición suele presentarse con síndrome nefrótico y pérdida progresiva de la función renal. Con la epidemia mundial de obesidad, se produjo un aumento progresivo de la GRO del 0.2% entre 1986 y 1990 al 2% entre 1996 y 2000, y se ha convertido en un tema emergente en el ámbito de la nefrología [15]. Etiología y patogénesis de la ERC-AO La obesidad se caracteriza por un exceso de desequilibrios hormonales adipocíticos (adipoquinas), desregulación del sistema de equilibrio energético y desequilibrios en la homeostasis metabólica [12]. Hay dos tipos de tejido adiposo presentes en los humanos: tejido adiposo blanco (WAT) y tejido adiposo marrón (BAT) [17-19]. El depósito de grasa ectópica primariamente ocurre en lugares donde no se almacena fisiológicamente, como el hígado, el páncreas, el corazón y el músculo esquelético; secundariamente hay un cambio en la distribución del tejido adiposo visceral con almacenamiento de tejido adiposo en los espacios intraperitoneal y retroperitoneal; luego se presenta la desregulación inflamatoria y de adipoquinas; y por último la resistencia a la insulina [20]. Tejido adiposo blanco (WAT) El tejido adiposo blanco (WAT) se caracteriza por ser un tejido blanco o amarillo con menor vascularización e inervación que el tejido marrón. Las células grasas tienen un tamaño que oscila entre 20 y 200 µm y contienen una única vacuola lipídica (uniloculares). En dicha vacuola se almacenan lípidos para su uso cuando hay demanda energética. De la totalidad de los lípidos que abarca la vacuola lipídica del adipocito blanco, del 90 al 99% son triacilgliceroles. El tejido adiposo blanco genera una gran cantidad de adipocinas y lipocinas. Las adipocinas son péptidos que actúan como hormonas o mensajeros que regulan el metabolismo. El tejido adiposo blanco se localiza en el tejido omental, mesentérico, retroperitoneal, perirrenal, gonadal y pericárdico [19]. Este tejido al igual que el tejido adiposo de otros sitios, está compuesto por una variedad de células que incluyen macrófagos, neutrófilos, células T CD4 y CD8, células B, neutrófilos, mastocitos, células T reguladoras y células T asesinas naturales (NK) [21, 22]. El tejido adiposo es responsable de la secreción de muchas moléculas de señalización, incluidas adipocinas, hormonas, citocinas y factores de crecimiento, como leptina, adiponectina, resistina, factor de necrosis tumoral-α (TNF-α), interleucina 6 (IL-6), monocito, proteína quimioatrayente-1 (MCP-1), factor de crecimiento transformante-β (TGF-β) y angiotensina II [23]. Tejido adiposo marrón o pardo (BAT) La coloración marrón del tejido adiposo se debe a que está más vascularizado y tiene un alto contenido de mitocondrias, las células grasas que componen el tejido adiposo pardo son multiloculares o tienen varias vacuolas lipídicas. Estas células tienen forma poligonal y miden de 15 a 50 µm. A diferencia del tejido adiposo blanco, el tejido marrón no tiene la función de almacenar energía, sino que la disipa a través de la termogénesis. Para lograr la regulación de la temperatura corporal, el tejido adiposo pardo se localiza en sitios superficiales y profundos [18]. Clasificación de la ERC-AO Se ha establecido que la obesidad es una enfermedad con un comportamiento pro inflamatorio crónico con múltiples comorbilidades asociadas [19]. El tejido adiposo como se describió previamente funciona como un órgano con actividad endocrina y esta infiltrado por diferentes poblaciones celulares que incluyen macrófagos y otras células con actividad inmune como linfocitos T, B y células dendríticas [19]. La mayor parte de la grasa corporal total, se considera como un sistema de órganos endocrinos, la perturbación de este tejido tiene como resultado una respuesta patológica al balance calórico positivo en individuos susceptibles que directa e indirectamente contribuye a la enfermedad cardiovascular y metabólica, se tiene conocimiento de tres principales mecanismos de disfunción del tejido adiposo “adiposopatía” [20]. Estos mecanismos incluyen alteraciones hemodinámicas, metabólicas e inflamatorias, lo que es la base de la clasificación de la ERC-AO propuesta en esta revisión (Tabla 1). ERC-AO tipo 1 La obesidad produce un daño renal de forma directa a través de alteraciones hemodinámicas, inflamatorias, y desregulación de factores de crecimiento y adipocitoquinas, además de aumento de leptina y disminución de adiponectina, aun cuando la función renal y las pruebas convencionales sean normales [16]. La obesidad desencadena una serie de eventos, que incluyen resistencia a la insulina, intolerancia a la glucosa, hiperlipidemia, aterosclerosis e hipertensión, todos los cuales están asociados con un mayor riesgo cardiovascular [4, 16] (Figura 1). La obesidad conduce a un incremento en la reabsorción tubular de sodio, alterando la natriuresis y provocando una expansión de volumen extracelular debido a la activación del sistema nervioso simpático (SNS) y el sistema renina-angiotensina-aldosterona (SRAA)(16). El aumento en la reabsorción tubular de sodio y la consiguiente expansión de volumen extracelular es un evento central en el desarrollo de HTA en la obesidad [4, 16]. Algunos estudios sugieren que se produce un aumento de la reabsorción de sodio en algunos segmentos además del túbulo proximal, posiblemente en el asa de Henle. Además, hay un aumento del flujo sanguíneo renal, la tasa de filtración glomerular (TFG) y la fracción de filtración [16]. La hiperfiltración glomerular, asociada con el aumento de la presión arterial y otras alteraciones metabólicas como la resistencia a la insulina y la DM, finalmente resultan en daño renal y disminución del filtrado glomerular [16]. Por otro lado, la activación del SNS también contribuye a la hipertensión relacionada con la obesidad [4]. Hay evidencia de que la denervación renal reduce la retención de sodio y la hipertensión en la obesidad, lo que sugiere que la activación del SNS inducida por la obesidad aumenta la presión arterial principalmente debido al estímulo de retención de sodio, más que a la vasoconstricción [16]. Los mecanismos que conducen a la activación del SNS en la obesidad aún no se conocen por completo, pero se han propuesto varios factores como desencadenantes de este estímulo, entre ellos la hiperinsulinemia, la hiperleptinemia, el aumento de los niveles de ácidos grasos, los niveles de angiotensina II y las alteraciones del reflejo barorreceptor. El aumento de los niveles de leptina está asociado a la activación del SNS y su efecto sobre el aumento de los niveles de presión arterial incluye también la inhibición de la síntesis de óxido nítrico (potente vasodilatador) [16, 24, 25].También se ha descrito un aumento de la producción de endotelina-1 en sujetos obesos, lo que contribuye aún más a la elevación de los niveles de presión arterial y, en consecuencia, a la disfunción renal. Estudios recientes han demostrado que la endotelina-1 está aumentada en pacientes con hipertensión intradiálisis, lo que sugiere que esta sustancia juega un papel clave en la génesis de la hipertensión en pacientes con ERC y posiblemente esté asociada con la hipertensión en pacientes obesos [16, 25]. Por lo anterior, las alteraciones hemodinámicas en los pacientes con obesidad conllevan a progresión de la ERC e incremento del riesgo cardiovascular derivado del desarrollo de enfermedades adicionales como la HTA, potencialmente estos cambios son reversibles con el control de la obesidad. ERC-AO Tipo 2 Mantener el estado de obesidad más allá de los efectos renales funcionales produce cambios estructurales irreversibles a nivel glomerular [25]. El estudio de pacientes con ERC y obesidad ha permitido identificar la presencia de enfermedad glomerular asociada a la obesidad, denominada glomerulopatía relacionada con la obesidad (GRO). En esta condición la hipertrofia glomerular parece ser la lesión inicial que estimula el borramiento de los podocitos y desencadena la respuesta inflamatoria local [25, 26]. Es relevante mencionar que las señales profibrogénicas inducen la formación de depósitos en la matriz extracelular de las nefronas, que conduce al engrosamiento de la membrana basal glomeruloesclerosis y fibrosis tubulointersticial [26]. Dentro del curso patogénico de la enfermedad la expansión de la superficie glomerular conduce a que los podocitos sean incapaces de cubrirla, esto lleva a disfunción y borramiento de los mismos, generando ruptura de la barrera de filtración glomerular con sobrecarga de las células restantes, lo que finalmente conduce a hiperfiltración y proteinuria [25, 26]. No obstante, no todos los pacientes con obesidad o IMC aumentado desarrollan ERC, lo cual sugiere que el incremento del IMC por sí solo no genera aumento en la incidencia o progresión de la ERC, ameritando alteraciones metabólicas adicionales. En los siguientes apartados se describen algunas de estas vías fisiopatológicas comunes a todos los tipos de ERC-AO. ERC-AO Tipo 3 La obesidad produce daño renal de forma secundaria ya que aumenta el riesgo de diabetes mellitus, hipertensión y daño cardiovascular, estas patologías causan enfermedad renal diabética (ERD), nefroangioesclerosis, y glomerulopatía asociada a hipertensión pulmonar e insuficiencia cardíaca. La mortalidad no solo se ve afectada por la presencia de la obesidad sino por la presencia de diabetes tipo 2, hipertensión arterial, hipertensión pulmonar e insuficiencia cardíaca. Los peores resultados en supervivencia lo padecen los pacientes con falla cardíaca, obesidad e insuficiencia renal. ERC-AO Tipo 4 En pacientes en hemodiálisis los niveles más elevados de adiponectina se asocian paradójicamente con tres veces más riesgo de muerte [24]. La obesidad se asocia a niveles muy bajos adiponectina por lo que la obesidad en el grupo poblacional que se realiza hemodiálisis es un fuerte factor protector con mejores resultados de supervivencia a 3 años comparados con pacientes con índice de masa corporal normal o baja. Mecanismos fisiopatológicos comunes en la ERC-AO Lipotoxicidad derivada del tejido adiposo En pacientes obesos el exceso de energía conduce a un microambiente sometido a estrés crónico, lo cual resulta en hipertrofia del tejido adiposo hasta que los adipocitos alcanzan su límite de crecimiento [25]. En ese momento, el exceso de especies toxicas lipídicas se acumula ectópicamente en diferentes órganos, induciendo un efecto nocivo conocido como lipotoxicidad; especialmente a nivel renal [27]. La lipotoxicidad se asocia a cambios estructurales y funcionales de las células mesangiales, podocitos y células tubulares proximales [28]. En los podocitos, esto interferiría con la vía de la insulina, crítica para la supervivencia y el mantenimiento de la estructura de los podocitos, lo que conduciría a la apoptosis de los podocitos e induciría una respuesta hipertrófica compensatoria en los podocitos restantes [25]. En el riñón, los depósitos de lípidos ectópicos contribuyen tanto a la inflamación local como al estrés oxidativo [27]. En modelos de ERD, la dislipidemia puede favorecer la acumulación de lípidos ectópicos e intermediarios lipídicos, no solo en el riñón sino también en tejidos extrarrenales como hígado, páncreas y corazón [27]. La acumulación de lípidos en el parénquima renal, genera daño en varias poblaciones celulares, incluídos podocitos, células epiteliales tubulares proximales y el tejido tubulointersticial a través de distintos mecanismos descritos en las siguientes apartados, pudiendo general compromiso a largo plazo de la función renal [27]. El tejido adiposo es una fuente importante de producción de diferentes factores proteicos activos, conocidos como adipocitocinas, las cuales participan en diferentes procesos metabólicos. Alteraciones en la secreción y señalización de moléculas derivadas del tejido adiposo durante la obesidad en gran medida puede mediar en la patogenia de los trastornos metabólicos [25]. A continuaciones se describe el rol de las adipocinas en la patogenia de la ERC y obesidad. Adiponectina La adiponectina es una proteína secretada principalmente por los adipocitos WAT, las principales funciones biológicas de la adiponectina incluyen una mayor biosíntesis de