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Aderinola, Musefiu, Bokolo Abovie, Festus Okosi, Igoniderigha Daniel, and G. F. Odubo. "Analysis of Different Ways of Crosstalk Measurement in GSM Network." International Journal of Reconfigurable and Embedded Systems (IJRES) 5, no. 2 (July 1, 2016): 106. http://dx.doi.org/10.11591/ijres.v5.i2.pp106-110.
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<p>Crosstalk is one of the problems that affect the performance operation of global system mobile (GSM) network. Among the effect of crosstalk are call mute, call drop, wire propagation delay, dynamic power dissipation etc. Crosstalk is an undesirable signal arising due to the coupling capacitances between adjacent interconnecting wires and measured in decibel. In this paper some literature were reviewed and different ways of measuring crosstalk such as Near end croosstalk (NEXT), far end crosstalk (FEXT), Power sum crosstalk (PSNEXT) and alien crosstalk (AXT) were analyzed. </p>
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Hangleiter, Dominik. "Crosstalk diagnosis for the next generation of quantum processors." Quantum Views 4 (October 29, 2020): 46. http://dx.doi.org/10.22331/qv-2020-10-29-46.
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Venne, A. Saskia, Laxmikanth Kollipara, and René P. Zahedi. "The next level of complexity: Crosstalk of posttranslational modifications." PROTEOMICS 14, no. 4-5 (January 6, 2014): 513–24. http://dx.doi.org/10.1002/pmic.201300344.
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Hussein, Ahmed Ali. "Using rectangular trace to reduce the crosstalk of the coupled microstrip lines." International Journal of Engineering & Technology 5, no. 1 (December 29, 2015): 7. http://dx.doi.org/10.14419/ijet.v5i1.4771.
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New electronic products must have high-speed, small size and lower voltages supply. With such layout, signal integrity (SI) becomes an actual important issue because sensitive equipment is affected on electromagnetic interference (EMI). Crosstalk is a major factor in signal integrity (SI) of printed circuit boards (PCBs). Crosstalk noise is usually represented in terms of Near-End crosstalk (NEXT) and Far-End crosstalk (FEXT). Crosstalk is a common problem that degrades circuit performance. To reduce this problem, via hole-fences connected by guard trace between double microstrip lines are used, in this case the crosstalk will be reduce by 6 dB than use 3W rule, but when it replaced by rectangular metal the crosstalk was reduce by 7dB, is better than use via hole-fences by 1 dB. The simulation result was done by using FEKO 5.5 simulator.
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Sarovar, Mohan, Timothy Proctor, Kenneth Rudinger, Kevin Young, Erik Nielsen, and Robin Blume-Kohout. "Detecting crosstalk errors in quantum information processors." Quantum 4 (September 11, 2020): 321. http://dx.doi.org/10.22331/q-2020-09-11-321.
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Crosstalk occurs in most quantum computing systems with more than one qubit. It can cause a variety of correlated and nonlocal crosstalk errors that can be especially harmful to fault-tolerant quantum error correction, which generally relies on errors being local and relatively predictable. Mitigating crosstalk errors requires understanding, modeling, and detecting them. In this paper, we introduce a comprehensive framework for crosstalk errors and a protocol for detecting and localizing them. We give a rigorous definition of crosstalk errors that captures a wide range of disparate physical phenomena that have been called ``crosstalk'', and a concrete model for crosstalk-free quantum processors. Errors that violate this model are crosstalk errors. Next, we give an equivalent but purely operational (model-independent) definition of crosstalk errors. Using this definition, we construct a protocol for detecting a large class of crosstalk errors in a multi-qubit processor by finding conditional dependencies between observed experimental probabilities. It is highly efficient, in the sense that the number of unique experiments required scales at most cubically, and very often quadratically, with the number of qubits. We demonstrate the protocol using simulations of 2-qubit and 6-qubit processors.
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Jin, Jieqi, Mengkai Guang, Anthony Chukwunonso Ogbuehi, Simin Li, Kai Zhang, Yihong Ma, Aneesha Acharya, et al. "Shared Molecular Mechanisms between Alzheimer’s Disease and Periodontitis Revealed by Transcriptomic Analysis." BioMed Research International 2021 (April 1, 2021): 1–22. http://dx.doi.org/10.1155/2021/6633563.
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Objective. To investigate the genetic crosstalk mechanisms that link periodontitis and Alzheimer’s disease (AD). Background. Periodontitis, a common oral infectious disease, is associated with Alzheimer’s disease (AD) and considered a putative contributory factor to its progression. However, a comprehensive investigation of potential shared genetic mechanisms between these diseases has not yet been reported. Methods. Gene expression datasets related to periodontitis were downloaded from the Gene Expression Omnibus (GEO) database, and differential expression analysis was performed to identify differentially expressed genes (DEGs). Genes associated with AD were downloaded from the DisGeNET database. Overlapping genes among the DEGs in periodontitis and the AD-related genes were defined as crosstalk genes between periodontitis and AD. The Boruta algorithm was applied to perform feature selection from these crosstalk genes, and representative crosstalk genes were thus obtained. In addition, a support vector machine (SVM) model was constructed by using the scikit-learn algorithm in Python. Next, the crosstalk gene-TF network and crosstalk gene-DEP (differentially expressed pathway) network were each constructed. As a final step, shared genes among the crosstalk genes and periodontitis-related genes in DisGeNET were identified and denoted as the core crosstalk genes. Results. Four datasets (GSE23586, GSE16134, GSE10334, and GSE79705) pertaining to periodontitis were included in the analysis. A total of 48 representative crosstalk genes were identified by using the Boruta algorithm. Three TFs (FOS, MEF2C, and USF2) and several pathways (i.e., JAK-STAT, MAPK, NF-kappa B, and natural killer cell-mediated cytotoxicity) were identified as regulators of these crosstalk genes. Among these 48 crosstalk genes and the chronic periodontitis-related genes in DisGeNET, C4A, C4B, CXCL12, FCGR3A, IL1B, and MMP3 were shared and identified as the most pivotal candidate links between periodontitis and AD. Conclusions. Exploration of available transcriptomic datasets revealed C4A, C4B, CXCL12, FCGR3A, IL1B, and MMP3 as the top candidate molecular linkage genes between periodontitis and AD.
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Sathyakam, P. Uma, P. S. Mallick, and Paridhi Singh. "Geometry-Based Crosstalk Reduction in CNT Interconnects." Journal of Circuits, Systems and Computers 29, no. 06 (August 19, 2019): 2050094. http://dx.doi.org/10.1142/s0218126620500942.
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This paper proposes novel triangular cross-sectioned geometry of carbon nanotube (CNT) bundles for crosstalk and delay reduction in CNT bundle interconnects for VLSI circuits. First, we formulate the equivalent single conductor (ESC) transmission line models of the interconnects. Through SPICE analysis of the ESC circuits, we find the propagation delays of the proposed CNT bundles. Next, we model the capacitively coupled interconnects for crosstalk analysis. It is found that the coupling capacitance of triangular CNT bundle is 29% lesser than the traditionally used square CNT bundles. Further, the crosstalk-induced delay of triangular interconnects is found to be 30% lesser when compared to square bundle interconnects. The reduction in delay is found to increase as the number of CNTs in the bundle increases. So, we suggest that triangular CNT bundles are the most suitable candidates as global interconnects.
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von Allmen, Douglas C., Lauren J. Francey, Garrett M. Rogers, Marc D. Ruben, Aliza P. Cohen, Gang Wu, Robert E. Schmidt, et al. "Circadian Dysregulation: The Next Frontier in Obstructive Sleep Apnea Research." Otolaryngology–Head and Neck Surgery 159, no. 6 (September 11, 2018): 948–55. http://dx.doi.org/10.1177/0194599818797311.
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Objective To review the effects of the circadian clock on homeostasis, the functional interaction between the circadian clock and hypoxia-inducible factors, and the role of circadian dysregulation in the progression of cardiopulmonary disease in obstructive sleep apnea (OSA). Data Sources The MEDLINE database was accessed through PubMed. Review Methods A general review is presented on molecular pathways disrupted in OSA, circadian rhythms and the role of the circadian clock, hypoxia signaling, crosstalk between the circadian and hypoxia systems, the role of the circadian clock in cardiovascular disease, and implications for practice. Studies included in this State of the Art Review demonstrate the potential contribution of the circadian clock and hypoxia in animal models or human disease. Conclusions Molecular crosstalk between the circadian clock and hypoxia-inducible factors has not been evaluated in disease models of OSA. Implications for Practice Pediatric OSA is highly prevalent and, if left untreated, may lead to cardiopulmonary sequelae. Changes in inflammatory markers that normally demonstrate circadian rhythmicity are also seen among patients with OSA. Hypoxia-inducible transcription factors interact with core circadian clock transcription factors; however, the interplay between these pathways has not been elucidated in the cardiopulmonary system. This gap in knowledge hinders our ability to identify potential biomarkers of OSA and develop alternative therapeutic strategies. A deeper understanding of the mechanisms by which OSA impinges on clock function and the impact of clock dysregulation on the cardiopulmonary system may lead to future advancements for the care of patients with OSA. The aim of this review is to shed light on this important clinical topic.
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Liu, Yike, Xuejian Liu, Are Osen, Yu Shao, Hao Hu, and Yingcai Zheng. "Least-squares reverse time migration using controlled-order multiple reflections." GEOPHYSICS 81, no. 5 (September 2016): S347—S357. http://dx.doi.org/10.1190/geo2015-0479.1.