ácidos grasos y la inhibición de la gluconeogénesis hepática [17]. Es probablemente la adipocina secretada más abundantemente, forma alrededor del 0.05 % de las proteínas séricas y mide de 3 a 30 mg/ml en humanos, para su activación utiliza dos isoformas del receptor (AdipoR1 y AdipoR2) son receptores de siete transmembranas y tienen una homología del 66.7 % en su estructura [17]. Sin embargo, AdipoR1 y AdipoR2 son estructural y funcionalmente distintos de los receptores acoplados a proteína G porque su terminal N es intracelular, mientras que el terminal C es extracelular [29, 30]. La señalización de adiponectina se basa principalmente en interacciones de tipo receptor-ligando, en las que la adiponectina se une a sus receptores afines e inicia la activación de varias cascadas de señalización intracelular a través de las vías AMPK, mTOR, NF-κB, STAT3 y JNK [17]. La adiponectina inicia la activación de la señalización de AMPK mediada por la proteína adaptadora APPL1, que se une al dominio intracelular de AdipoR. Eso produce la activación de la biosíntesis de moléculas, otras proteínas reguladoras e importantes factores de transcripción. AMPK es un regulador que participa principalmente en la proliferación celular [17]. Hay dos tipos de macrófagos, M1 participan en la estimulación de los factores pro inflamatorios e induce la resistencia a la insulina y M2 bloquean una respuesta inflamatoria y promueve el metabolismo oxidativo; En los macrófagos, la adiponectina promueve la diferenciación celular de monocitos a macrófagos M2 y suprime su diferenciación a macrófagos M1, lo que muestra efectos pro inflamatorios y antiinflamatorios. Además, también activa los factores antiinflamatorios IL-10 pero reduce las citoquinas pro inflamatorias como IFN-γ, IL-6 y TNF-α en los macrófagos humanos [17]. Los pacientes con ERC muestran niveles elevados de proteína C reactiva (PCR), IL-6 y TNF-α y tienen una activación aberrante de receptor tipo toll (TLR)-4 [25]; en un estudio realizado en el año 2005 en 29 pacientes con ERC no diabéticos en etapa 5 y 14 controles sanos, se identificó que los pacientes con ERC tenían una expresión elevada del gen y la proteína TLR4, la estimulación de TLR-4 in vitro indujo la activación de TNF-α y NF-κB en células C2C12. Esto sugiere indirectamente que la activación de TLR-4 podría promover la inflamación muscular de los pacientes con ERC [31]. Los niveles de adiponectina se consideran predictivos de ERC, dado que estos se encuentran aumentados en pacientes con etapa pre diálisis [17, 29, 32]. Adicionalmente, en un estudio prospectivo realizado en el año 2008 en pacientes con ERC primaria no diabética identificó niveles elevados de adiponectina como un predictor novedoso de progresión de la ERC en hombres [33]. En estudios realizados en animales (ratones) muestran que la deficiencia de adiponectina se relaciona con varias alteraciones histológicas, incluida la fusión segmentaria procesos podocitarios, albuminuria y aumento del estrés oxidativo en los riñones [34]. Por otro lado, en pacientes obesos la producción de adiponectina se encuentra disminuida por lo que se cree que puede generar una función protectora sobre el riñón [29]. No obstante, paradójicamente, algunos estudios muestran que los pacientes con ERC y enfermedad renal crónica en diálisis (ERCT) tienen altos niveles de adipocinas, las explicaciones a esta situación son controversiales, se ha planteado podrían corresponder a un mecanismo compensatorio, otras consideraciones sugieren una disminución de la sensibilidad a la adiponectina o una reducción en el aclaramiento de la misma [35]. Leptina En pacientes con ERC independiente de la presencia de obesidad o no, se asocian a niveles elevados de leptina sérica. La leptina es una proteína de 167 aminoácidos, con una masa molecular de aproximadamente 16 kDa que está codificada por el gen LEP [23] secretada principalmente por los adipocitos, es una adipocina pleiotrópica. La leptina circulante llega a los órganos diana, donde se une a receptores específicos (conocidos como ObR, LR o LEPR), se conocen cinco isoformas del receptor de leptina en humanos (ObRa, ObRb, ObRc, ObRd y ObRe), de estas solo la isoforma ObRb (isoforma larga) se considera un receptor completamente activo, ya que es capaz de transducir completamente una señal de activación en la célula. Esta isoforma se encuentra altamente expresada en el sistema nervioso central (SNC), especialmente en el hipotálamo, donde participa en la regulación de la actividad secretora de este órgano. Los efectos de la leptina están mediados por cinco vías principales de señalización. Estas vías incluyen las vías de señalización JAK-STAT, PI3K, MAPK, AMPK y mTOR [23]. Por esta razón la principal función fisiológica de la leptina es transmitir información al hipotálamo sobre la cantidad de energía almacenada, como la masa de tejido adiposo, e influir en el gasto de energía al reducir el apetito. Regula el metabolismo energético, tiene efecto sobre la ingesta de alimentos, procesos de coagulación, angiogénesis, funciones relacionadas con la insulina y la remodelación vascular, además funciona como un pro inflamatorio molecular [36]. La leptina tiene efectos sobre el apetito y se ha demostrado que la hiperleptinemia contribuye a la hipertensión asociada a la obesidad por sobre activación del sistema nervioso simpático [37]. En cuanto al curso de la ERC, la leptina puede modular diferentes vías de señalización en el riñón, debido a que las células endoteliales glomerulares y mesangiales expresan abundantes receptores de leptina [25]. La leptina inducirá un incremento en la expresión de genes profibróticos, como TGF-β1 y citocinas pro inflamatorias [25]. El aumento en la expresión de TGF-β1, también contribuirá al desarrollarlo de la fibrosis renal, al unirse a receptores específicos a nivel renal, estimulara la expresión de factores profibróticos en un ciclo de retroalimentación positiva. Además, TGF-β1 es un potente iniciador de proliferación de células mesangiales renales [25]. Debido a su tamaño relativamente pequeño, la leptina atraviesa libremente el filtro glomerular de los riñones y luego se reabsorbe en la parte proximal de los túbulos contorneados [23]. Por lo que el estado elevado de leptina puede indicar una función renal deficiente [36]. Promueve la inflamación y trastorno de los lípidos, que contribuyen al riesgo de ERC [36]; se considera como “toxina urémica”, estando implicada tanto en la progresión de la enfermedad renal a través de efectos pro-hipertensivos y profibróticos, como en el desarrollo de complicaciones relacionadas con la ERC (inflamación crónica, pérdida de proteínas) [38]. Como se mencionó previamente, la leptina estimula la proliferación de células endoteliales glomerulares renales y aumenta la expresión de TGF-β1, un mediador clave de la hidrogénesis en estas células, el aumento de los niveles de leptina también contribuye al aumento de la expresión de colágeno tipo IV en el riñón, induce la proliferación de células mesangiales glomerulares mediante la activación de la vía PI3K, la hipertrofia de las células mesangiales aumenta la cantidad de proteína filtrada y albúmina que llega a las células del túbulo proximal y, como resultado, activa las vías inflamatorias y la fibrosis [23]. Puede presentarse un aumento en la síntesis del receptor TGFβ-1 secretado por las células endoteliales, este actúa de manera parácrina sobre el mesangio uniéndose a su receptor y activando la síntesis de proteínas de la matriz extracelular (ECM), incluyendo colágeno, fibronectina, tenazina y proteoglicanos; consiguientemente, un aumento en el nivel de TGFβ-1 conduce a la acumulación de MEC y, en consecuencia, a fibrosis glomerular y glomeruloesclerosis. En los podocitos, la leptina contribuye a la disminución de la expresión de las proteínas responsables de la filtración glomerular adecuada, incluidas la podocina, la nefrina, la podoplanina y la podocalixina. En las células del túbulo contorneado proximal (PTC), la leptina reduce la actividad metabólica de las células al activar la vía de señalización de mTOR [23]. Por otro lado, la leptina inhibe el apetito y aumenta el gasto de energía conduciendo a anorexia y desnutrición en pacientes con ERC, particularmente en casos de hemodiálisis de mantenimiento [36]. Por ende, una elevación de la leptina no solo nos indicaría daño renal, sino que además nos indica mayor progresión de complicaciones secundarias [39]. La obesidad aumenta la carga sobre los riñones y es un factor de riesgo de lesión renal, además de contribuir en los trastornos metabólicos asociados. Por lo que, teniendo en cuenta los efectos inhibitorios de la leptina sobre la obesidad, se puede considerar que puede proteger contra la lesión renal [39, 40]. Un estudio experimental publicado en el año 2017 demostró que la leptina disminuyó la ingesta calórica y los niveles de glucosa en ratas diabéticas [41], ese mismo año se publicó un estudio retrospectivo donde demostraron que la metreleptina, una metionil leptina humana recombinante, reduce el peso corporal y la dosis diaria de insulina en la diabetes mellitus tipo 1 [42]. La metreleptina ejerce efectos terapéuticos en la lipodistrofia [43], lo que indica que es probable que la leptina se aplique en los trastornos metabólicos [36]. Otras adipocinas Las principales adipocinas corresponden a la adiponectina y leptina como se ha descrito previamente. Además de estas, se distinguen la actividad de la visfatina y resistina, las cuales muestran propiedades pro-inflamatorias y efectos aterogénicos [25]. La visfatina estimula la expresión de TGF-β1, inhibidor del activador del plasminógeno-1 (PAI-1) y colágeno tipo I, los cuales han demostrado un rol importante como agentes profibróticos. Por otro lado, la resistina estimula la producción de las moléculas de adhesión como la molécula de adhesión intracelular 1 (ICAM-1) y la proteína de adhesión celular vascular 1 (VCAM-1) y promueve la activación del sistema renal simpático. Los niveles de estas adipocinas están marcadamente elevados en la obesidad y ERC correlacionándose con parámetros proinflamatorios y disminución de la tasa de filtración glomerular (TFG) [25, 37]. Durante el curso de la obesidad se presenta una sobre activación del SRAA, el tejido adiposo también estaría involucrado en la producción o estimulación de algunos de los componentes del RAS. Por ello la sobre estimulación del SRAA en obesos, asociado a la glomerulomegalia y desregulación de la reabsorción de sodio/glucosa, generalmente conlleva a hipertensión glomerular e hiperfiltración [25]. Otra adipocina a considerar, es la actividad de la adipocina proinflamatoria lipocalina 2 (LCN2), también denominada lipocalina asociada con la gelatinasa de neutrófilo (NGAL), estudiada como biomarcador funcional tanto para la enfermedad renal aguda como ERC(25). LCN2 es conocido por su papel en la respuesta inmune innata a través de su unión a sideróforos derivados de una infección bacteriana. Sin embargo, LCN2 no es secretada únicamente por neutrófilos sino también por otros tejidos como hígado, pulmones y de interés para este artículo, a nivel renal [25]. Se han informado niveles elevados de LCN2 en suero y orina en la lesión renal, debido a una expresión aumentada de LCN2 en el túbulo distal renal y una reabsorción alterada en el túbulo proximal [44]. El tejido adiposo, también puede producir factores angiogénicos como el factor de crecimiento del endotelio vascular (VEGF). Este elemento podría inducir la formación de novo de capilares glomerulares en gran parte defectuosos dentro del riñón, lo que contribuye a la hipertrofia glomerular característica de GRO [25] (Figura 2). Conclusiones La obesidad y el sobrepeso se asocian a alteraciones hemodinámicas, estructurales e histopatológicas en el riñón, así como alteraciones metabólicas y bioquímicas que predisponen a la enfermedad renal, aun cuando la función renal y las pruebas convencionales sean normales. Por lo tanto, los efectos renales de la obesidad son estructurales y funcionales. Hay varios mecanismos actualmente descritos que involucran a la obesidad como generador de alteraciones renales. Teniendo en cuenta las bases fisiopatológicas, proponemos una clasificación de la ERC-AO basadas en 4 tipos. Abreviaturas ERC: enfermedad renal crónica. ERC-AO: enfermedad renal crónica-asociada a enfermedad. VEGF: factor de crecimiento del endotelio vascular. OR: Odds ratio. Información suplementaria Materiales suplementarios no han sido declarados. Agradecimientos No aplica. Contribuciones de los autores Jorge Rico-Fontalvo: Conceptualización, Curación de datos, Análisis formal, Adquisición de fondos, Investigación, Metodología, Administración de proyecto, Recursos, Software, Escritura – borrador original. Rodrigo Daza-Arnedo: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Tomás Rodríguez-Yanez: Metodología, validación, supervisión, redacción: Revisión y edición. Washington Osorio: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Beatriz Suarez-Romero: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Oscar Soto: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Juan Montejo-Hernandez: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. María Cardona-Blanco: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Juan Camilo Gutiérrez: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Todos los autores leyeron y aprobaron la versión final del manuscrito. Financiamiento Los autores proveyeron los gastos de la investigación. Disponibilidad de datos o materiales Los conjuntos de datos generados y analizados durante el estudio actual no están disponibles públicamente debido a la confidencialidad de los participantes, pero están disponibles a través del autor correspondiente a pedido académico razonable. Declaraciones Aprobación del comité de ética y consentimiento para participar No aplica para revisiones narrativas. Consentimiento para publicación No aplica cuando no se publican imágenes o fotografías del examen físico o radiografías/tomografías/resonancias de pacientes. Conflictos de interés Los autores reportan no tener conflictos de interés. Referencias Azhar A, Hassan N, Tapolyai M, Molnar MZ. Obesity, Chronic Kidney Disease, and Kidney Transplantation: An Evolving Relationship. Semin Nephrol. marzo de 2021;41(2):189-200. DOI: 10.1016/j.semnephrol.2021.03.013. PMID: 34140097. Barbieri D, Goicoechea M, Sánchez-Niño MD, Ortiz A, Verde E, Verdalles U, Pérez de José A, Delgado A, Hurtado E, Sánchez-Cámara L, Lopez-Lazareno N, García-Prieto A, Luño J. Obesity and chronic kidney disease progression-the role of a new adipocytokine: C1q/tumour necrosis factor-related protein-1. Clin Kidney J. 2018 Oct 11;12(3):420-426. DOI: 10.1093/ckj/sfy095. PMID: 31198543; PMCID: PMC6543966. Kopp JB, Rosenberg AZ, Levi M. Introduction: Obesity and the kidney. Semin Nephrol. 2021 Jul;41(4):295. DOI: 10.1016/j.semnephrol.2021.06.001. PMID: 34715959. Hall JE, Mouton AJ, da Silva AA, Omoto ACM, Wang Z, Li X, do Carmo JM. Obesity, kidney dysfunction, and inflammation: interactions in hypertension. Cardiovasc Res. 2021 Jul 7;117(8):1859-1876. DOI: 10.1093/cvr/cvaa336. PMID: 33258945; PMCID: PMC8262632. Kovesdy CP. Epidemiology of chronic kidney disease: an update 2022. Kidney Int Suppl (2011). 2022 Apr;12(1):7-11. DOI: 10.1016/j.kisu.2021.11.003. Epub 2022 Mar 18. PMID: 35529086; PMCID: PMC9073222. Kovesdy CP, Furth S, Zoccali C; World Kidney Day Steering Committee. Obesity and kidney disease: Hidden consequences of the epidemic. Saudi J Kidney Dis Transpl. 2017 Mar-Apr;28(2):241-252. DOI: 10.4103/1319-2442.202776. PMID: 28352003. Organización mundial de la salud -OMS. Obesidad y sobrepeso [Internet]. Disponible en: https://www.who.int/es/news-room/fact-sheets/detail/obesity-and-overweight Lin X, Li H. Obesity: Epidemiology, Pathophysiology, and Therapeutics. Front Endocrinol (Lausanne). 2021 Sep 6;12:706978. DOI: 10.3389/fendo.2021.706978. PMID: 34552557; PMCID: PMC8450866. Gorostidi M, Santamaría R, Alcázar R, Fernández-Fresnedo G, Galcerán JM, Goicoechea M, et al. Spanish Society of Nephrology document on KDIGO guidelines for the assessment and treatment of chronic kidney disease. Nefrologia. 2014 May 21;34(3):302-16. English, Spanish. DOI: 10.3265/Nefrologia.pre2014.Feb.12464. Epub 2014 Mar 6. PMID: 24798565. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020 Oct;98(4S):S1-S115. DOI: 10.1016/j.kint.2020.06.019. PMID: 32998798. Salvador González B, Rodríguez Pascual M, Ruipérez Guijarro L, Ferré González A, Cunillera Puertolas O, Rodríguez Latre LM. Enfermedad renal crónica en Atención Primaria: prevalencia y factores de riesgo asociados [Chronic kidney disease in Primary Health Care: prevalence and associated risk factors]. Aten Primaria. 2015 Apr;47(4):236-45. Spanish. DOI: 10.1016/j.aprim.2014.06.003. Epub 2014 Sep 9. PMID: 25212720; PMCID: PMC6985625. Lakkis JI, Weir MR. Obesity and Kidney Disease. Prog Cardiovasc Dis. 2018 Jul-Aug;61(2):157-167. DOI: 10.1016/j.pcad.2018.07.005. Epub 2018 Jul 5. PMID: 29981350. Stevens PE, Levin A; Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013 Jun 4;158(11):825-30. DOI: 10.7326/0003-4819-158-11-201306040-00007. PMID: 23732715. Anderson AH, Xie D, Wang X, Baudier RL, Orlandi P, Appel LJ, et al; CRIC Study Investigators. Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study. Am J Kidney Dis. 2021 Jan;77(1):56-73.e1. DOI: 10.1053/j.ajkd.2020.07.011. Epub 2020 Aug 28. PMID: 32866540; PMCID: PMC7752839. Friedman AN, Kaplan LM, le Roux CW, Schauer PR. Management of Obesity in Adults with CKD. J Am Soc Nephrol. 2021 Feb 18;32(4):777–90. DOI: 10.1681/ASN.2020101472. Epub ahead of print. PMID: 33602674; PMCID: PMC8017542. Silva Junior GB, Bentes AC, Daher EF, Matos SM. Obesity and kidney disease. J Bras Nefrol. 2017 Mar;39(1):65-69. Portuguese, English. DOI: 10.5935/0101-2800.20170011. PMID: 28355395. Choi HM, Doss HM, Kim KS. Multifaceted Physiological Roles of Adiponectin in Inflammation and Diseases. Int J Mol Sci. 2020 Feb 12;21(4):1219. DOI: 10.3390/ijms21041219. PMID: 32059381; PMCID: PMC7072842. Frigolet ME, Gutiérrez-Aguilar R. The colors of adipose tissue. Gac Med Mex. 2020;156(2):142-149. English. DOI: 10.24875/GMM.M20000356. PMID: 32285854. Chen Y, Dabbas W, Gangemi A, Benedetti E, Lash J, Finn PW, Perkins DL. Obesity Management and Chronic Kidney Disease. Semin Nephrol. 2021 Jul;41(4):392-402. DOI: 10.1016/j.semnephrol.2021.06.010. PMID: 34715968. Neeland IJ, Poirier P, Després JP. Cardiovascular and Metabolic Heterogeneity of Obesity: Clinical Challenges and Implications for Management. Circulation. 2018 Mar 27;137(13):1391-1406. DOI: 10.1161/CIRCULATIONAHA.117.029617. PMID: 29581366; PMCID: PMC5875734. Bjørndal B, Burri L, Staalesen V, Skorve J, Berge RK. Different adipose depots: their role in the development of metabolic syndrome and mitochondrial response to hypolipidemic agents. J Obes. 2011;2011:490650. DOI: 10.1155/2011/490650. Epub 2011 Feb 15. PMID: 21403826; PMCID: PMC3042633. Johnson AR, Milner JJ, Makowski L. The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Rev. 2012 Sep;249(1):218-38. DOI: 10.1111/j.1600-065X.2012.01151.x. PMID: 22889225; PMCID: PMC3422768. Korczynska J, Czumaj A, Chmielewski M, Swierczynski J, Sledzinski T. The Causes and Potential Injurious Effects of Elevated Serum Leptin Levels in Chronic Kidney Disease Patients. Int J Mol Sci. 2021 Apr 28;22(9):4685. DOI: 10.3390/ijms22094685. PMID: 33925217; PMCID: PMC8125133. Goicoechea M. Obesidad y Progresión de la Enfermedad Renal. Nefrología al día 2022(febrero):nefrologia_al_dia Martin-Taboada M, Vila-Bedmar R, Medina-Gómez G. From Obesity to Chronic Kidney Disease: How Can Adipose Tissue Affect Renal Function? Nephron. 2021;145(6):609-613. DOI: 10.1159/000515418. Epub 2021 Apr 21. PMID: 33882488. D'Agati VD, Chagnac A, de Vries AP, Levi M, Porrini E, Herman-Edelstein M, Praga M. Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat Rev Nephrol. 2016 Aug;12(8):453-71. DOI: 10.1038/nrneph.2016.75. Epub 2016 Jun 6. PMID: 27263398. Opazo-Ríos L, Mas S, Marín-Royo G, Mezzano S, Gómez-Guerrero C, Moreno JA, Egido J. Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities. Int J Mol Sci. 2020 Apr 10;21(7):2632. DOI: 10.3390/ijms21072632. PMID: 32290082; PMCID: PMC7177360. Zhu Q, Scherer PE. Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nat Rev Nephrol. 2018 Feb;14(2):105-120. DOI: 10.1038/nrneph.2017.157. Epub 2017 Dec 4. PMID: 29199276. Akingbemi BT. Adiponectin receptors in energy homeostasis and obesity pathogenesis. Prog Mol Biol Transl Sci. 2013;114:317-42. DOI: 10.1016/B978-0-12-386933-3.00009-1. PMID: 23317789. Zha D, Wu X, Gao P. Adiponectin and Its Receptors in Diabetic Kidney Disease: Molecular Mechanisms and Clinical Potential. Endocrinology. 1 de julio de 2017;158(7):2022-34. DOI: 10.1210/en.2016-1765. PMID: 28402446. Verzola D, Bonanni A, Sofia A, Montecucco F, D'Amato E, Cademartori V, Parodi EL, Viazzi F, Venturelli C, Brunori G, Garibotto G. Toll-like receptor 4 signalling mediates inflammation in skeletal muscle of patients with chronic kidney disease. J Cachexia Sarcopenia Muscle. 2017 Feb;8(1):131-144. DOI: 10.1002/jcsm.12129. Epub 2016 Oct 18. PMID: 27897392; PMCID: PMC5326826. Guebre-Egziabher F, Drai J, Fouque D. Adiponectin and chronic kidney disease. J Ren Nutr. 2007 Jan;17(1):9-12. DOI: 10.1053/j.jrn.2006.10.003. PMID: 17198925. Kollerits B, Fliser D, Heid IM, Ritz E, Kronenberg F; MMKD Study Group. Gender-specific association of adiponectin as a predictor of progression of chronic kidney disease: the Mild to Moderate Kidney Disease Study. Kidney Int. 2007 Jun;71(12):1279-86. DOI: 10.1038/sj.ki.5002191. Epub 2007 Apr 25. PMID: 17457380. Sharma K, Ramachandrarao S, Qiu G, Usui HK, Zhu Y, Dunn SR, Ouedraogo R, Hough K, McCue P, Chan L, Falkner B, Goldstein BJ. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest. 2008 May;118(5):1645-56. DOI: 10.1172/JCI32691. PMID: 18431508; PMCID: PMC2323186. Navarro-Díaz M, Serra A, López D, Granada M, Bayés B, Romero R. Obesity, inflammation, and kidney disease. Kidney Int Suppl. 2008 Dec;(111):S15-8. DOI: 10.1038/ki.2008.518. PMID: 19034319. Mao S, Fang L, Liu F, Jiang S, Wu L, Zhang J. Leptin and chronic kidney diseases. J Recept Signal Transduct Res. 2018 Apr;38(2):89-94. DOI: 10.1080/10799893.2018.1431278. Epub 2018 Feb 1. PMID: 29388492. Briffa JF, McAinch AJ, Poronnik P, Hryciw DH. Adipokines as a link between obesity and chronic kidney disease. Am J Physiol Renal Physiol. 2013 Dec 15;305(12):F1629-36. DOI: 10.1152/ajprenal.00263.2013. Epub 2013 Oct 9. PMID: 24107418. Katsiki N, Mikhailidis DP, Banach M. Leptin, cardiovascular diseases and type 2 diabetes mellitus. Acta Pharmacol Sin. 2018 Jul;39(7):1176-1188. DOI: 10.1038/aps.2018.40. Epub 2018 Jun 7. PMID: 29877321; PMCID: PMC6289384. de Luis DA, Perez Castrillón JL, Dueñas A. Leptin and obesity. Minerva Med. 2009 Jun;100(3):229-36. Epub 2008 Apr 4. PMID: 19182739. Mao S, Fang L, Liu F, Jiang S, Wu L, Zhang J. Leptin and chronic kidney diseases. J Recept Signal Transduct Res 2018 Apr; 38(2):89-94. DOI: 10.1080/10799893.2018.1431278. PMID: 29388492 da Silva AA, Hall JE, do Carmo JM. Leptin reverses hyperglycemia and hyperphagia in insulin deficient diabetic rats by pituitary-independent central nervous system actions. PLoS One. 2017 Nov 30;12(11):e0184805. DOI: 10.1371/journal.pone.0184805. PMID: 29190687; PMCID: PMC5708697. Vasandani C, Clark GO, Adams.HUet B, Quiiner C, Garg A. Efficacy and Safety of Metreleptin Therapy in Patients With Type 1 Diabetes: A Pilot Study. Diabetes care 2017 May;40(5): 694-697. PMID: 28223297 Brown RJ, Meehan CA, Cochran E, Rother KI, Kleiner DE, Walter M, Gorden P. Effects of Metreleptin in Pediatric Patients With Lipodystrophy. J Clin Endocrinol Metab. 2017 May 1;102(5):1511-1519. DOI: 10.1210/jc.2016-3628. PMID: 28324110; PMCID: PMC5443330. Abella V, Scotece M, Conde J, Gómez R, Lois A, Pino J, Gómez-Reino JJ, Lago F, Mobasheri A, Gualillo O. The potential of lipocalin-2/NGAL as biomarker for inflammatory and metabolic diseases. Biomarkers. 2015;20(8):565-71. DOI: 10.3109/1354750X.2015.1123354. Epub 2015 Dec 15. PMID: 26671823; PMCID: PMC4819811. Nota del Editor La REV SEN se mantiene neutral con respecto a los reclamos jurisdiccionales sobre mapas publicados y afiliaciones institucionales.