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Reverse time migration (RTM) using multiples generates inherent crosstalk artifacts due to the interference among multiples of different orders. We have developed a method to remove such crosstalk. This approach first separates the recorded seismic data into primary reflections and multiples using the surface-related multiples elimination algorithm and then isolates the multiples into different orders. We can take any specified, say the [Formula: see text]th, order of multiples data as the incident wave and the next higher order multiples data, ([Formula: see text])th order, as the corresponding primary reflection data for imaging. We have applied the least-squares migration scheme to these two successive orders of multiples. Our method is denoted as least-squares RTM using controlled-order multiples (LSRTM-CM). Our numerical tests demonstrated that LSRTM-CM can significantly improve imaging quality compared with straightforward seismic imaging using multiples without multiples separation.
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Peer, Elisabeth, Suzana Tesanovic, and Fritz Aberger. "Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy." Cancers 11, no. 4 (April 15, 2019): 538. http://dx.doi.org/10.3390/cancers11040538.
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The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious therapeutic approaches targeting CSC pathways, such as HH/GLI signaling in combination with chemo, radiation or immunotherapy are, therefore, of high medical need. Pharmacological inhibition of HH/GLI pathway activity represents a promising approach to eliminate malignant CSC. Clinically approved HH/GLI pathway inhibitors target the essential pathway effector Smoothened (SMO) with striking therapeutic efficacy in skin and brain cancer patients. However, multiple genetic and molecular mechanisms resulting in de novo and acquired resistance to SMO inhibitors pose major limitations to anti-HH/GLI therapies and, thus, the eradication of CSC. In this review, we summarize reasons for clinical failure of SMO inhibitors, including mechanisms caused by genetic alterations in HH pathway effectors or triggered by additional oncogenic signals activating GLI transcription factors in a noncanonical manner. We then discuss emerging novel and rationale-based approaches to overcome SMO-inhibitor resistance, focusing on pharmacological perturbations of enzymatic modifiers of GLI activity and on compounds either directly targeting oncogenic GLI factors or interfering with synergistic crosstalk signals known to boost the oncogenicity of HH/GLI signaling.
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Aldhaibani, A. O., S. A. Aljunid, Hilal A. Fadhil, and M. S. Anuar. "Increasing Capacity and Suppress the Crosstalk by Using Hybrid Optical OFDM/WDM System." Key Engineering Materials 594-595 (December 2013): 1041–44. http://dx.doi.org/10.4028/www.scientific.net/kem.594-595.1041.
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Hybrid optical OFDM/WDM system is proposed to provide longer reach and larger capacity comparing with existing PON systems in order to meet the ever increasing bandwidth demand and data rate of next generation optical access networks. In this paper, two channels using different modulation at 10 Gb/s are used for downstream link. OFDM signals occupy different portions of the available signal spectrum for signal transmissions by using WDM. As a result, the system has good performance based on SNR with 50 km distance and QAM modulation delivers better performance compared with PSK.
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Chung, Carolina H., Da-Wei Lin, Alec Eames, and Sriram Chandrasekaran. "Next-Generation Genome-Scale Metabolic Modeling through Integration of Regulatory Mechanisms." Metabolites 11, no. 9 (September 7, 2021): 606. http://dx.doi.org/10.3390/metabo11090606.
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Genome-scale metabolic models (GEMs) are powerful tools for understanding metabolism from a systems-level perspective. However, GEMs in their most basic form fail to account for cellular regulation. A diverse set of mechanisms regulate cellular metabolism, enabling organisms to respond to a wide range of conditions. This limitation of GEMs has prompted the development of new methods to integrate regulatory mechanisms, thereby enhancing the predictive capabilities and broadening the scope of GEMs. Here, we cover integrative models encompassing six types of regulatory mechanisms: transcriptional regulatory networks (TRNs), post-translational modifications (PTMs), epigenetics, protein–protein interactions and protein stability (PPIs/PS), allostery, and signaling networks. We discuss 22 integrative GEM modeling methods and how these have been used to simulate metabolic regulation during normal and pathological conditions. While these advances have been remarkable, there remains a need for comprehensive and widespread integration of regulatory constraints into GEMs. We conclude by discussing challenges in constructing GEMs with regulation and highlight areas that need to be addressed for the successful modeling of metabolic regulation. Next-generation integrative GEMs that incorporate multiple regulatory mechanisms and their crosstalk will be invaluable for discovering cell-type and disease-specific metabolic control mechanisms.
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Enguita, Francisco, Marina Costa, Ana Fusco-Almeida, Maria Mendes-Giannini, and Ana Leitão. "Transcriptomic Crosstalk between Fungal Invasive Pathogens and Their Host Cells: Opportunities and Challenges for Next-Generation Sequencing Methods." Journal of Fungi 2, no. 1 (January 14, 2016): 7. http://dx.doi.org/10.3390/jof2010007.
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Hur, Y., Moonkyun Maeng, C. Chun, F. Bien, Hyoungsoo Kim, S. Chandramouli, E. Gebara, and J. Laskar. "Equalization and near-end crosstalk (NEXT) noise cancellation for 20-Gb/s 4-PAM backplane serial I/O interconnections." IEEE Transactions on Microwave Theory and Techniques 53, no. 1 (January 2005): 246–55. http://dx.doi.org/10.1109/tmtt.2004.839311.
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Mishra, Jitendra K., B. M. A. Rahman, and Vishnu Priye. "Rectangular Array Multicore Fiber Realizing Low Crosstalk Suitable for Next-Generation Short-Reach Optical Interconnects With Low Misalignment Loss." IEEE Photonics Journal 8, no. 4 (August 2016): 1–14. http://dx.doi.org/10.1109/jphot.2016.2591002.
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Grozovsky, Renata, Cameron Fraser, Karin M. Hoffmeister, Kristopher Sarosiek, and Silvia Giannini. "Desialylation and Apoptosis Crosstalk to Modulate Platelet Clearance." Blood 134, Supplement_1 (November 13, 2019): 1055. http://dx.doi.org/10.1182/blood-2019-122184.
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Our understanding of cell biological processes involved in aging has advance greatly over the past decades. Platelets are small cells that circulate for 4-5 days in mice and 7-10 days in humans. And even though, platelets are anucleated cells, a growing body of evidence shows that platelet clearance is a well-regulated mechanism. We have recently demonstrated that platelets lose sialic acid as they circulate and age in blood and are rapidly cleared by the hepatic Ashwell-Morell receptor (AMR). And others have shown, in a series of studies using genetically modified mice or pharmacological inhibitors that platelets undergo apoptosis by triggering the intrinsic mitochondrial apoptotic machinery. Here, we investigate if desialylation and apoptosis are related events. First, using a newly developed state-of-the-art technique called dynamic BH3 profiling (DBP), we investigated the mitochondria readiness to undergo apoptosis on platelets derived from WT and AMR deficient (Asgr2-/-) mice. In our assay, digitonin-permeabilized platelets were exposed to activators signaling peptides (such as Bim, Bid and PUMA), and as cells undergo apoptosis due to peptide treatment, they released Cytochrome C. Our data showed that desialylated platelets derived from Asgr2-/-mice have high background levels of Cytochrome C release when compared to WT platelets in the presence of all activator peptides, indicating that desialylated platelets are highly primed to apoptosis. We also tested the level of dependence on pro-survival protein, by using sensitizer peptides (Bad, Hrk and MS1). We observed that desialylated platelets (Asgr2-/-platelets), and to a certain degree, WT platelets, are extremely sensitive to BCL-xL inhibition, as indicated by the extremely high response to Bad and Hrk peptides even at lower concentrations (0.1 and 1uM). Surprisingly, WT and Asgr2-/-platelets show very little response to the MS1 peptide, indicating that they are not dependent on MCL1 for survival, as otherwise suggested. Flow cytometry analysis revealed desialylated platelets from Asgr2-/-mice have a ~2-fold increase in Phosphatidylserine (PS) surface exposure when compared to WT platelets. In addition, western blot analysis showed increased expression of cleaved caspase 3 in Asgr2-/-platelets, but no changes in Bcl-xL protein expression between WT and Asgr2-/-platelets. Next, WT and Asgr2-/-mice received a single dose of the BH3 mimetic, ABT-737, which binds and inhibits pro-survivor proteins (Bcl-2, Bcl-xL and Bcl-w) inducing apoptosis in vivo. Approximately 2 hours after the injection of ABT-737, we observed a big drop on platelets counts in both WT (~42%) and Asgr2-/-(~59%) mice. Importantly, platelets from Asgr2-/-mouse were cleared more efficiently (~20%) from the circulation when compared to those in WT mice, consistent with the ~20% increment in platelet number observed in this mouse model and supporting the notion that the platelets that circulate longer in the Asgr2-/-mice are more sensitive to apoptotic events. To investigate if apoptosis could be triggering platelet desialylation, WT mice were treated with ABT-737 and 1hour later (time point before platelet count drop), platelets were collected and analyzed by flow cytometry. Interestingly, analysis of galactose exposure by RCA-I lectin showed no differences in desialylation between ABT-737 and PBS control groups. On the other hand, Phosphatidylserine (PS) exposure was significantly elevated on ABT-737 group, indicating that platelets were undergoing apoptosis without changing their sialylated status. To confirm our in vivodata, freshly isolated washed WT platelets were treated with ABT-737 to induce apoptosis or Neuraminidase (NA) to desialylated platelets. NA treatment induced platelet desialylation (increased RCA-I binding) in WT platelets, as expected, and interestingly triggered apoptosis, judge by increased PS exposure in both ABT-737 and NA treated groups. However, ABT-737 treatment wasn't able to induce desialylation as levels of RCA-I binding to platelets was the same when compared to PBS control platelets. Taken together, our data shows that desialylated platelets in circulation are prone to apoptosis. In addition, our findings strongly support the hypothesis that desialylation of platelet surface glycoproteins trigger the intrinsic apoptotic pathway in platelets in vivo. Disclosures No relevant conflicts of interest to declare.