Object segmentation is an important task which is widely employed in many computer vision applications such as object detection, tracking, recognition, and retrieval. It can be seen as a two-phase process: object detection and segmentation. Object segmentation becomes more challenging in case there is no prior knowledge about the object in the scene. In such conditions, visual attention analysis via saliency mapping may offer a mean to predict the object location by using visual contrast, local or global, to identify regions that draw strong attention in the image. However, in such situations as clutter background, highly varied object surface, or shadow, regular and salient object segmentation approaches based on a single image feature such as color or brightness have shown to be insufficient for the task. This work proposes a new salient object segmentation method which uses a depth map obtained from the input image for enhancing the accuracy of saliency mapping. A deep learning-based method is employed for depth map estimation. Our experiments showed that the proposed method outperforms other state-of-the-art object segmentation algorithms in terms of recall and precision. KeywordsSaliency map, Depth map, deep learning, object segmentation References[1] Itti, C. Koch, E. Niebur, A model of saliency-based visual attention for rapid scene analysis, IEEE Transactions on pattern analysis and machine intelligence 20(11) (1998) 1254-1259.[2] Goferman, L. Zelnik-Manor, A. Tal, Context-aware saliency detection, IEEE transactions on pattern analysis and machine intelligence 34(10) (2012) 1915-1926.[3] Kanan, M.H. Tong, L. Zhang, G.W. Cottrell, Sun: Top-down saliency using natural statistics, Visual cognition 17(6-7) (2009) 979-1003.[4] Liu, Z. Yuan, J. Sun, J. Wang, N. Zheng, X. Tang, H.-Y. Shum, Learning to detect a salient object, IEEE Transactions on Pattern analysis and machine intelligence 33(2) (2011) 353-367.[5] Perazzi, P. Krähenbühl, Y. Pritch, A. Hornung, Saliency filters: Contrast based filtering for salient region detection, in: Computer Vision and Pattern Recognition (CVPR), 2012 IEEE Conference on, IEEE, 2012, pp. 733-740.[6] M. Cheng, N.J. Mitra, X. Huang, P.H. Torr, S.M. Hu, Global contrast based salient region detection, IEEE Transactions on Pattern Analysis and Machine Intelligence 37(3) (2015) 569-582.[7] Borji, L. Itti, State-of-the-art in visual attention modeling, IEEE transactions on pattern analysis and machine intelligence 35(1) (2013) 185-207.[8] Simonyan, A. Vedaldi, A. Zisserman, Deep inside convolutional networks: Visualising image classification models and saliency maps, arXiv preprint arXiv:1312.6034.[9] Li, Y. Yu, Visual saliency based on multiscale deep features, in: Proceedings of the IEEE conference on computer vision and pattern recognition, 2015, pp. 5455-5463.[10] Liu, J. Han, Dhsnet: Deep hierarchical saliency network for salient object detection, in: Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition, 2016, pp. 678-686.[11] Achanta, S. Hemami, F. Estrada, S. Susstrunk, Frequency-tuned saliency detection model, CVPR: Proc IEEE, 2009, pp. 1597-604.Fu, J. Cheng, Z. Li, H. Lu, Saliency cuts: An automatic approach to object segmentation, in: Pattern Recognition, 2008. ICPR 2008. 19th International Conference on, IEEE, 2008, pp. 1-4Borenstein, J. Malik, Shape guided object segmentation, in: Computer Vision and Pattern Recognition, 2006 IEEE Computer Society Conference on, Vol. 1, IEEE, 2006, pp. 969-976.Jiang, J. Wang, Z. Yuan, T. Liu, N. Zheng, S. Li, Automatic salient object segmentation based on context and shape prior., in: BMVC. 6 (2011) 9.Ciptadi, T. Hermans, J.M. Rehg, An in depth view of saliency, Georgia Institute of Technology, 2013.Desingh, K.M. Krishna, D. Rajan, C. Jawahar, Depth really matters: Improving visual salient region detection with depth., in: BMVC, 2013.Li, J. Ye, Y. Ji, H. Ling, J. Yu, Saliency detection on light field, in: Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition, 2014, pp. 2806-2813.Koch, S. Ullman, Shifts in selective visual attention: towards the underlying neural circuitry, in: Matters of intelligence, Springer, 1987, pp. 115-141.Laina, C. Rupprecht, V. Belagiannis, F. Tombari, N. Navab, Deeper depth prediction with fully convolutional residual networks, in: 3D Vision (3DV), 2016 Fourth International Conference on, IEEE, 2016, pp. 239-248.Bruce, J. Tsotsos, Saliency based on information maximization, in: Advances in neural information processing systems, 2006, pp. 155-162.Ren, X. Gong, L. Yu, W. Zhou, M. Ying Yang, Exploiting global priors for rgb-d saliency detection, in: Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition Workshops, 2015, pp. 25-32.Fang, J. Wang, M. Narwaria, P. Le Callet, W. Lin, Saliency detection for stereoscopic images., IEEE Trans. Image Processing 23(6) (2014) 2625-2636.Hou, L. Zhang, Saliency detection: A spectral residual approach, in: Computer Vision and Pattern Recognition, 2007. CVPR’07. IEEE Conference on, IEEE, 2007, pp. 1-8.Guo, Q. Ma, L. Zhang, Spatio-temporal saliency detection using phase spectrum of quaternion fourier transform, in: Computer vision and pattern recognition, 2008. cvpr 2008. ieee conference on, IEEE, 2008, pp. 1-8.Fang, W. Lin, B.S. Lee, C.T. Lau, Z. Chen, C.W. Lin, Bottom-up saliency detection model based on human visual sensitivity and amplitude spectrum, IEEE Transactions on Multimedia 14(1) (2012) 187-198.Lang, T.V. Nguyen, H. Katti, K. Yadati, M. Kankanhalli, S. Yan, Depth matters: Influence of depth cues on visual saliency, in: Computer vision-ECCV 2012, Springer, 2012, pp. 101-115.Zhang, G. Jiang, M. Yu, K. Chen, Stereoscopic visual attention model for 3d video, in: International Conference on Multimedia Modeling, Springer, 2010, pp. 314-324.Wang, M.P. Da Silva, P. Le Callet, V. Ricordel, Computational model of stereoscopic 3d visual saliency, IEEE Transactions on Image Processing 22(6) (2013) 2151-2165.Peng, B. Li, W. Xiong, W. Hu, R. Ji, Rgbd salient object detection: A benchmark and algorithms, in: European Conference on Computer Vision (ECCV), 2014, pp. 92-109.Wu, L. Duan, L. Kong, Rgb-d salient object detection via feature fusion and multi-scale enhancement, in: CCF Chinese Conference on Computer Vision, Springer, 2015, pp. 359-368.Xue, Y. Gu, Y. Li, J. Yang, Rgb-d saliency detection via mutual guided manifold ranking, in: Image Processing (ICIP), 2015 IEEE International Conference on, IEEE, 2015, pp. 666-670.Katz, A. Adler, Depth camera based on structured light and stereo vision, uS Patent App. 12/877,595 (Mar. 8 2012).Chatterjee, G. Molina, D. Lelescu, Systems and methods for determining depth from multiple views of a scene that include aliasing using hypothesized fusion, uS Patent App. 13/623,091 (Mar. 21 2013).Matthies, T. Kanade, R. Szeliski, Kalman filter-based algorithms for estimating depth from image sequences, International Journal of Computer Vision 3(3) (1989) 209-238.Y. Schechner, N. Kiryati, Depth from defocus vs. stereo: How different really are they?, International Journal of Computer Vision 39(2) (2000) 141-162.Delage, H. Lee, A.Y. Ng, A dynamic bayesian network model for autonomous 3d reconstruction from a single indoor image, in: Computer Vision and Pattern Recognition, 2006 IEEE Computer Society Conference on, Vol. 2, IEEE, 2006, pp. 2418-2428.Saxena, M. Sun, A.Y. Ng, Make3d: Learning 3d scene structure from a single still image, IEEE transactions on pattern analysis and machine intelligence 31(5) (2009) 824-840.Hedau, D. Hoiem, D. Forsyth, Recovering the spatial layout of cluttered rooms, in: Computer vision, 2009 IEEE 12th international conference on, IEEE, 2009, pp. 1849-1856.Liu, S. Gould, D. Koller, Single image depth estimation from predicted semantic labels, in: Computer Vision and Pattern Recognition (CVPR), 2010 IEEE Conference on, IEEE, 2010, pp. 1253-1260.Ladicky, J. Shi, M. Pollefeys, Pulling things out of perspective, in: Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition, 2014, pp. 89-96.K. Nathan Silberman, Derek Hoiem, R. Fergus, Indoor segmentation and support inference from rgbd images, in: ECCV, 2012.Liu, J. Yuen, A. Torralba, Sift flow: Dense correspondence across scenes and its applications, IEEE transactions on pattern analysis and machine intelligence 33(5) (2011) 978-994.Konrad, M. Wang, P. Ishwar, 2d-to-3d image conversion by learning depth from examples, in: Computer Vision and Pattern Recognition Workshops (CVPRW), 2012 IEEE Computer Society Conference on, IEEE, 2012, pp. 16-22.Liu, C. Shen, G. Lin, Deep convolutional neural fields for depth estimation from a single image, in: Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition, 2015, pp. 5162-5170.Wang, X. Shen, Z. Lin, S. Cohen, B. Price, A.L. Yuille, Towards unified depth and semantic prediction from a single image, in: Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition, 2015, pp. 2800-2809.Geiger, P. Lenz, C. Stiller, R. Urtasun, Vision meets robotics: The kitti dataset, International Journal of Robotics Research (IJRR).Achanta, S. Süsstrunk, Saliency detection using maximum symmetric surround, in: Image processing (ICIP), 2010 17th IEEE international conference on, IEEE, 2010, pp. 2653-2656.E. Rahtu, J. Kannala, M. Salo, J. Heikkilä, Segmenting salient objects from images and videos, in: Computer Vision-ECCV 2010, Springer, 2010, pp. 366-37.

Members of the Ralstonia solanacearum (Rs) species complex have recently been reported to cause bacterial wilt on southern highbush (SHB) blueberries in Florida (Norman et al. 2018), a disease first reported on blueberry (northern highbush; Vaccinium corymbosum) in New Jersey (Patel et al. 2013). SHB blueberries are widely grown in the southern United States, and SHB cultivars represent the majority of the blueberry acreage in Georgia - the U.S. state with the largest blueberry acreage (NASS 2022). In Fall 2020, three-year old SHB plants (cv. ‘Indigocrisp’) showing leaf bronzing, wilting, and dieback were collected from two field sites in Clinch County, GA. At these locations, numerous plants were rapidly dying, with symptoms appearing to have spread down rows. Plant material tested positive using the ImmunoStrip® for Rs (Agdia, Inc., Elkhart, IN). From one location, the remaining sample was submitted to USDA-APHIS Select Agent Services who determined that Rs was present but a select agent (Rs Race 3, Biovar 2) was not. Following this, six adjacent, symptomatic SHB plants were collected from the same field location. These plants tested positive using the ImmunoStrip® for Rs, and red-pigmented mucoid colonies typical of Rs formed within 48 h at 28°C on triphenyltetrazolium chloroide (TZC) isolation medium (Kelman 1954). DNA was extracted from pure Rs cultures using the cetyltrimethylammonium bromide (CTAB) method (Doyle and Doyle 1987) and tested using polymerase chain reaction (PCR). Primers pairs AMB013/AMB014 (Fegan and Prior 2005) and ENDO-F/ENDO-R (Ji et al. 2007) were used to amplify 558 nt and 843 nt portions of the 16S rRNA region and Rs endoglucanase gene, respectively. Resulting amplicons were purified using an E.Z.N.A.® Cycle Pure Kit (Omega Bio-Tek, Norcross, GA), Sanger sequenced in both directions (Eurofins Genomics, Louisville, KY), and compared to publicly available Rs sequences in Genbank. The 16 rRNA sequence from all obtained isolates (accession ON938207) had 100% identity to Rs strain CFBP2957 (FP885897), while the endoglucase sequence (ON938206) had 100% identity to phylotype IIa, sequevar 5 Rs strain CIP-426 (MF461810) and phylotype IIa, sequevar 39 Rs strain 19-058 (MT314067), among others. To fulfill Koch’s postulates, an isolate (‘Ral21-1’) was grown on TZC medium for 48 h at 28°C and suspended in 8.5 g/L NaCl at 1 x 108 CFU/ml. Five young, tissue cultured SHB plants (cv. ‘Kestrel’) in 25 cm pots were drenched with 50 ml of Rs suspension. For six weeks, plants were maintained in the greenhouse at 21-32°C. Typical bacterial wilt symptoms (leaf bronzing/scorching) developed in all inoculated plants, and infections were confirmed using Immunostrip®. Rs was reisolated and confirmed via PCR and sequencing as previously described. While Ralstonia has been known to cause disease on numerous crops in Georgia, this represents a first report of bacterial wilt in Georgia blueberries. Relative to rabbiteye blueberries (V. virgatum), recent reports suggest that SHB are much more susceptible to bacterial wilt (Conner et al. 2022). Accordingly, given the transition from rabbiteye to SHB within Georgia’s blueberry production region over the past two decades and the ability of Rs to spread easily in water, soil, or via infected plant material, the presence of this disease within the state represents a significant threat to blueberry production. Additional characterization of Ralstonia isolates from Georgia may help assess the risk of future outbreaks.

Objective: Use of optimal Atlas segmentation algorithm to study the imaging signs of mycoplasma pneumonia with multi-slice spiral CT (HRCT), and to explore the value of HRCT in the diagnosis and efficacy in evaluation of mycoplasma pneumonia in children. Methods: The study retrospectively analyzed 72 patients diagnosed with mycoplasma pneumonia in our hospital from January 2017 to January 2019. The imaging data and clinical data of 72 patients were collected. The optimal Atlas segmentation algorithm was used to analyze the characteristics of CT examination, and the value of CT in the diagnosis of mycoplasma pneumonia and the evaluation of curative effect was summarized. Results: Among all patients, 37 cases were unilateral lesions, 35 cases were bilateral lesions, 19 cases were in the left upper lobe, 24 cases were in the left lower lobe, 21 cases were in the right upper lobe, 13 cases were in the right middle lobe, 25 The lesion was located in the right lower lobe. The main CT findings of the lesions before treatment were large patchy, spot-shaped shadows, and strip-shaped or ground-glass shadows. After treatment, the main CT findings of the lesions were reduced lesion density and reduced lesion range. Conclusion: CT can clearly show the pulmonary lesions of mycoplasma pneumonia, and its unique imaging signs can improve the clinical diagnosis accuracy. In addition, CT scans can evaluate the treatment effect according to the changes in the characteristics of the lesion, which has important value for the evaluation of the effect for clinical diagnosis and efficacy evaluation of mycoplasma pneumonia. doi: https://doi.org/10.12669/pjms.37.6-WIT.4860 How to cite this:Fu X, Yang N, Ji J. Application of CT images based on the optimal atlas segmentation algorithm in the clinical diagnosis of Mycoplasma Pneumoniae Pneumonia in Children. Pak J Med Sci. 2021;37(6):1647-1651. doi: https://doi.org/10.12669/pjms.37.6-WIT.4860 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objectives: Changes in coagulation indexes, thromboelastogram(TEG) and autoantibodies in patients with recurrent pregnancy loss (RPL) with different number of abortions were analyzed. Methods: Medical records of 48 patients with recurrent abortion, treated in Quzhou people’s Hospital from November 2019 to October 2020, were collected as the observation group. Based on the number of abortions, patients were divided into Group-A (Two abortions, n=21), Group-B (Three abortions, n=16) and group C (Abortion ≥ four times, n=11). Records of 50 healthy pregnant women in our hospital in the same period were selected as the control group. Coagulation indexes [prothrombin time (PT), activated partial prothrombin time (APTT), fibrinogen (FIB), D-Dimer (DD)], thromboelastogram (TEG) parameters [reaction time (R), coagulation time(K), maximum thrombus amplitude (MA), coagulation angle (α)], changes in the levels of autoantibodies [anticardiolipin antibody (ACA), anti-endometrial antibody (EmAb), anti-thyroid antibody(ATA)] were compared between the groups. Results: There were significant differences in the levels of ATPP, Pt, FIB and DD among the groups. Higher number of abortions correlated with lower the levels of ATPP and Pt, and higher levels of FIB and DD (P<0.05). Compared to the control group, R and K in Group-A,B and C decreased, while α and MA increased (P<0.05). There were significant differences in α and MA indexes. The positive rates of ACA, EmAb and ATA in Group-A were higher than those in the control group, but the difference was not statistically significant (P>0.05), while the above indexes in groups B and C were significantly higher than those in the control group(P<0.05). The positive rates of ACA and ATA in group C were significantly higher than those in Group-A(P<0.05), but there was no significant difference in the positive rate of EmAb (P>0.05). Conclusion: RPL was related to the decrease of APTT, PT, and the increase of FIB and DD levels. TEG indicated that the increase of α and MA values indicated that the risk of multiple abortion was increased. The positive rates of ACA, EmAb and ATA were closely related to multiple abortions, especially the positive rates of ACA and ATA. doi: https://doi.org/10.12669/pjms.38.7.6284 How to cite this:Yao H, Ji Y, Zhou Y. Analysis of blood coagulation indexes, thromboelastogram and autoantibodies in patients with recurrent pregnancy loss. Pak J Med Sci. 2022;38(7):2005-2010. doi: https://doi.org/10.12669/pjms.38.7.6284 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In this paper, we analyze an underlay two-way decode-and-forward scheme in which secondary relays use successive interference cancellation (SIC) technology to decode data of two secondary sources sequentially, and then generate a coded signal by superposition coding (SC) technology, denoted as SIC-SC protocol. The SIC-SC protocol is designed to operate in two time slots under effects from an interference constraint of a primary receiver and residual interference of imperfect SIC processes. Transmit powers provided to carry the data are allocated dynamically according to channel powers of interference and transmission, and a secondary relay is selected from considering strongest channel gain subject to increase in decoding capacity of the first data and decrease in collection time of channel state information. Closed-form outage probability expressions are derived from mathematical manipulations and verified by performing Monte Carlo simulations. An identical scheme of underlay two-way decodeand-forward relaying with random relay selection and fixed power allocations is considered to compare with the proposed SIC-SC protocol, denoted as RRS protocol. Simulation and analysis results show that the non-identical outage performances of the secondary sources in the proposed SIC-SC protocol are improved by increasing the number of the secondary relays and the interference constraint as well as decreasing the residual interference powers. Secondly, the performance of the nearer secondary source is worse than that of the farther secondary source. In addition, the proposed SIC-SC protocol outperforms the RRS comparison protocol, and effect of power allocations through channel powers is discovered. Finally, derived theory values are precise to simulation results. Keywords: Successive interference cancellation, superposition coding, power allocation, underlay cognitive radio, non-orthogonal multiple access, outage probability. References [1] Popovski, H. Yomo, Physical Network Coding in Two-Way Wireless Relay Channels, presented at 2007 IEEE International Conference on Communications (ICC), Glasgow, 2007, pp. 707-712. https://doi.org/10.1109/ICC.2007.121. [2] Cao, X. Ji, J. Wang, S. Zhang, Y. Ji, J. Wang, Security-Reliability Tradeoff Analysis for Underlay Cognitive Two-Way Relay Networks, IEEE Transactions on Wireless Communications 18(12) (2019) 6030-6042. https://doi.org/10.1109/ TWC.2019.2941944. [3] Mitola, G.Q. Maguire, Cognitive radio: making software radios more personal, IEEE Personal Communications 6(4) (1999) 13-18. https://doi. org /10.1109/98.788210. [4] M.C. Chu, H. Zepernick, Performance Optimization for Hybrid Two-Way Cognitive Cooperative Radio Networks With Imperfect Spectrum Sensing, IEEE Access 6 (2018) 70582-70596. https://doi.org/10.1109/ICC.2007.121. [5] Ho-Van, T. Do-Dac, Security Analysis for Underlay Cognitive Network with Energy-Scavenging Capable Relay over Nakagami-m Fading Channels, Wireless Communications and Mobile Computing 2019 1-16. https://doi.org/ 10.1155/2019/5080952. [6] Zhang, Z. Zhang, J. Xing, R. Yu, P. Zhang, W.Wang, Exact Outage Analysis in Cognitive Two-WayRelay Networks With Opportunistic Relay SelectionUnder Primary User’s Interference, IEEE Transactionson Vehicular Technology 64(6) (2015) 2502-2511. https://doi.org/10.1109/2014.2346615. [7] T. Duy, H.Y. Kong, Exact outage probability of cognitive two-way relaying scheme with opportunistic relay selection under interference constraint, IET Communications 6(16) (2012), 2750-2759. https://doi.org/ 10.1049/iet-com. 2012.0235. [8] V. Toan, V.N.Q. Bao, Opportunistic relaying for cognitive two-way network with multiple primary receivers over Nakagami-m fading, presented at 2016 International Conference on Advanced Technologies for Communications (ATC), Hanoi city, 2016, pp.141-146. https://doi.org/1109/ATC.2016.7764762. [9] V. Toan, V.N.Q. Bao, H. Nguyen-Le, Cognitive two-way relay systems with multiple primary receivers: exact and asymptotic outage formulation, IET Communications 11(16) (2017) 2490-2497. https://doi.org/10.1049/iet-com.2017. 0400. [10] V.Toan, V.N.Q. Bao, K.N. Le,Performance analysis of cognitive underlay two-wayrelay networks with interference and imperfect channelstate information, EURASIP Journal on WirelessCommunications and Networking 2018 53 (2018).https://doi.org/10.1186/s13638-018-1063-z. [11] Solanki, P.K. Sharma, P.K. Upadhyay,Adaptive Link Utilization in Two-Way SpectrumSharing Relay Systems Under Average Interference Constraints, IEEE Systems Journal 12(4) (2018) 3461-3472. https://doi.org/10.1109/ JSYST.2017.2713887. [12] Yue, Y. Liu, S. Kang, A. Nallanathan, Y. Chen, Modeling and Analysis of Two-WayRelay Non-Orthogonal Multiple Access Systems, IEEETransactions on Communications 66(9) (2018) 3784-3796. https://doi.org/10.1109/TCOMM. 