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Tan, Mengtian, Lai Jiang, Yinglei Li, and Wei Jiang. "Dual Inhibition of BMP and WNT Signals Promotes Pancreatic Differentiation from Human Pluripotent Stem Cells." Stem Cells International 2019 (December 1, 2019): 1–15. http://dx.doi.org/10.1155/2019/5026793.
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Pathological or functional loss of pancreatic beta cells is the cause of diabetes. Understanding how signaling pathways regulate pancreatic lineage and searching for combinations of signal modulators to promote pancreatic differentiation will definitely facilitate the robust generation of functional beta cells for curing hyperglycemia. In this study, we first tested the effect of several potent BMP inhibitors on pancreatic differentiation using human embryonic stem cells. Next, we examined the endodermal lineage bias upon potent BMP inhibitor treatment and further checked the crosstalk between signal pathways governing endodermal lineage determination. Furthermore, we improved current pancreatic differentiation system based on the signaling pathway study. Finally, we used human-induced pluripotent stem cells to validate our finding. We found BMP inhibitors indeed not only blocked hepatic lineage but also impeded intestinal lineage from human definitive endoderm unexpectedly. Signaling pathway analysis indicated potent BMP inhibitor resulted in the decrease of WNT signal activity and inhibition of WNT could contribute to the improved pancreatic differentiation. Herein, we combined the dual inhibition of BMP and WNT signaling and greatly enhanced human pancreatic progenitor differentiation as well as beta cell generation from both embryonic stem cells and induced pluripotent stem cells. Conclusively, our present work identified the crosstalk between the BMP and WNT signal pathways during human endoderm patterning and pancreas specification, and provided an improved in vitro pancreatic directed differentiation protocol from human pluripotent stem cells.
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YUE, C. PATRICK, JAEJIN PARK, RUIFENG SUN, L. RICK CARLEY, and FRANK O'MAHONY. "LOW-POWER, PARALLEL INTERFACE WITH CONTINUOUS-TIME ADAPTIVE PASSIVE EQUALIZER AND CROSSTALK CANCELLATION." International Journal of High Speed Electronics and Systems 15, no. 02 (June 2005): 459–76. http://dx.doi.org/10.1142/s0129156405003260.
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This paper presents the low-power circuit techniques suitable for high-speed digital parallel interfaces each operating at over 10 Gbps. One potential application for such high-performance I/Os is the interface between the channel IC and the magnetic read head in future compact hard disk systems. First, a crosstalk cancellation technique using a novel data encoding scheme is introduced to suppress electromagnetic interference (EMI) generated by the adjacent parallel I/Os . This technique is implemented utilizing a novel 8-4-PAM signaling with a data look-ahead algorithm. The key circuit components in the high-speed interface transceiver including the receive sampler, the phase interpolator, and the transmitter output driver are described in detail. Designed in a 0.13-μm digital CMOS process, the transceiver consumes 310 mW per 10-Gps channel from a I-V supply based on simulation results. Next, a 20-Gbps continuous-time adaptive passive equalizer utilizing on-chip lumped RLC components is described. Passive equalizers offer the advantages of higher bandwidth and lower power consumption compared with conventional designs using active filter. A low-power, continuous-time servo loop is designed to automatically adjust the equalizer frequency response for the optimal gain compensation. The equalizer not only adapts to different channel characteristics, but also accommodates temperature and process variations. Implemented in a 0.25-μm, 1P6M BiCMOS process, the equalizer can compensate up to 20 dB of loss at 10 GHz while only consumes 32 mW from a 2.5-V supply.
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Ennishi, Daisuke, Fong Chun Chan, David W. Scott, Christoffer Hother, Barbara Meissner, Merrill Boyle, Ryan D. Morin, et al. "Genetic Alterations In Immune Cell Crosstalk Genes In Diffuse Large B-Cell Lymphoma Predict Survival." Blood 122, no. 21 (November 15, 2013): 500. http://dx.doi.org/10.1182/blood.v122.21.500.500.
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Abstract Background Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype accounting for ∼40% of all non-Hodgkin lymphomas. Although R-CHOP has significantly improved outcome in DLBCL, 35% of patients still experience relapsed/refractory disease. Further investigation into the genomic architecture of DLBCL is needed to determine the biological correlates that underlie treatment failure. Immune cell signatures have been shown to impact survival in DLBCL (Lenz et al, NEJM 2008). Recurrent mutations and/or copy number alterations (CNAs) in genes that impact the tumor's immune-cell crosstalk have recently been described, but their clinical impact is unknown. Moreover, mutations and copy-number loss involving genes that foster immune escape has been implicated as a dominant oncogenic mechanism in DLBCL (Challa-Malladi et al, Can Cell 2011). We sought to determine the relationship between genetic alterations involving immune-cell crosstalk pathways and survival in a cohort of DLBCL patients treated with R-CHOP. Methods Following our initial analysis of 91 whole transcriptome sequencing (RNA-seq) including 40 with whole genome sequencing, we validated SNVs in the genes of interest by Sanger sequencing in the tumor and matched germline DNAs if available. RNA-seq-derived gene expression data were also used to determine the cell of origin (COO) distinction. Affymetrix SNP 6.0 microarrays were used to ascertain the CNAs in all 91 DLBCL samples. Clinical outcome correlations were analyzed by Cox regression and the log-rank test in the 82 patients treated with R-CHOP (median follow-up; 82 months). Results Using next-generation sequencing, we identified 97 SNVs in 16 genes (B2M, CD274, CD276, CD58, CD83, CIITA, NLRC4, NLRC5, RFXAP, RFXANK, TNFRSF14, TNFRSF25, TNFSF9, TAP1, TAP2 and TAPBP) that were selected based on an extensive literature review implicating these genes in immune-cell crosstalk pathways in DLBCL. Among them, eight genes were mutated in more than one case including B2M (7%), CD58 (7%), TNFRSF14 (7%), CIITA (4%), TNFSF9 (2%), NLRC5 (3%), CD83 (11%), and RFXAP (2%). These eight loci were further analyzed for CNAs, gene expression and outcome correlations. SNP 6.0 microarrays revealed either focal heterozygous or homozygous deletions in B2M (22%), CD58 (14%), TNFSF9 (10%), and heterozygous deletions in TNFRSF14 (12%), CIITA (3%), NLRC5 (7%), CD83 (2%), and RFXAP (7%). Amongst the 91 cases, 35 cases (38%) had no genetic aberration. 56 cases (62%) had at least one aberration, while 29 (32%) had multiple genetic aberrations indicating that genetic aberrations associated with immune-cell crosstalk are not mutually exclusive in DLBCL. Mutations and CNAs were not COO specific, with the exception of TNFRSF14, which was significantly restricted to the GCB-subtype (p=0.001). We evaluated outcome correlations for each genetic aberrations in the 82 cases with uniform therapy, including two recognized major histocompatibility class (MHC) groups; MHC class I (B2M and NLRC5) and MHC class II (CIITA, RFXAP and CD83). In univariate analysis, the presence of genetic aberrations in the MHCI group and NLRC5 individually were prognostic (5yr PFS, 59% vs 78%, p=0.025, 44% vs 77%, p=0.005, respectively), but not the MHCII group or other individual loci. In subgroup analyses according to COO, both MHCI and MHCII genetic aberrations were associated with inferior 5yr PFS in the ABC subtype (MHCI, 27% vs 79%, p<0.0001) (MHCII, 40% vs 68%, p=0.018), but not in GCB. We next assessed the prognostic impact of the total number of genetic hits and revealed that patients with at least one genetic hit had a 5yr OS and PFS of 65% and 57%, respectively, while those with no genetic hit had a 5yr OS and PFS of 100% and 97%, respectively (both comparisons, p<0.0001). In a Cox model of PFS including IPI and COO, any genetic hit in immune-cell crosstalk pathways remained strongly predictive (HR=15.1 [2.0-113.2], p= 0.008) and was independent of both IPI (HR= 2.1 [1.1-4.0], p= 0.030) and COO (HR= 0.6 [0.3-1.4], p=0.26). Conclusions Recurrent genetic alterations involving genes related to immune-cell crosstalk in DLBCL are frequent (56%), co-occur and independently contribute to outcome in patients treated with R-CHOP. MHCI and MHCII perturbations are only prognostic in the ABC subtype. Disclosures: No relevant conflicts of interest to declare.
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Maulana, Yudi Yuliyus, and Dadin Mahmudin. "Design of 3-stages Parallel Cascade Micro-ring Resonator Type of Interleave Filter for Optical Communication Application." Jurnal Elektronika dan Telekomunikasi 15, no. 2 (June 29, 2016): 66. http://dx.doi.org/10.14203/jet.v15.66-70.