2018.2816063. [13] Zou, B. He, H. Jafarkhani, An Analysis of TwoUser Uplink Asynchronous Non-orthogonal MultipleAccess Systems, IEEE Transactions on WirelessCommunications 18(2) (2019) 1404-1418. https://doi.org/10.1109/TWC.2019.2892486. [14] Yang, Z. Ding, P. Fan, N. Al-Dhahir, TheImpact of Power Allocation on Cooperative Nonorthogonal Multiple Access Networks With SWIPT,IEEE Transactions on Wireless Communications 16(7) (2017) 4332-4343. https://doi.org/10.1109/TWC.2017.2697380. [15] N. Son, T.T. Duy, K. Ho-Van, SIC-Coding Schemes for Underlay Two-Way Relaying Cognitive Networks, Wireless Communications and Mobile Computing 2020, pp.1-24. https://doi.org/ 10.1155/2020/8860551. [16] F. Kader, M.B. Shahab, S.Y. Shin, ExploitingNon-Orthogonal Multiple Access in Cooperative RelaySharing, IEEE Communications Letters 21(5) (2017) 1159-1162. https://doi.org/1109/LCOMM.2017.2653777. [17] Yue, Y. Liu, S. Kang, A. Nallanathan, Z. Ding,Spatially Random Relay Selection for Full/Half-DuplexCooperative NOMA Networks, IEEE Transactions onCommunications 66(8) (2018) 3294-3308. https://doi.org/10.1109/TCOMM. 2018.2809740. [18] Liu, Z. Ding, M. Elkashlan, J. Yuan,Nonorthogonal Multiple Access in Large-Scale UnderlayCognitive Radio Networks, IEEE Transactions onVehicular Technology 65(12) (2016)10152-10157. https://doi.org/10.1109/ TVT.2016.2524694. [19] Song, W. Yang, Z. Xiang, N. Sha, H. Wang, Y.Yang, An Analysis on Secure Millimeter Wave NOMACommunications in Cognitive Radio Networks, IEEE Access 8 (2020), 78965-78978. https://doi.org/10.1109/ACCESS.2020.2989860. [20] Ding, T. Song, Y. Zou, X. Chen, L. Hanzo,Security-Reliability Tradeoff Analysis of Artificial NoiseAided Two-Way Opportunistic Relay Selection, IEEE Transactions on Vehicular Technology 66(5) (2017) 3930-3941. https://doi.org/10.1109/TVT.2016.2601112. [21] Zheng, M. Wen, F. Chen, J. Tang, F. Ji, SecureNOMA Based Full-Duplex Two-Way Relay Networkswith Artificial Noise against Eavesdropping, presented at 2018IEEE International Conference on Communications(ICC), Kansas City, 2018,pp.1-6. https://doi.org/ 10.1109/ICC.2018.8422946. [22] N. Son,H.Y. Kong, Exact Outage Analysisof Energy Harvesting Underlay Cooperative CognitiveNetworks, IEICE Transactions on Communications E98-B(4) (2015),pp.661-672. https://doi.org/10.1587/transcom.E98.B.661. [23] Tourki, K.A. Qaraqe, M. Alouini, OutageAnalysis for Underlay Cognitive Networks UsingIncremental Regenerative Relaying, IEEE Transactions on Vehicular Technology 62(2) (2013) 721-734. https://doi.org/10.1109/TVT. 2012.2222947. [24] Papoulis, S.U. Pillai, Probability, randomvariables and stochastic processes, 4th ed., McGrawHill, New York, 2002. [25] Pei, T. Zhifeng, L. Zinan, E. Erkip, S.Panwar, Cooperative wireless communications: a cross-layer approach, IEEE Wireless Communications 13(4) (2006) 84-92. https://doi.org/10.1109/2006.1678169. [26] Ghasemi, E.S. Sousa, Fundamental limitsof spectrum-sharing in fading environments, IEEETransactions on Wireless Communications 6(2) (2007) 649-658. https://doi.org/10.1109/TWC. 2007.05447. [27] M. Peha, Approaches to spectrum sharing, IEEECommunications Magazine 43(2) (2005) 10-12. https://doi.org/10.1109/MCOM.2005. 1391490. [28] Kim, S. Lim, H. Wang, D. Hong, Optimal PowerAllocation and Outage Analysis for Cognitive FullDuplex Relay Systems, IEEE Transactions on Wireless Communications 11(10) (2012) 3754-3765. https://doi.org/10.1109/TWC. 2012.083112.120127. [29] N. Son,T.T. Duy, Performance analysisof underlay cooperative cognitive full-duplexnetworks with energy-harvesting relay, ComputerCommunications 122 (2018) 9-19. https://doi.org/1016/j.comcom.2018.03.003. [30] V. Nguyen, T. Do, V.N.Q. Bao, D.B.d.Costa, B. An, On the Performance of MultihopCognitive Wireless Powered D2D Communications inWSNs, IEEE Transactions on Vehicular Technology 69(3) (2020) 2684-2699. https://doi.org/10.1109/TVT.2020.2963841. [31] Ruan, Y. Li, C. Wang, R. Zhang, H.Zhang, Energy Efficient Power Allocation for DelayConstrained Cognitive Satellite Terrestrial NetworksUnder Interference Constraints, IEEE Transactions on Wireless Communications 18(10) (2019) 4957-4969. https://doi.org/10.1109/TWC. 2019.2931321. [32] Gao, S. Zhang, Y. Su, M. Diao, M. Jo, Joint Multiple Relay Selection and Time Slot Allocation Algorithm for the EH-Abled Cognitive Multi-User Relay Networks, IEEE Access 7 (2019) 111993- 112007. https://doi.org/10.1109/2019.2932955. [33] Arezumand, H. Zamiri-Jafarian, E. Soleimani-Nasab, Exact and Asymptotic Analysis of Partial Relay Selection for Cognitive RF-FSO Systems With Non-Zero Boresight Pointing Errors, IEEE Access 7 (2019) 58611-58625. https://doi.org/1109/ACCESS.2019.2914480. [34] N. Son, H.Y. Kong, Energy-Harvesting Relay Selection Schemes for Decode-and-Forward Dual-Hop Networks, IEICE TRANSACTIONS on Communications E98-B(12) (2015) 2485-2495. https://doi.org/10.1587/transcom.E98.B.2485. [35] N. Nguyen, T.H. Quang Minh, P.T. Tran, M. Voznak, T.T. Duy, T.-L. Nguyen, P.T. Tin, Performance enhancement for energy harvesting based two-way relay protocols in wireless ad-hoc networks with partial and full relay selection methods, Ad Hoc Networks 84 (2019) 178-187. https://doi.org/10.1016/j.adhoc.2018.10.005. [36] Pan, Z. Li, Z. Wang, F. Zhang, Joint Relay Selection and Power Allocation for the Physical Layer Security of Two-Way Cooperative Relaying Networks, Wireless Communications and Mobile Computing, 2019, pp. 1-7. https://doi.org/10.1155/2019/1839256. [37] A. Nasir, Z. Xiangyun, S. Durrani, R.A. Kennedy, Relaying Protocols for Wireless Energy Harvesting and Information Processing, IEEE Transactions on Wireless Communications 12(7) (2013) 3622-3636. https://doi.org/10.1109/TWC. 2013.062413.122042. [38] I. Gradshteyn, I.M. Ryzhik, A.Jeffrey, D. Zwillinger, Table of integral, series and products, 7th ed., Elsevier, Amsterdam, 2007. [39] Haiyan, L. Zan, S. Jiangbo, G. Lei, Underlay cognitive relay networks with imperfect channel state information and multiple primary receivers, IET Communications 9(4) (2015) 460-467. https://doi.org/10.1049/iet-com.2014.0429. [40] Zhong, Z. Zhang, Opportunistic Two-Way Full-Duplex Relay Selection in Underlay Cognitive Networks, IEEE Systems Journal 12(1) (2018) 725-734.https://doi.org/10.1109/JSYST. 2016.2514601.

IntroductionIn this article, I set out to accomplish two tasks. The first is to map coffee and cafés in Mainland China in different historical periods. The second is to focus on coffee and cafés in the socio-cultural milieu of contemporary China in order to understand the symbolic value of the emerging coffee/café-scape. Cafés, rather than coffee, are at the centre of this current trend in contemporary Chinese cities. With instant coffee dominating as a drink, the Chinese have developed a cultural and social demand for cafés, but have not yet developed coffee palates. Historical Coffee Map In 1901, coffee was served in a restaurant in the city of Tianjin. This restaurant, named Kiessling, was run by a German chef, a former solider who came to China with the eight-nation alliance. At that time, coffee was reserved mostly for foreign politicians and military officials as well as wealthy businessmen—very few ordinary Chinese drank it. (For more history of Kiessling, including pictures and videos, see Kiessling). Another group of coffee consumers were from the cultural elites—the young revolutionary intellectuals and writers with overseas experience. It was almost a fashion among the literary elite to spend time in cafés. However, this was negatively judged as “Western” and “bourgeois.” For example, in 1932, Lu Xun, one of the most important twentieth century Chinese writers, commented on the café fashion during 1920s (133-36), and listed the reasons why he would not visit one. He did not drink coffee because it was “foreigners’ food”, and he was too busy writing for the kind of leisure enjoyed in cafés. Moreover, he did not, he wrote, have the nerve to go to a café, and particularly not the Revolutionary Café that was popular among cultural celebrities at that time. He claimed that the “paradise” of the café was for genius, and for handsome revolutionary writers (who he described as having red lips and white teeth, whereas his teeth were yellow). His final complaint was that even if he went to the Revolutionary Café, he would hesitate going in (Lu Xun 133-36). From Lu Xun’s list, we can recognise his nationalism and resistance to what were identified as Western foods and lifestyles. It is easy to also feel his dissatisfaction with those dilettante revolutionary intellectuals who spent time in cafés, talking and enjoying Western food, rather than working. In contrast to Lu Xun’s resistance to coffee and café culture, another well-known writer, Zhang Ailing, frequented cafés when she lived in Shanghai from the 1920s to 1950s. She wrote about the smell of cakes and bread sold in Kiessling’s branch store located right next to her parents’ house (Yuyue). Born into a wealthy family, exposed to Western culture and food at a very young age, Zhang Ailing liked to spend her social and writing time in cafés, ordering her favourite cakes, hot chocolate, and coffee. When she left Shanghai and immigrated to the USA, coffee was an important part of her writing life: the smell and taste reminding her of old friends and Shanghai (Chunzi). However, during Zhang’s time, it was still a privileged and elite practice to patronise a café when these were located in foreign settlements with foreign chefs, and served mainly foreigners, wealthy businessmen, and cultural celebrities. After 1949, when the Chinese Communist Party established the People’s Republic of China, until the late 1970s, there were no coffee shops in Mainland China. It was only when Deng Xiaoping suggested neo-liberalism as a so-called “reform-and-open-up” economic policy that foreign commerce and products were again seen in China. In 1988, ten years after the implementation of Deng Xiaoping’s policy, the Nestlé coffee company made the first inroads into the mainland market, featuring homegrown coffee beans in Yunnan province (China Beverage News; Dong; ITC). Nestlé’s bottled instant coffee found its way into the Chinese market, avoiding a direct challenge to the tea culture. Nestlé packaged its coffee to resemble health food products and marketed it as a holiday gift suitable for friends and relatives. As a symbol of modernity and “the West”, coffee-as-gift meshed with the traditional Chinese cultural custom that values gift giving. It also satisfied a collective desire for foreign products (and contact with foreign cultures) during the economic reform era. Even today, with its competitively low price, instant coffee dominates coffee consumption at home, in the workplace, and on Chinese airlines. While Nestlé aimed their product at native Chinese consumers, the multinational companies who later entered China’s coffee market, such as Sara Lee, mainly targeted international hotels such as IHG, Marriott, and Hyatt. The multinationals also favoured coffee shops like Kommune in Shanghai that offered more sophisticated kinds of coffee to foreign consumers and China’s upper class (Byers). If Nestlé introduced coffee to ordinary Chinese families, it was Starbucks who introduced the coffee-based “third space” to urban life in contemporary China on a signficant scale. Differing from the cafés before 1949, Starbucks stores are accessible to ordinary Chinese citizens. The first in Mainland China opened in Beijing’s China World Trade Center in January 1999, targeting mainly white-collar workers and foreigners. Starbucks coffee shops provide a space for informal business meetings, chatting with friends, and relaxing and, with its 500th store opened in 2011, dominate the field in China. Starbucks are located mainly in the central business districts and airports, and the company plans to have 1,500 sites by 2015 (Starbucks). Despite this massive presence, Starbucks constitutes only part of the café-scape in contemporary Chinese cities. There are two other kinds of cafés. One type is usually located in universities or residential areas and is frequented mainly by students or locals working in cultural professions. A representative of this kind is Sculpting in Time Café. In November 1997, two years before the opening of the first Starbucks in Beijing, two newlywed college graduates opened the first small Sculpting in Time Café near Beijing University’s East Gate. This has been expanded into a chain, and boasts 18 branches on the Mainland. (For more about its history, see Sculpting in Time Café). Interestingly, both Starbucks and Sculpting in Time Café acquired their names from literature, Starbucks from Moby Dick, and Sculpting in Time from the Russian filmmaker Andrei Tarkovsky’s film diary of the same name. For Chinese students of literature and the arts, drinking coffee is less about acquiring more energy to accomplish their work, and more about entering a sensual world, where the aroma of coffee mixes with the sounds from the coffee machine and music, as well as the lighting of the space. More importantly, cafés with this ambience become, in themselves, cultural sites associated with literature, films, and music. Owners of this kind of café are often lovers of foreign literatures, films, and