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Filter will be one of the most important components of the next generation of optical communications. Micro-ring resonators have been widely studied as a potential device for dense wavelength filter due to its advantages. In this paper, a waveguide-based microring-resonator type of interleave filter is investigated. The cascade structure is applied to obtain better characteristics of filter spectra. Our calculation shows that, compared with 2-stage or 4-stage cascade, 3-stage cascaded microring resonator has better performance with pass-band width of 22 GHz, ripple ratio < 1 dB, crosstalk of -33 dB for 1×2 interleaver and -24 dB for 1×4 interleaver. Numerical calculation also clearly shows that general optical waveguide types is reasonable as microring resonator with insertion loss < 2 dB
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Broberg, Martin, Johanna Hästbacka, and Emmi Helle. "From Stem Cells to Populations—Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects." Genes 12, no. 6 (June 16, 2021): 921. http://dx.doi.org/10.3390/genes12060921.
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Congenital heart defects (CHD) are developmental malformations affecting the heart and the great vessels. Early heart development requires temporally regulated crosstalk between multiple cell types, signaling pathways, and mechanical forces of early blood flow. While both genetic and environmental factors have been recognized to be involved, identifying causal genes in non-syndromic CHD has been difficult. While variants following Mendelian inheritance have been identified by linkage analysis in a few families with multiple affected members, the inheritance pattern in most familial cases is complex, with reduced penetrance and variable expressivity. Furthermore, most non-syndromic CHD are sporadic. Improved sequencing technologies and large biobank collections have enabled genome-wide association studies (GWAS) in non-syndromic CHD. The ability to generate human to create human induced pluripotent stem cells (hiPSC) and further differentiate them to organotypic cells enables further exploration of genotype–phenotype correlations in patient-derived cells. Here we review how these technologies can be used in unraveling the genetics and molecular mechanisms of heart development.
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Calender, Alain, Thomas Weichhart, Dominique Valeyre, and Yves Pacheco. "Current Insights in Genetics of Sarcoidosis: Functional and Clinical Impacts." Journal of Clinical Medicine 9, no. 8 (August 13, 2020): 2633. http://dx.doi.org/10.3390/jcm9082633.
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Sarcoidosis is a complex disease that belongs to the vast group of autoinflammatory disorders, but the etiological mechanisms of which are not known. At the crosstalk of environmental, infectious, and genetic factors, sarcoidosis is a multifactorial disease that requires a multidisciplinary approach for which genetic research, in particular, next generation sequencing (NGS) tools, has made it possible to identify new pathways and propose mechanistic hypotheses. Codified treatments for the disease cannot always respond to the most progressive forms and the identification of new genetic and metabolic tracks is a challenge for the future management of the most severe patients. Here, we review the current knowledge regarding the genes identified by both genome wide association studies (GWAS) and whole exome sequencing (WES), as well the connection of these pathways with the current research on sarcoidosis immune-related disorders.
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Giménez-Llort, L., EK Oghagbon, F. Dogo, M. Ogiator, and J. Prieto-Pino. "438 - Nigerian women are more susceptible to the impact of diabetes-and-dementia: State-of-art, Future perspectives and Directions." International Psychogeriatrics 32, S1 (October 2020): 156. http://dx.doi.org/10.1017/s1041610220002902.
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Among the preventable complications of diseases that require urgent effective health literacy programs in sub-Saharan Africa, crosstalk between diabetes and dementia stands out for women's health. Type 2 diabetes mellitus (DM2) in midlife is a recognised risk factor for dementia. This crosstalk is more significant in persons of African ancestry. Globally, the prevalence of DM will increase dramatically in the next few years with 75% of cases living in low-to-middle-income countries. Some major risk factors for DM2 accelerates the development of dementia in Africa-Americans, thus leading to higher prevalence of dementia compared to Caucasians. It is known that 58% of the global 46.8 million dementia subjects lives in economically developing countries. This proportion may reach 63% and 68% in 12 and 32 years' time, respectively. Females are 1.5 times likely to develop dementia, but sub-Saharan Africa women have a disproportionately two-to-eight fold increased dementia risk. In the eye of this storm is Nigeria which is home to the highest number of diabetics in Africa. Diabetes prevalence in the country is rising parallel to increased incidence of obesity, hypertension and rising population age. The socioeconomic impact of increasing prevalence of DM2 and dementia will be unsustainable for Nigeria healthcare system, given the experiences in developed economies. This study analyses the current situation of women's health in Nigeria, and explore future policy directions. The complex interplay of factors involved in the DM2-dementia crosstalk in Nigerian women include those due to biological processes (metabolic syndrome, vascular damage, inflammation, oxidative stress, insulin resistance and anaemia), nutritional habits and sedentary lifestyles. Other factors that predisposes Nigerian diabetic women to dementia are, restricted resources, lack of visibility and poor health management. They add up to increase the burden of disease in the Nigerian woman, irrespective of age. We advise urgent implementation of heath policies and actions that will increase ratio of mental health professionals / number of patients, especially in rural areas and the establishment of proactive primary healthcare centres. Importantly, interventions targeting adolescents and adult women, and others specific to mother- child interactions, are strongly needed in Nigeria and the sub-region for mitigating dementia in women.
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Guo, Xiangzhou, Muhammad Asif, Anyong Hu, Zhiping Li, and Jungang Miao. "A 1-GHz 64-Channel Cross-Correlation System for Real-Time Interferometric Aperture Synthesis Imaging." Sensors 19, no. 7 (April 11, 2019): 1739. http://dx.doi.org/10.3390/s19071739.
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We present a 64-channel 1-bit/2-level cross-correlation system for a passive millimeter wave imager used for indoor human body security screening. Sixty-four commercial comparators are used to perform 1-bit analog-to-digital conversion, and a Field Programmable Gate Array (FPGA) is used to perform the cross-correlation processing. This system can handle 2016 cross-correlations at the sample frequency of 1GHz, and its power consumption is 48.75 W. The data readout interface makes it possible to read earlier data while simultaneously performing the next correlation when imaging at video rate. The longest integration time is up to 68.7 s, which can satisfy the requirements of video rate imaging and system calibration. The measured crosstalk between neighboring channels is less than 0.068%, and the stability is longer than 10 s. A correlation efficiency greater than 96% is achieved for input signal levels greater than −25 dBm.
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McKinsey, Timothy A., Thomas M. Vondriska, and Yibin Wang. "Epigenomic regulation of heart failure: integrating histone marks, long noncoding RNAs, and chromatin architecture." F1000Research 7 (October 29, 2018): 1713. http://dx.doi.org/10.12688/f1000research.15797.1.
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Epigenetic processes are known to have powerful roles in organ development across biology. It has recently been found that some of the chromatin modulatory machinery essential for proper development plays a previously unappreciated role in the pathogenesis of cardiac disease in adults. Investigations using genetic and pharmacologic gain- and loss-of-function approaches have interrogated the function of distinct epigenetic regulators, while the increased deployment of the suite of next-generation sequencing technologies have fundamentally altered our understanding of the genomic targets of these chromatin modifiers. Here, we review recent developments in basic and translational research that have provided tantalizing clues that may be used to unlock the therapeutic potential of the epigenome in heart failure. Additionally, we provide a hypothesis to explain how signal-induced crosstalk between histone tail modifications and long non-coding RNAs triggers chromatin architectural remodeling and culminates in cardiac hypertrophy and fibrosis.
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Jakopin and Corsini. "THP-1 Cells and Pro-inflammatory Cytokine Production: An in Vitro Tool for Functional Characterization of NOD1/NOD2 Antagonists." International Journal of Molecular Sciences 20, no. 17 (August 30, 2019): 4265. http://dx.doi.org/10.3390/ijms20174265.
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THP-1 cells express high levels of native functional nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptor 4 (TLR4) receptors, and have often been used for investigating the immunomodulatory effects of small molecules. We postulated that they would represent an ideal cell-based model for our study, the aim of which was to develop a new in vitro tool for functional characterization of NOD antagonists. NOD antagonists were initially screened for their effect on NOD agonist-induced interleukin-8 (IL-8) release. Next, we examined the extent to which the selected NOD antagonists block the NOD-TLR4 synergistic crosstalk by measuring the effect of NOD antagonism on tumor necrosis factor-α (TNF-α) secretion from doubly activated THP-1 cells. Overall, the results obtained indicate that pro-inflammatory cytokine secretion from THP-1 provides a valuable, simple and reproducible in vitro tool for functional characterization of NOD antagonists.
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de la Cruz-Merino, Luis, Marylène Lejeune, Esteban Nogales Fernández, Fernando Henao Carrasco, Ana Grueso López, Ana Illescas Vacas, Mariano Provencio Pulla, Cristina Callau, and Tomás Álvaro. "Role of Immune Escape Mechanisms in Hodgkin's Lymphoma Development and Progression: A Whole New World with Therapeutic Implications." Clinical and Developmental Immunology 2012 (2012): 1–24. http://dx.doi.org/10.1155/2012/756353.
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Hodgkin's lymphoma represents one of the most frequent lymphoproliferative syndromes, especially in young population. Although HL is considered one of the most curable tumors, a sizeable fraction of patients recur after successful upfront treatment or, less commonly, are primarily resistant. This work tries to summarize the data on clinical, histological, pathological, and biological factors in HL, with special emphasis on the improvement of prognosis and their impact on therapeutical strategies. The recent advances in our understanding of HL biology and immunology show that infiltrated immune cells and cytokines in the tumoral microenvironment may play different functions that seem tightly related with clinical outcomes. Strategies aimed at interfering with the crosstalk between tumoral Reed-Sternberg cells and their cellular partners have been taken into account in the development of new immunotherapies that target different cell components of HL microenvironment. This new knowledge will probably translate into a change in the antineoplastic treatments in HL in the next future and hopefully will increase the curability rates of this disease.
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Patil, Ashwini M., Stefanie Kesper, Vishal Khairnar, Marco Luciani, Michael Möllmann, Ulrich Dührsen, and Joachim R. Göthert. "A CXCL10/CXCR3 Driven Thymic Epithelium-Leukemia Cell Crosstalk Augments T Cell Acute Lymphoblastic Leukemia Notch1 Signalling." Blood 134, Supplement_1 (November 13, 2019): 2537. http://dx.doi.org/10.1182/blood-2019-125331.
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Introduction: The thymus is a specialized hematopoietic organ, which is responsible for the generation of T cells. The central thymic cell type controlling T cell development are thymic epithelial cells (TECs). Based on their specific function and anatomic location TECs are separated into cortical and medullary subsets (cTECs and mTECs). cTECs express pivotal NOTCH-ligands such as DLL4 controlling T cell lineage commitment while mTECs play a central role in negative selection of developing T cells. Acquisition of NOTCH1 gain-of-function mutations play a central role in acute T cell lymphoblastic leukemia (T-ALL) development. During T-ALL leukemogenesis aberrant expression of transcription factors such as SCL/TAL1 and LMO1 block T cell differentiation and increase self-renewal while NOTCH1 mutations promote survival and proliferation. Since most acquired NOTCH1 mutations still require ligand binding to exert augmented signaling we propose DLL4-expressing TECs playing a critical role during T-ALL leukemogenesis. Methods: In the present study, we used a Scl/Lmo1 T-ALL transgenic mouse model, murine ANV and TE71 TEC cell lines and human T-ALL cell lines (Jurkat, ALL-SIL, DND-41, and HPB-ALL) to investigate TEC dynamics and function in the T-ALL context. Results: First, we demonstrated T-ALL supporting potential of TEC cell lines in vitro, which was comparable to the mesenchymal cell line OP9. Next, we showed in the Scl/Lmo1 T-ALL mouse model which had a mean survival rate of 90 days that preleukemic thymocytes displayed a striking upregulation of Notch1 target genes. Interestingly, fluorescence microscopy revealed a relative expansion of cortical and a relative reduction of the medullary thymic areas in Scl/Lmo1 thymi (Fig. 1A). Correspondingly, absolute numbers of cTECs expanded while mTEC numbers declined (Fig. 1B). Gene expression profiling of sorted preleukemic Scl/Lmo1 cTECs revealed upregulation of the chemokine CXCL10 (Fig. 1C). Moreover, increased CXCL10 chemokine concentrations were detected in Scl/Lmo1 thymic interstitial fluid (Fig.1D). Strikingly, we demonstrated T-ALL dependence of TEC Cxcl10 upregulation. We showed that Cxcl10 upregulation in TEC cell lines was only induced by direct cellular contact with Scl/Lmo1 thymocytes while wild-type control thymocytes did not alter TEC cell line Cxcl10 expression (Fig. 1E). Next, a high proportion of the CXCL10 receptor CXCR3 expressing cells was revealed in Scl/Lmo1 thymi (Fig. 1F) and by human T-ALL cell lines. Finally, we demonstrated a CXCL10 dependent pro-survival effect within cultured SCL/LMO1 thymocytes (Fig. 1G), which was associated with the activation of NOTCH1 signaling (Fig. 1H). Conclusions: In summary, the data support a novel T-ALL-promoting regulatory circuit in which emerging T-ALL lymphoblasts induce CXCL10 in expanding TECs which positively feeds back to T-ALL cells via the CXCL10 receptor CXCR3. Disclosures Dührsen: Celgene: Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Teva: Honoraria; Novartis: Consultancy, Honoraria; Alexion: Honoraria; Roche: Honoraria, Research Funding; CPT: Consultancy, Honoraria; Janssen: Honoraria. Göthert:Proteros Biostructures: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Other: Travel support; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel support; AOP Orphan Pharmaceuticals: Honoraria, Other: Travel support.
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Magarò, Maria Sara, Jessika Bertacchini, Francesca Florio, Manuela Zavatti, Francesco Potì, Francesco Cavani, Emanuela Amore, et al. "Identification of Sclerostin as a Putative New Myokine Involved in the Muscle-to-Bone Crosstalk." Biomedicines 9, no. 1 (January 12, 2021): 71. http://dx.doi.org/10.3390/biomedicines9010071.
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Bone and muscle have been recognized as endocrine organs since they produce and secrete “hormone-like factors” that can mutually influence each other and other tissues, giving rise to a “bone–muscle crosstalk”. In our study, we made use of myogenic (C2C12 cells) and osteogenic (2T3 cells) cell lines to investigate the effects of muscle cell-produced factors on the maturation process of osteoblasts. We found that the myogenic medium has inhibitory effects on bone cell differentiation and we identified sclerostin as one of the myokines produced by muscle cells. Sclerostin is a secreted glycoprotein reportedly expressed by bone/cartilage cells and is considered a negative regulator of bone growth due to its role as an antagonist of the Wnt/β-catenin pathway. Given the inhibitory role of sclerostin in bone, we analyzed its expression by muscle cells and how it affects bone formation and homeostasis. Firstly, we characterized and quantified sclerostin synthesis by a myoblast cell line (C2C12) and by murine primary muscle cells by Western blotting, real-time PCR, immunofluorescence, and ELISA assay. Next, we investigated in vivo production of sclerostin in distinct muscle groups with different metabolic and mechanical loading characteristics. This analysis was done in mice of different ages (6 weeks, 5 and 18 months after birth) and revealed that sclerostin expression is dynamically modulated in a muscle-specific way during the lifespan. Finally, we transiently expressed sclerostin in the hind limb muscles of young mice (2 weeks of age) via in vivo electro-transfer of a plasmid containing the SOST gene in order to investigate the effects of muscle-specific overproduction of the protein. Our data disclosed an inhibitory role of the muscular sclerostin on the bones adjacent to the electroporated muscles. This observation suggests that sclerostin released by skeletal muscle might synergistically interact with osseous sclerostin and potentiate negative regulation of osteogenesis possibly by acting in a paracrine/local fashion. Our data point out a role for muscle as a new source of sclerostin.
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Koudoufio, Mireille, Yves Desjardins, Francis Feldman, Schohraya Spahis, Edgard Delvin, and Emile Levy. "Insight into Polyphenol and Gut Microbiota Crosstalk: Are Their Metabolites the Key to Understand Protective Effects against Metabolic Disorders?" Antioxidants 9, no. 10 (October 13, 2020): 982. http://dx.doi.org/10.3390/antiox9100982.
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Lifestyle factors, especially diet and nutrition, are currently regarded as essential avenues to decrease modern-day cardiometabolic disorders (CMD), including obesity, metabolic syndrome, type 2 diabetes, and atherosclerosis. Many groups around the world attribute these trends, at least partially, to bioactive plant polyphenols given their anti-oxidant and anti-inflammatory actions. In fact, polyphenols can prevent or reverse the progression of disease processes through many distinct mechanisms. In particular, the crosstalk between polyphenols and gut microbiota, recently unveiled thanks to DNA-based tools and next generation sequencing, unravelled the central regulatory role of dietary polyphenols and their intestinal micro-ecology metabolites on the host energy metabolism and related illnesses. The objectives of this review are to: (1) provide an understanding of classification, structure, and bioavailability of dietary polyphenols; (2) underline their metabolism by gut microbiota; (3) highlight their prebiotic effects on microflora; (4) discuss the multifaceted roles of their metabolites in CMD while shedding light on the mechanisms of action; and (5) underscore their ability to initiate host epigenetic regulation. In sum, the review clearly documents whether dietary polyphenols and micro-ecology favorably interact to promote multiple physiological functions on human organism.
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Favreau, Mérédis, Eline Menu, Karin Vanderkerken, Sylvia Faict, Ken Maes, Els Van Valckenborgh, Elke De Bruyne, et al. "The Crosstalk Between Leptin Receptor Activation and iNKT Mediated Anti-Tumor Immunity in Multiple Myeloma." Blood 128, no. 22 (December 2, 2016): 2075. http://dx.doi.org/10.1182/blood.v128.22.2075.2075.
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Abstract In recent years, researchers have showed a growing interest in the mechanistic relationship between bone marrow adipose tissue and adjacent tumors. However, the impact of bone marrow adipocytes on development of hematological malignancies, particularly multiple myeloma is unknown. With aging, bone marrow changes occur and fatty deposits can occupy up to 70% of the BM cavity. Interactions of bone marrow adipose tissue with bone cells and other immune cells, possibly suggest indirect ways in which bone marrow adipocytes may affect MM disease progression. Leptin, an adipokine released by adipocytes and crucial in energy homeostasis, displays immune modulatory properties but its role in anti-tumor immunity remains unclear. In this study we aimed to investigate the intriguing relationship between leptin receptor activation and invariant natural killer T (iNKT) cell mediated anti-tumor immunity in multiple myeloma. The murine immunocompetent 5T33MM model, mimicking the human disease closely, and human samples of newly diagnosed patients were used to investigate this research topic. A marked increase in serum leptin levels and an upregulation of the leptin receptor expression on iNKT cells was observed in multiple myeloma, in both mice and newly diagnosed patients. In vitro functional analysis demonstrated a direct role for leptin in the downmodulation of the iNKT cell function and an indirect role by acting on the MM cells itself, potentiating the immunosuppressive effect on iNKT cells. We next evaluated the in vivo effects of blocking the leptin receptor together with activating iNKT cells with the prototypic glycolipid a-galactosylceramide (a-GalCer), in the 5T33 myeloma model. Remarkably, strong protection was seen in the combined regimen (a-GalCer and leptin receptor blockade), which was found to be linked to an amplified and sustained activation of iNKT cells, preventing them to become hypoactive. These findings suggest that leptin has a crucial immune suppressive role in myeloma development. Overall, our data reveal the leptin receptor axis as a novel target to treat multiple myeloma. Disclosures Leleu: TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria.