cultures, and their cafés host various cultural events, including forums, book clubs, movie screenings, and music clubs. Generally speaking, coffee served in this kind of café is simpler than in the kind discussed below. This third type of café includes those located in tourist and entertainment sites such as art districts, bar areas, and historical sites, and which are frequented by foreign and native tourists, artists and other cultural workers. If Starbucks cultivates a fast-paced business/professional atmosphere, and Sculpting in Time Cafés an artsy and literary atmosphere, this third kind of café is more like an upscale “bar” with trained baristas serving complicated coffees and emphasising their flavour. These coffee shops are more expensive than the other kinds, with an average price three times that of Starbucks. Currently, cafés of this type are found only in “first-tier” cities and usually located in art districts and tourist areas—such as Beijing’s 798 Art District and Nanluo Guxiang, Shanghai’s Tai Kang Road (a.k.a. “the art street”), and Hangzhou’s Westlake area. While Nestlé and Starbucks use coffee beans grown in Yunnan provinces, these “art cafés” are more inclined to use imported coffee beans from suppliers like Sara Lee. Coffee and Cafés in Contemporary China After just ten years, there are hundreds of cafés in Chinese cities. Why has there been such a demand for coffee or, more accurately, cafés, in such a short period of time? The first reason is the lack of “third space” environments in Mainland China. Before cafés appeared in the late 1990s, stores like KFC (which opened its first store in 1987) and McDonald’s (with its first store opened in 1990) filled this role for urban residents, providing locations where customers could experience Western food, meet friends, work, or read. In fact, KFC and McDonald’s were once very popular with college students looking for a place to study. Both stores had relatively clean food environments and good lighting. They also had air conditioning in the summer and heating in the winter, which are not provided in most Chinese university dormitories. However, since neither chain was set up to be a café and customers occupying seats for long periods while ordering minimal amounts of food or drink affected profits, staff members began to indirectly ask customers to leave after dining. At the same time, as more people were able to afford to eat at KFC and McDonald’s, their fast foods were also becoming more and more popular, especially among young people. As a consequence, both types of chain restaurant were becoming noisy and crowded and, thus, no longer ideal for reading, studying, or meeting with friends. Although tea has been a traditional drink in Chinese culture, traditional teahouses were expensive places more suitable for business meetings or for the cultural or intellectual elite. Since almost every family owns a tea set and can readily purchase tea, friends and family would usually make and consume tea at home. In recent years, however, new kinds of teahouses have emerged, similar in style to cafés, targeting the younger generation with more affordable prices and a wider range of choices, so the lack of a “third space” does not fully explain the café boom. Another factor affecting the popularity of cafés has been the development and uptake of Internet technology, including the increasing use of laptops and wireless Internet in recent years. The Internet has been available in China since the late 1990s, while computers and then laptops entered ordinary Chinese homes in the early twenty-first century. The IT industry has created not only a new field of research and production, but has also fostered new professions and demands. Particularly, in recent years in Mainland China, a new socially acceptable profession—freelancing in such areas as graphic design, photography, writing, film, music, and the fashion industry—has emerged. Most freelancers’ work is computer- and Internet-based. Cafés provide suitable working space, with wireless service, and the bonus of coffee that is, first of all, somatically stimulating. In addition, the emergence of the creative and cultural industries (which are supported by the Chinese government) has created work for these freelancers and, arguably, an increasing demand for café-based third spaces where such people can meet, talk and work. Furthermore, the flourishing of cafés in first-tier cities is part of the “aesthetic economy” (Lloyd 24) that caters to the making and selling of lifestyle experience. Alongside foreign restaurants, bars, galleries, and design firms, cafés contribute to city branding, and link a city to the global urban network. Cafés, like restaurants, galleries and bars, provide a space for the flow of global commodities, as well as for the human flow of tourists, travelling artists, freelancers, and cultural specialists. Finally, cafés provide a type of service that contributes to friendly owner/waiter-customer relations. During the planned-economy era, most stores and hotels in China were State-owned, staff salaries were not related to individual performance, and indifferent (and even unfriendly) service was common. During the economic reform era, privately owned stores and shops began to replace State-owned ones. At the same time, a large number of people from the countryside flowed into the cities seeking opportunities. Most had little if any professional training and so could only find work in factories or in the service industry. However, most café employees are urban, with better educational backgrounds, and many were already familiar with coffee culture. In addition, café owners, particularly those of places like Sculpting in Time Cafe, often invest in creating a positive, community atmosphere, learning about their customers and sharing personal experiences with their regular clients. This leads to my next point—the generation of the 1980s’ need for a social community. Cafés’ Symbolic Value—Community A demand for a sense of community among the generation of the 1980s is a unique socio-cultural phenomenon in China, which paradoxically co-exists with their desire for individualism. Mao Zedong started the “One Child Policy” in 1979 to slow the rapid population growth in China, and the generations born under this policy are often called “the lonely generations,” with both parents working full-time. At the same time, they are “the generation of me,” labelled as spoiled, self-centred, and obsessed with consumption (de Kloet; Liu; Rofel; Wang). The individuals of this generation, now aged in their 20s and 30s, constitute the primary consumers of coffee in China. Whereas individualism is an important value to them, a sense of community is also desirable in order to compensate for their lack of siblings. Furthermore, the 1980s’ generation has also benefitted from the university expansion policy implemented in 1999. Since then, China has witnessed a surge of university students and graduates who not only received scientific and other course-based knowledge, but also had a better chance to be exposed to foreign cultures through their books, music, and movies. With this interesting tension between individualism and collectivism, the atmosphere provided by cafés has fostered a series of curious temporary communities built on cultural and culinary taste. Interestingly, it has become an aspiration of many young college students and graduates to open a community-space style café in a city. One of the best examples is the new Henduoren’s (Many People’s) Café. This was a project initiated by Wen Erniu, a recent college graduate who wanted to open a café in Beijing but did not have sufficient funds to do so. She posted a message on the Internet, asking people to invest a minimum of US$316 to open a café with her. With 78 investors, the café opened in September 2011 in Beijing (see pictures of Henduoren’s Café). In an interview with the China Daily, Wen Erniu stated that, “To open a cafe was a dream of mine, but I could not afford it […] We thought opening a cafe might be many people’s dream […] and we could get together via the Internet to make it come true” (quoted in Liu 2011). Conclusion: Café Culture and (Instant) Coffee in China There is a Chinese saying that, if you hate someone—just persuade him or her to open a coffee shop. Since cafés provide spaces where one can spend a relatively long time for little financial outlay, owners have to increase prices to cover their expenses. This can result in fewer customers. In retaliation, cafés—particularly those with cultural and literary ambience—host cultural events to attract people, and/or they offer food and wine along with coffee. The high prices, however, remain. In fact, the average price of coffee in China is often higher than in Europe and North America. For example, a medium Starbucks’ caffè latte in China averaged around US$4.40 in 2010, according to the price list of a Starbucks outlet in Shanghai—and the prices has recently increased again (Xinhua 2012). This partially explains why instant coffee is still so popular in China. A bag of instant Nestlé coffee cost only some US$0.25 in a Beijing supermarket in 2010, and requires only hot water, which is accessible free almost everywhere in China, in any restaurant, office building, or household. As an habitual, addictive treat, however, coffee has not yet become a customary, let alone necessary, drink for most Chinese. Moreover, while many, especially those of the older generations, could discern the quality and varieties of tea, very few can judge the quality of the coffee served in cafés. As a result, few Mainland Chinese coffee consumers have a purely somatic demand for coffee—craving its smell or taste—and the highly sweetened and creamed instant coffee offered by companies like Nestlé or Maxwell has largely shaped the current Chinese palate for coffee. Ben Highmore has proposed that “food spaces (shops, restaurants and so on) can be seen, for some social agents, as a potential space where new ‘not-me’ worlds are encountered” (396) He continues to expand that “how these potential spaces are negotiated—the various affective registers of experience (joy, aggression, fear)—reflect the multicultural shapes of a culture (its racism, its openness, its acceptance of difference)” (396). Cafés in contemporary China provide spaces where one encounters and constructs new “not-me” worlds, and more importantly, new “with-me” worlds. While café-going communicates an appreciation and desire for new lifestyles and new selves, it can be hoped that in the near future, coffee will also be appreciated for its smell, taste, and other benefits. Of course, it is also necessary that future Chinese coffee consumers also recognise the rich and complex cultural, political, and social issues behind the coffee economy in the era of globalisation. References Byers, Paul [former Managing Director, Sara Lee’s Asia Pacific]. Pers. comm. Apr. 2012. China Beverage News. “Nestlé Acquires 70% Stake in Chinese Mineral Water Producer.” (2010). 31 Mar. 2012 ‹http://chinabevnews.wordpress.com/2010/02/21/nestle-acquires-70-stake-in-chinese-mineral-water-producer›. Chunzi. 张爱玲地图[The Map of Eileen Chang]. 汉语大词典出版 [Hanyu Dacidian Chubanshe], 2003. de Kloet, Jeroen. China with a Cut: Globalization, Urban Youth and Popular Music. Amsterdam: Amsterdam UP, 2010. Dong, Jonathan. “A Caffeinated Timeline: Developing Yunnan’s Coffee Cultivation.” China Brief (2011): 24-26. Highmore, Ben. “Alimentary Agents: Food, Cultural Theory and Multiculturalism.” Journal of Intercultural Studies, 29.4 (2008): 381-98. ITC (International Trade Center). The Coffee Sector in China: An Overview of Production, Trade And Consumption, 2010. Liu, Kang. Globalization and Cultural Trends in China. Honolulu: University of Hawai’i Press, 2004. Liu, Zhihu. “From Virtual to Reality.” China Daily (Dec. 2011) 31 Mar. 2012 ‹http://www.chinadaily.com.cn/life/2011-12/26/content_14326490.htm›. Lloyd, Richard. Neobohemia: Art and Commerce in the Postindustrial City. London: Routledge, 2006. Lu, Xun. “Geming Kafei Guan [Revolutionary Café]”. San Xian Ji. Taibei Shi: Feng Yun Shi Dai Chu Ban Gong Si: Fa Xing Suo Xue Wen Hua Gong Si, Mingguo 78 (1989): 133-36. Rofel, Lisa. Desiring China: Experiments in Neoliberalism, Sexuality, and Public Culture. Durham and London: Duke UP, 2007: 1-30. “Starbucks Celebrates Its 500th Store Opening in Mainland China.” Starbucks Newsroom (Oct. 2011) 31 Mar. 2012. ‹http://news.starbucks.com/article_display.cfm?article_id=580›. Wang, Jing. High Culture Fever: Politics, Aesthetics, and Ideology in Deng’s China. Berkeley, Los Angeles, London: U of California P, 1996. Xinhua. “Starbucks Raises Coffee Prices in China Stores.” Xinhua News (Jan. 2012). 31 Mar. 2012 ‹http://news.xinhuanet.com/english/china/2012-01/31/c_131384671.htm›. Yuyue. Ed. “On the History of the Western-Style Restaurants: Aileen Chang A Frequent Customer of Kiessling.” China.com.cn (2010). 31 Mar. 2012 ‹http://www.china.com.cn/culture/txt/2010-01/30/content_19334964.htm›.