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Zheng, Hong, Bai-Hui Li, Chang Liu, Li Jia, and Feng-Ting Liu. "Comprehensive Analysis of lncRNA-Mediated ceRNA Crosstalk and Identification of Prognostic Biomarkers in Wilms’ Tumor." BioMed Research International 2020 (February 22, 2020): 1–13. http://dx.doi.org/10.1155/2020/4951692.
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Wilms’ tumor (WT) is the most common type of childhood kidney cancer, and most cases present with favorable histology and respond well to standard treatment. However, a subset of patients with WT is diagnosed with bilateral, relapsed, and high-risk tumors which remain the leading cause of cancer-related death in children. Long noncoding RNAs (lncRNAs) and their aberrant expression have currently been attracting great attention as oncogenes or tumor suppressors during tumor initiation and progression. So far, their roles and related competitive endogenous RNA (ceRNA) network remain unelucidated in nephroblastoma pathogenesis. We comprehensively integrated lncRNA, microRNA (miRNA), and messenger RNA (mRNA) expression profiles from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and screened out differentially expressed mRNAs (DEMs), lncRNAs (DELs), and miRNAs (DEMis) to construct a ceRNA network based on the information generated from miRcode, miRTarBase, TargetScan, and miRDB. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to analyze the functional characteristics of DEMs in the ceRNA network. The interaction between protein molecules was also analyzed by establishing a protein-protein interaction network. Finally, prognosis-related biomarkers were identified via survival analysis. Initially, 1647 DELs, 115 DEMis, and 3280 DEMs (|log FC| > 2; FDR < 0.01) were obtained using the R package. Next, we constructed a lncRNA-miRNA-mRNA network (ceRNA network), in which 176 DELs, 24 DEMis, and 141 DEMs were identified. Furthermore, 148 functional enrichment terms from GO were identified and 29 KEGG pathways were found to be significantly enriched. We also integrated patient clinical information to analyze the association between DERNAs and patient prognosis. We found that high expression of 8 DELs (LINC00473, AL445228.2, DENND5B−AS1, DLEU2, AC123595.1, AC135178.1, LINC00535, and LMO7−AS1) and 4 DEMs (CEP55, DEPDC1, PHF19, and TRIM36) correlated with poor survival in a patient with WT, whereas high expression of 2 DELs (MEG3 and RMST), 1 DEM (KIAA0922), and 1 DEMi (hsa−mir−200a) could possibly lead to better clinical outcomes. For the first time, the present study provided a novel insight into lncRNA-related ceRNA networks and identified potential prognostic biomarkers in Wilms’ tumor.
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Nambara, Eiji, Masanori Okamoto, Kiyoshi Tatematsu, Ryoichi Yano, Mitsunori Seo, and Yuji Kamiya. "Abscisic acid and the control of seed dormancy and germination." Seed Science Research 20, no. 2 (February 5, 2010): 55–67. http://dx.doi.org/10.1017/s0960258510000012.
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AbstractAbscisic acid (ABA) is a plant hormone that regulates seed dormancy and germination. Seeds undergo changes in both ABA content and sensitivity during seed development and germination in response to internal and external cues. Recent advances in functional genomics have revealed the integral components involved in ABA metabolism (biosynthesis and catabolism) and perception, the core signalling pathway, as well as the factors that trigger ABA-mediated transcription. These allow for comparative studies to be conducted on seeds under different environmental conditions and from different genetic backgrounds. This review summarizes our understanding of the control of ABA content and the responsiveness of seeds to afterripening, light, high temperature and nitrate, with a focus on which tissues are involved in its metabolism and signalling. Also described are the regulators of ABA metabolism and signalling, which potentially act as the node for hormone crosstalk. Integration of such knowledge into the complex and diverse events occurring during seed germination will be the next challenge, which will allow for a clearer understanding of the role of ABA.
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Zubcevic, Jasenka, Elaine M. Richards, Tao Yang, Seungbum Kim, Colin Sumners, Carl J. Pepine, and Mohan K. Raizada. "Impaired Autonomic Nervous System-Microbiome Circuit in Hypertension." Circulation Research 125, no. 1 (June 21, 2019): 104–16. http://dx.doi.org/10.1161/circresaha.119.313965.
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Hypertension affects an estimated 103 million Americans, yet gaps in knowledge continue to limit its successful management. Rapidly emerging evidence is linking gut dysbiosis to many disorders and diseases including hypertension. The evolution of the -omics techniques has allowed determination of the abundance and potential function of gut bacterial species by next-generation bacterial sequencing, whereas metabolomics techniques report shifts in bacterial metabolites in the systemic circulation of hypertensive patients and rodent models of hypertension. The gut microbiome and host have evolved to exist in balance and cooperation, and there is extensive crosstalk between the 2 to maintain this balance, including during regulation of blood pressure. However, an understanding of the mechanisms of dysfunctional host-microbiome interactions in hypertension is still lacking. Here, we synthesize some of our recent data with published reports and present concepts and a rationale for our emerging hypothesis of a dysfunctional gut-brain axis in hypertension. Hopefully, this new information will improve the understanding of hypertension and help to address some of these knowledge gaps.
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Xu, Chong, Guo Dong Liu, Le Feng, Cong Hui Zhang, and Fang Wang. "Identification of O-GlcNAcylation Modification in Diabetic Retinopathy and Crosstalk with Phosphorylation of STAT3 in Retina Vascular Endothelium Cells." Cellular Physiology and Biochemistry 49, no. 4 (2018): 1389–402. http://dx.doi.org/10.1159/000493444.
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Background/Aims: Recently, we observed an increase in O-GlcNAc (O-linked-ß-N-acetylglucosamine) modification, and signal transducer and activator of transcription proteins 3 (STAT3) expression in primary retinal vascular endothelial cells (RVECs) under high glucose conditions and tissues altered by diabetic retinopathy (DR). In this study, we focused on the correlations between O-GlcNAcylation and STAT3 phosphorylation, and their potential effects with regards to DR. Methods: Expression of O-GlcNAcylation and STAT3 were detected in DR-affected tissues and primary RVECs. The relationship between O-GlcNAcylation and STAT3 was further delineated by immunoprecipitation and Western blot analysis. Effects of O-GlcNAcylation on human RVEC apoptosis and involved protein expression were assayed with flow cytometry and Western blot. Results: Global O-GlcNAcylation and pSTAT3 levels were significantly elevated in diabetic rat retina and primary RVECs under high glucose conditions. In vitro assays demonstrated that the Tyr705 site was sensitive to high glucose. While O-GlcNAcylation inhibited p727STAT3 expression, augmented O-GlcNAcylation could balance p705STAT3 expression within relatively high levels corresponding to vascular endothelial growth factor (VEGF) changes. Immunoprecipitation revealed that STAT3 was modified by O-GlcNAcylation and phosphorylation simultaneously. Next, we observed that overexpression of O-GlcNAcylation could relieve human RVEC apoptosis related to the JAK2-Tyr705STAT3-VEGF pathway. Conclusion: O-GlcNAcylation could relieve RVECs apoptosis through the STAT3 pathway in DR, and O-GlcNAcylation combined with STAT3 phosphorylation might open up new insights into the mechanisms of DR and other diabetic complications.
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Pandian, Balaji Aravindhan, Rajendran Sathishraj, Maduraimuthu Djanaguiraman, P. V. Vara Prasad, and Mithila Jugulam. "Role of Cytochrome P450 Enzymes in Plant Stress Response." Antioxidants 9, no. 5 (May 25, 2020): 454. http://dx.doi.org/10.3390/antiox9050454.
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Cytochrome P450s (CYPs) are the largest enzyme family involved in NADPH- and/or O2-dependent hydroxylation reactions across all the domains of life. In plants and animals, CYPs play a central role in the detoxification of xenobiotics. In addition to this function, CYPs act as versatile catalysts and play a crucial role in the biosynthesis of secondary metabolites, antioxidants, and phytohormones in higher plants. The molecular and biochemical processes catalyzed by CYPs have been well characterized, however, the relationship between the biochemical process catalyzed by CYPs and its effect on several plant functions was not well established. The advent of next-generation sequencing opened new avenues to unravel the involvement of CYPs in several plant functions such as plant stress response. The expression of several CYP genes are regulated in response to environmental stresses, and they also play a prominent role in the crosstalk between abiotic and biotic stress responses. CYPs have an enormous potential to be used as a candidate for engineering crop species resilient to biotic and abiotic stresses. The objective of this review is to summarize the latest research on the role of CYPs in plant stress response.
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Tarte, Karin. "Role of the microenvironment across histological subtypes of NHL." Hematology 2017, no. 1 (December 8, 2017): 610–17. http://dx.doi.org/10.1182/asheducation-2017.1.610.