O curso de graduação em Odontologia não pode se apartar de seu papel social formador e transformador na construção de um profissional cidadão, reflexivo e que transforme a sua realidade em função das demandas da sociedade. O ensino de graduação que permeie a educação com base na comunidade pode se consubstanciar como ferramenta essencial na construção do olhar sociocomportamental em estudantes universitários, na medida em que promovam a compreensão dos fatores que afetam o bem estar e a qualidade de vida dos indivíduos no cotidiano, tendo o corpo docente como construtor de conhecimentos e fundamentos, gestor de ações planejadas, metódicas e realizadas com determinado objetivo, recriando e superando os modelos de ensino/aprendizagem. A Organização Mundial de Saúde (OMS) recomenda que os currículos de graduação em saúde comportem estratégias pedagógicas capazes de levar à formação de profissionais sensíveis aos problemas de sua comunidade, preparados para a prestação de cuidados em todos os níveis de serviços de saúde. Neste contexto, o propósito deste trabalho foi analisar o papel do professor na percepção dos alunos de Odontologia considerando o impacto do ensino de graduação baseado na comunidade.Descritores: Aprendizagem; Docentes; Estudantes; Percepção; Universidades; Relações Comunidade-Instituição.ReferênciasDornan T, Littlewood S, Margolis SA, Scherpbier A, Spencer J, Ypinazar V. How can experience in clinical and community settings contribute to early medical education? A BEME systematic review. Med Teach. 2006;28(1):3-18.Art B, De Roo L, De Maeseneer J. Towards unity for health utilising community-oriented primary care in education and practice. Educ Health (Abingdon). 2007;20(2):74.Dolmans DH, Wolfhagen HA, Scherpbier AJ. From quality assurance to total quality management: how can quality assurance result in continuous improvement in health professions education?. Educ Health (Abingdon). 2003;16(2):210-17.Community-based education of health personnel. Report of a WHO study group [published correction appears in World Health Organ Tech Rep Ser 1987;746:preceding 1]. World Health Organ Tech Rep Ser. 1987;746:1-89.Deogade SC, Naitam D. Reflective learning in community-based dental education. Educ Health (Abingdon). 2016;29(2):119-23.Silverman J, Draper J, Kurtz S. Skills for communicating with patients. Oxon: Radcliffe Medical Press; 2008.Interprofessional education collaborative expert panel . Core competencies for interprofessional collaborative practice: report of an expert panel (update) 2016.Forte FDS, Pontes AA, Morais HG, Barbosa AS, Sousa Nétto OB. Olhar discente e a formação em Odontologia: interseções possíveis com a Estratégia Saúde da Família. Interface. 2019;23:e170407. Lestari E, Stalmeijer RE, Widyandana D, Scherpbier A. Understanding attitude of health care professional teachers toward interprofessional health care collaboration and education in a Southeast Asian country. J Multidiscip Healthc. 2018;11:557-71.Roop SA, Pangaro L. Effect of clinical teaching on student performance during a medicine clerkship. Am J Med. 2001;110(3):205-209.Irby DM, Papadakis M. Does good clinical teaching really make a difference. Am J Med. 2001;110:231-32.Dybowski C, Sehner S, Harendza S. Influence of motivation, self-efficacy and situational factors on the teaching quality of clinical educators. BMC Med Educ. 2017;17(1):84. Mahler D, Großschedl J, Harms U. Does motivation matter? - The relationship between teachers' self-efficacy and enthusiasm and students' performance. PLoS One. 2018;13(11):e0207252.Hattie J. Visible learning: A synthesis of over 800 meta-analyses relating to achievement London: Routledge; 2009.Walters L, Greenhill J, Richards J, Ward H, Campbell N, Ash J, et al. Outcomes of longitudinal integrated clinical placements for students, clinicians and society. Med Educ 2012;46:1028-41.Evans CA, Bolden AJ, Hryhorczuk C, Noorullah K. Management of experiences in community-based dental education. J Dent Educ. 2010;74(10 Suppl):S25-32.Knight GW. Community-based dental education at the University of Illinois at Chicago. J Dent Educ. 2011;75(10 Suppl):S14-S20.Abuzar MA, Owen J. A Community Engaged Dental Curriculum: A Rural Indigenous Outplacement Programme. J Public Health Res. 2016;5(1):668.Warmiling CM, Rossoni E, Hugo FN, Toassi RFC, Lemos VA, Slavutzki SMB, et al. Estágios curriculares no SUS: experiências da Faculdade de Odontologia da UFGRS. Rev ABENO. 2011; 11(2):63-70. Donate-Bartfield E, Lobb WK, Roucka TM. Teaching culturally sensitive care to dental students: a multidisciplinary approach. J Dent Educ. 2014;78(3):454-64.Araújo ME, Zilbovicius C. O ensino da epidemiologia na educação odontológica. In: Ferreira Antunes JLF, Peres MAP. (Org.). Epidemiologia da saúde bucal. São Paulo: Guanabara Koogan; 2006. p. 363-72.Aguiar Neta A, Alves MSCF. A comunidade como local de protagonismo na integração ensino-serviço e atuação multiprofissional. Trab educ saúde. 2016;14(1):221-35.Amundsen C, Wilson M. Are we asking the right questions? A conceptual review of the educational development literature in higher education. Rev Educa Res. 2012;82(1):90–126.Ceccim RB, Ferla AA. Educação e saúde: ensino e cidadania como travessia de fronteiras. Trab educ saúde. 2008;6(3):443-56.Mohan M, Ravindran TKS. Conceptual Framework Explaining "Preparedness for Practice" of Dental Graduates: A Systematic Review. J Dent Educ. 2018;82(11):1194-202.Holden ACL. "Preparedness for Practice" for Dental Graduates Is a Multifaceted Concept That Extends Beyond Academic and Clinical Skills. J Evid Based Dent Pract. 2020;20(1):101421.Elmberger A, Björck E, Liljedahl M, Nieminen J, Bolander Laksov K. Contradictions in clinical teachers' engagement in educational development: an activity theory analysis. Adv Health Sci Educ Theory Pract. 2019;24(1):125-40.Steinert Y, O'Sullivan PS, Irby DM. Strengthening Teachers' Professional Identities Through Faculty Development. Acad Med. 2019;94(7):963-68.Lazzarin HC, Nakama L, Cordoni Júnior L. Percepção de professores de odontologia no processo de ensino-aprendizagem [Perceptions of dentistry teachers in the teaching and learning process]. Cien Saude Colet. 2010;15 Suppl 1:1801-10.Seijo MO, Ferreira EF, Ribeiro Sobrinho AP, Paiva SM, Martins RC. Learning experience in endodontics: Brazilian students' perceptions. J Dent Educ. 2013;77(5):648-55.Victoroff KZ, Hogan S. Students' perceptions of effective learning experiences in dental school: a qualitative study using a critical incident technique. J Dent Educ. 2006;70(2):124-32.Divaris K, Barlow PJ, Chendea SA, Cheong WS, Dounis A, Dragan IF et al. O ambiente acadêmico: a perspectiva dos alunos. Eur J Dent Educ . 2008; 12 Suppl 1:120-30. Pöhlmann K, Jonas I, Ruf S, Harzer W. Stress, burnout and health in the clinical period of dental education. Eur J Dent Educ. 2005;9(2):78-84.Toassi RFC, Davoglio RS, Lemos VMA. Integração ensino-serviço-comunidade: o estágio na atenção básica da graduação em Odontologia. Educ rev. 2012; 28(4):223-42.Ayers CS, Abrams RA, McCunniff MD, Goldstein BR. A comparison of private and public dental students' perceptions of extramural programming. J Dent Educ. 2003;67(4):412-17.DeCastro JE, Matheson PB, Panagakos FS, Stewart DC, Feldman CA. Alumni perspectives on community-based and traditional curricula. J Dent Educ. 2003;67(4):418-26.DeCastro JE, Bolger D, Feldman CA. Clinical competence of graduates of community-based and traditional curricula. J Dent Educ. 2005;69(12):1324-31.Bean CY, Rowland ML, Soller H, et al. Comparing fourth-year dental student productivity and experiences in a dental school with community-based clinical education. J Dent Educ. 2007;71(8):1020-26.Henzi D, Davis E, Jasinevicius R, Hendricson W. North American dental students' perspectives about their clinical education. J Dent Educ. 2006;70(4):361-77.Henzi D, Davis E, Jasinevicius R, Hendricson W. In the students' own words: what are the strengths and weaknesses of the dental school curriculum?. J Dent Educ. 2007;71(5):632-45.Batra M, Ivanišević Malčić A, Shah AF, Sagtani RA, Mikić IM, Knežević PT et al. Self assessment of dental students' perception of learning environment in Croatia, India and Nepal. Acta Stomatol Croat. 2018;52(4):275-85.Henzi D, Davis E, Jasinevicius R, Hendricson W, Cintron L, Isaacs M. Appraisal of the dental school learning environment: the students' view. J Dent Educ. 2005;69(10):1137-47.Riquelme A, Oporto M, Oporto J, Méndez JI, Viviani P, Salech F et al. Measuring students' perceptions of the educational climate of the new curriculum at the Pontificia Universidad Católica de Chile: performance of the Spanish translation of the Dundee Ready Education Environment Measure (DREEM). Educ Health (Abingdon). 2009;22(1):112.Mayya S, Roff S. Students' perceptions of educational environment: a comparison of academic achievers and under-achievers at kasturba medical college, India. Educ Health (Abingdon). 2004;17(3):280-91.Batista CG, Nascimento CL, Rolim GS, Rocha RASS, Rodrigues AF, Ambrosano GMB et al. Student self-confidence in coping with uncooperative behaviours in paediatric dentistry. Eur J Dent Educ. 2011;15(4):199-204.Freire Mdo C, Jordao LM, de Paula Ferreira N, de Fatima Nunes M, Queiroz MG, Leles CR. Motivation towards career choice of Brazilian freshman students in a fifteen-year period. J Dent Educ. 2011;75(1):115-21.Arheiam A, Bankia I, Ingafou M. Perceived competency towards preventive dentistry among dental graduates: the need for curriculum change. Libyan J Med. 2015;10:26666. Pınar Erdem A, Peker K, Kuru S, Sepet E. Evaluation of Final-Year Turkish Dental Students' Knowledge, Attitude, and Self-Perceived Competency towards Preventive Dentistry. Biomed Res Int. 2019;2019:2346061. Schönwetter DJ, Law D, Mazurat R, Sileikyte R, Nazarko O. Assessing graduating dental students' competencies: the impact of classroom, clinic and externships learning experiences. Eur J Dent Educ. 2011;15(3):142-52. Shetty VB, Shirahatti RV, Pawar P. Students' perceptions of their education on graduation from a dental school in India. J Dent Educ. 2012;76(11):1520-26.Lanning SK, Wetzel AP, Baines MB, Ellen Byrne B. Evaluation of a revised curriculum: a four-year qualitative study of student perceptions. J Dent Educ. 2012;76(10):1323-33.Leadbeatter D, Peck C. Are dental students ready for supercomplex dental practice?. Eur J Dent Educ. 2018;22(1):e116-21.