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AbstractRecent progress in next-generation sequencing strategies has revealed the genetic landscape of B-cell non-Hodgkin lymphoma, but the tumor microenvironment is increasingly recognized as crucial to sustaining malignant B-cell survival and growth, subclonal evolution, and drug resistance. The tumor niche is made up of a dynamic and organized network of strongly heterogeneous immune and stromal cell subsets characterized by specific phenotypic, transcriptomic, and functional features. Nonmalignant cell recruitment and plasticity are dictated by lymphoma B cells, which convert their surrounding microenvironment into a supportive niche. In addition, they are also influenced by the crosstalk between the various components of this niche. In agreement with this, the B-cell lymphoma subtype is a key determinant of the organization of the tumor niche, but genetic alteration patterns, tumor localization, stage of the disease, and treatment strategy may also modulate its composition and activity. Moreover, the complex set of bidirectional interactions between B cells and their microenvironment has been proposed as a promising therapeutic target with the aim of reinforcing antitumor immunity and/or of abbrogating the lymphoma-promoting signals delivered by the tumor niche.
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Hwang, K. A., S. H. Kim, and K. C. Choi. "125 BISPHENOL A-INDUCED GROWTH OF OVARIAN CANCER CELLS WAS REVERSED BY A PHYTOESTROGEN, GENISTEIN, BY INHIBITION OF A CROSSTALK BETWEEN ESTROGEN RECEPTOR AND INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR IN IN VITRO AND XENOGRAFT MOUSE MODELS." Reproduction, Fertility and Development 26, no. 1 (2014): 176. http://dx.doi.org/10.1071/rdv26n1ab125.
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It has been shown that oestrogen (E2) up-regulated the expression of components of insulin-like growth factor-1 (IGF-1) signaling pathway and induced the downstream of mitogenic signaling cascades via phosphorylation of insulin receptor substrate-1 (IRS-1). An interaction between oestrogen receptor (ER) and IGF-1 receptor (IGF-1R) signaling pathway plays an important role in proliferation of and resistance to endocrine therapy to oestrogen-dependent cancers (i.e. breast and endometrial cancers). In the present study, we evaluated xenoestrogenic effect of bisphenol A (BPA) and antiproliferative activity of genistein (GEN) in accordance with the influence on this crosstalk. The gene expressions in mRNA and protein levels were examined by semiquantitative RT-PCR and Western blot analysis, in which the primers for ERα, IGF-1R, and GAPDH and the antibodies against pIRS-1, pAkt, and GAPDH were used, respectively. Total RNA and protein samples were isolated from BG-1 cells treated with dimethyl sulfoxide (DMSO), estradiol (E2; 10–9 M), BPA (10–5 M), E2 (10–9 M) + GEN (10–4 M), and BPA (10–5 M) + GEN (10–4 M). The DMSO was used a vehicle of E2, BPA, and GEN in in vitro experiments. All in vitro experiments were done in triplicates. The effects on tumour growth and immunohistologic alterations were identified in in vivo mouse models. The mice were injected subcutaneously with corn oil (vehicle, n = 6), E2 (n = 6), BPA (n = 6), E2+GEN (n = 6), and BPA+GEN (n = 6) for 8 weeks. The BPA treatment resulted in up-regulation of ERα and IGF-1R mRNA, and induced phosphorylation of IRS-1 and Akt proteins compared with a control (DMSO) in BG-1 ovarian cancer cells as E2 did in triplicates. In the mouse model xenografted with BG-1 cells, BPA significantly increased a tumour burden of mice and expressions of ERα, pIRS-1, and cyclin D1 in tumour mass compared with the vehicle (corn oil), indicating that BPA induces ovarian cancer growth by promoting the crosstalk between ER and IGF-1R signals. On the other hand, GEN effectively reversed estrogenicity of BPA by reversing mRNA and protein expressions of ERα, IGF-1R, pIRS-1, and pAkt induced by BPA in cellular model with triplicates. The GEN also significantly decreased tumour growth and in vivo expressions of ERα, pIRS-1, and pAkt in a xenografted mouse model. Also, GEN was confirmed to have an antiproliferative effect by inducing apoptotic signaling cascades. Taken together, these results suggest that GEN effectively reversed the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ER and IGF-1R signaling pathways up-regulated by BPA or E2. This work was supported by a grant from the Next-Generation BioGreen 21 Program (No. PJ009599), Rural Development Administration, Republic of Korea.
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Brandao, Joana G., Joao T. Barata, Raquel Nunes, Lee M. Nadler, and Angelo A. Cardoso. "Crosstalk between Breast Cancer Cells and Bone Marrow Endothelium Require the Engagement of PI3K/AKT Signaling." Blood 104, no. 11 (November 16, 2004): 1299. http://dx.doi.org/10.1182/blood.v104.11.1299.1299.
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Abstract The presence of breast cancer cells in the patient’s bone marrow (BM) at diagnosis is associated with resistance to treatment, disease relapse and poor prognosis. Identification of the factors implicated in the homing, survival and latency of breast cancer cells in the BM should contribute to the design of more efficient therapeutic strategies for breast cancer. There is evidence that breast cancer can recruit endothelial progenitors from the BM. Also, other epithelial tumors seem to preferentially adhere to BM endothelial cells. Therefore, we hypothesized that BM endothelium may play a significant role in the biology of breast cancer cells residing in the BM. Co-cultures in Matrigel showed that breast cancer cells interact with BM endothelium to form heterotypic multicellular networks. Moreover, breast cancer cells migrate towards BM endothelium assembled as capillary-like structures, but not to structures of BM mesenchymal stem cells or BM stroma. This migration was abrogated by pertussis toxin-mediated blockade of chemokine receptor signaling, suggesting the involvement of endothelium-secreted chemokine(s). We then evaluated the impact of breast cancer cells in the survival and proliferation of BM endothelium. All breast cancer lines tested (n=4) promoted the proliferation of BM-derived endothelial cells. This effect is mediated through the engagement of the PI3K/Akt pathway (phosphorylation of Akt at Ser437 and Thr308, and activation of its downstream substrates GSK3β, PRAS-40 and FKHRL1) since its specific blockade abrogated the stimulatory effects of breast cancer on BM endothelium. We next determined whether, reciprocally, BM endothelium impacts on breast cancer cell survival. These experiments were performed in serum-free media to enhance dependency of breast cancer cells from microenvironmental stimuli. In all cases tested, BM endothelium promoted survival/proliferation of breast cancer cells. This stimulation was accompanied by the engagement of the PI3K/Akt pathway in breast cancer cells and, in three of the four lines, the phosphorylation of Erk1/2. These effects were also observed for breast cancer cells that showed constitutive activation of Akt (MCF-7 and ZR-75-1 cells). Specific blockade of PI3K/Akt abrogated the BM endothelium-promoted survival of breast cancer cells, thus demonstrating the critical role of this pathway. These studies show that crosstalk between BM endothelial cells and breast cancer cells may impact on the survival of both cell types. These findings provide new light on the mechanisms that may facilitate the development of a tumor-permissive BM microenvironment in breast cancer, and the creation of breast cancer-supporting BM niches. Importantly, this study implicates BM endothelium as a therapeutic target in breast cancer and suggest that blockade of PI3K/Akt may impact the outcome of patients with metastatic breast cancer.
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Ruhs, Stefanie, Alexander Nolze, Ralf Hübschmann, and Claudia Grossmann. "30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor." Journal of Endocrinology 234, no. 1 (July 2017): T107—T124. http://dx.doi.org/10.1530/joe-16-0659.
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The mineralocorticoid receptor (MR) belongs to the steroid hormone receptor family and classically functions as a ligand-dependent transcription factor. It is involved in water-electrolyte homeostasis and blood pressure regulation but independent from these effects also furthers inflammation, fibrosis, hypertrophy and remodeling in cardiovascular tissues. Next to genomic effects, aldosterone elicits very rapid actions within minutes that do not require transcription or translation and that occur not only in classical MR epithelial target organs like kidney and colon but also in nonepithelial tissues like heart, vasculature and adipose tissue. Most of these effects can be mediated by classical MR and its crosstalk with different signaling cascades. Near the plasma membrane, the MR seems to be associated with caveolin and striatin as well as with receptor tyrosine kinases like EGFR, PDGFR and IGF1R and G protein-coupled receptors like AT1 and GPER1, which then mediate nongenomic aldosterone effects. GPER1 has also been named a putative novel MR. There is a close interaction and functional synergism between the genomic and the nongenomic signaling so that nongenomic signaling can lead to long-term effects and support genomic actions. Therefore, understanding nongenomic aldosterone/MR effects is of potential relevance for modulating genomic aldosterone effects and may provide additional targets for intervention.
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Rushworth, Stuart A., Lyubov Zaitseva, Lingling Xian, Kristian M. Bowles, and Linda M. S. Resar. "High Mobility Group A1 (HMGA1) Chromatin Remodeling Protein Mediates Crosstalk Between Acute Myeloid Leukemia Blasts & the Tumor Microenvironment." Blood 124, no. 21 (December 6, 2014): 3564. http://dx.doi.org/10.1182/blood.v124.21.3564.3564.
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Abstract Introduction: Acute myeloid leukemias (AMLs) are highly lethal hematologic malignancies that arise from diverse genetic abnormalities in hematopoietic progenitor cells. Unfortunately, most patients with AML will die of their disease due to failure of currently available cytotoxic chemotherapies. Accordingly, there is an urgent need to better understand the biologic interactions between AML blasts and signals from bone marrow stromal cells (BMSCs) within the niche that support their survival and protect them from exposure to chemotherapy. The high mobility group A1 (HMGA1) chromatin remodeling proteins are present at high levels during development and enriched in AML blasts, leukemic stem cells, diverse solid tumors, embryonic stem cells, and adult stem cells, such as hematopoietic stem cells (HSCs). HMGA1 proteins regulate gene expression by modulating chromatin structure and recruiting NF-κB and other transcription factor complexes to DNA. We discovered that HMGA1 acts as a potent oncogene in transgenic mouse and cultured cell models (Xu et. al, Cancer Research, 2004) by inducing stem cell transcriptional networks (Schuldenfrei et. al, BMC Genomics, 2011, Shah et. al, PLoS ONE, 2013). Here, we describe a novel role for HMGA1 in mediating crosstalk between AML blasts and BMSCs within the bone marrow microenvironment. Methods & Results: To investigate HMGA1 in regulating AML-niche signaling, we used potent lentiviruses to deliver short hairpin RNA and silence HMGA1 in AML blasts or BMSCs. We found that silencing HMGA1 rapidly halts proliferation and induces apoptotic cell death in 3 different AML cell lines. To determine how HMGA1 mediates survival in AML blasts, we assessed expression of pro-survival genes in AML cell lines and primary AML blasts, including those encoding NF-E2-related factor 2 (NRF2), cMYC, and the C-X-C chemokine receptor type 4 (CXCR4). CXCR4 is the receptor for stromal cell-derived factor 1 (SDF-1 or CXCL12), a growth factor secreted by BMSCs that also serves as a chemo-attractant for AML blasts or HSCs within the bone marrow microenvironment. We found that silencing HMGA1 represses expression of NRF2, cMYC, and CXCR4. This led us to hypothesize that HMGA1 regulates crosstalk between AML blasts and the leukemic cell niche via CXCR4 and SDF-1. To test this, we silenced HMGA1 in cultured AML cells and assessed migration in the presence of SDF-1. Strikingly, migration was significantly impaired in the AML cells with HMGA1 knock-down. Next, we silenced HMGA1 in primary, patient-derived BMSCs, which were co-cultured with primary AML blasts from the same patients to mimic the bone marrow microenvironment. We found that knock-down of HMGA1 in BMSCs also results in apoptosis in primary AML blasts. Conclusions: Together, our results demonstrate for the first time that HMGA1 mediates AML survival through cell-autonomous pathways in AML blasts and through non-cell-autonomous crosstalk from BMSCs within the bone marrow microenvironment. Studies are underway to determine if HMGA1 directly regulates expression of SDF-1 or other factors secreted by BMSCs within the hematopoietic niche. This knowledge should inform biologically rational strategies to enhance existing treatments and facilitate the design of novel therapies. Disclosures No relevant conflicts of interest to declare.
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Hsu, Ya-Ling, Yi-Jen Chen, Wei-An Chang, Shu-Fang Jian, Hsiao-Li Fan, Jaw-Yuan Wang, and Po-Lin Kuo. "Interaction between Tumor-Associated Dendritic Cells and Colon Cancer Cells Contributes to Tumor Progression via CXCL1." International Journal of Molecular Sciences 19, no. 8 (August 16, 2018): 2427. http://dx.doi.org/10.3390/ijms19082427.
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Crosstalk of a tumor with its microenvironment is a critical factor contributing to cancer development. This study investigates the soluble factors released by tumor-associated dendritic cells (TADCs) responsible for increasing cancer stem cell (CSC) properties, cell mobility, and epithelial-to-mesenchymal transition (EMT). Dendritic cells (DCs) of colon cancer patients were collected for phenotype and CXCL1 expression by flow cytometry and Luminex assays. The transcriptome of CXCL1-treated cancer cells was established by next generation sequencing. Inflammatory chemokine CXCL1, present in large amounts in DCs isolated from colon cancer patients, and SW620-conditioned TADCs, enhance CSC characteristics in cancer, supported by enhanced anchorage-independent growth, CD133 expression and aldehyde dehydrogenase activity. Additionally, CXCL1 increases the metastatic ability of a cancer by enhancing cell migration, matrix metalloproteinase-7 expression and EMT. The enhanced CXCL1 expression in DCs is also noted in mice transplanted with colon cancer cells. Transcriptome analysis of CXCL1-treated SW620 cells indicates that CXCL1 increases potential oncogene expression in colon cancer, including PTHLH, TYRP1, FOXO1, TCF4 and ZNF880. Concurrently, CXCL1 displays a specific microRNA (miR) upregulated by the prototypical colon cancer onco-miR miR-105. Analysis of publicly available data reveals CXCL1-driven oncogenes and miR-105 have a negative prognostic impact on the outcome of colon cancer. This study indicates a new mechanism by which the colon cancer milieu exploits DC plasticity to support cancer progression.
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Sousa, Luis, Ines Pankonien, Luka A. Clarke, Iris Silva, Karl Kunzelmann, and Margarida D. Amaral. "KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway." Cells 9, no. 7 (July 2, 2020): 1607. http://dx.doi.org/10.3390/cells9071607.
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Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, and, when dysfunctional, cancer. However, the mechanisms that regulate such relationships are not fully elucidated. Krüppel-like factors (KLFs) are a family of transcription factors (TFs) playing central roles in development, stem cell differentiation, and proliferation. Herein, we hypothesized that these TFs might have an impact on CFTR expression and function, being its missing link to differentiation. Our results indicate that KLF4 (but not KLF2 nor KLF5) is upregulated in CF vs. non-CF cells and that it negatively regulates wt-CFTR expression and function. Of note, F508del–CFTR expressing cells are insensitive to KLF4 modulation. Next, we investigated which KLF4-related pathways have an effect on CFTR. Our data also show that KLF4 modulates wt-CFTR (but not F508del–CFTR) via both the serine/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3β) signaling. While AKT acts positively, GSK3β is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3β signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation.
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Li, Han, Youbo Lin, Ting Y. Tsui, and Joost J. Vlassak. "The effect of porogen loading on the stiffness and fracture energy of brittle organosilicates." Journal of Materials Research 24, no. 1 (January 2009): 107–16. http://dx.doi.org/10.1557/jmr.2009.0005.
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Integrating porous low-permittivity dielectrics into Cu metallization is one of the strategies to reduce power consumption, signal propagation delays, and crosstalk between interconnects for the next generation of integrated circuits. The porosity and pore structure of these low-k dielectric materials, however, also affect other important material properties in addition to the dielectric constant. In this paper, we investigate the impact of porogen loading on the stiffness and cohesive fracture energy of a series of porous organosilicate glass (OSG) thin films using nanoindentation and the double-cantilever beam (DCB) technique. The OSG films were deposited by plasma-enhanced chemical vapor deposition (PECVD) and had a porosity in the range of 7−45%. We show that the degree of porogen loading during the deposition process changes both the network structure and the porosity of the dielectric, and we resolve the contributions of both effects to the stiffness and fracture energy of the films. The experimental results for stiffness are compared with micromechanical models and finite element calculations. It is demonstrated that the stiffness of the OSG films depends sensitively on their porosity and that considerable improvements in stiffness may be obtained through further optimization of the pore microstructure. The cohesive fracture energy of the films decreases linearly with increasing porosity, consistent with a simple planar through-pore fracture mechanism.
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Van Acker, Heleen H., Zoë P. Van Acker, Maarten Versteven, Peter Ponsaerts, Daniela Pende, Zwi N. Berneman, Sébastien Anguille, Viggo F. Van Tendeloo, and Evelien L. Smits. "CD56 Homodimerization and Participation in Anti-Tumor Immune Effector Cell Functioning: A Role for Interleukin-15." Cancers 11, no. 7 (July 22, 2019): 1029. http://dx.doi.org/10.3390/cancers11071029.
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A particularly interesting marker to identify anti-tumor immune cells is the neural cell adhesion molecule (NCAM), also known as cluster of differentiation (CD)56. Namely, hematopoietic expression of CD56 seems to be confined to powerful effector immune cells. Here, we sought to elucidate its role on various killer immune cells. First, we identified the high motility NCAM-120 molecule to be the main isoform expressed by immune cells. Next, through neutralization of surface CD56, we were able to (1) demonstrate the direct involvement of CD56 in tumor cell lysis exerted by CD56-expressing killer cells, such as natural killer cells, gamma delta (γδ) T cells, and interleukin (IL)-15-cultured dendritic cells (DCs), and (2) reveal a putative crosstalk mechanism between IL-15 DCs and CD8 T cells, suggesting CD56 as a co-stimulatory molecule in their cell-to-cell contact. Moreover, by means of a proximity ligation assay, we visualized the CD56 homophilic interaction among cancer cells and between immune cells and cancer cells. Finally, by blocking the mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase (PI3K)–Akt pathway, we showed that IL-15 stimulation directly led to CD56 upregulation. In conclusion, these results underscore the previously neglected importance of CD56 expression on immune cells, benefiting current and future immune therapeutic options.
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Li, Linda Xiaoyan, and Xiaogang Li. "Epigenetically Mediated Ciliogenesis and Cell Cycle Regulation, and Their Translational Potential." Cells 10, no. 7 (July 2, 2021): 1662. http://dx.doi.org/10.3390/cells10071662.
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Primary cilia biogenesis has been closely associated with cell cycle progression. Cilia assemble when cells exit the cell cycle and enter a quiescent stage at the post-mitosis phase, and disassemble before cells re-enter a new cell cycle. Studies have focused on how the cell cycle coordinates with the cilia assembly/disassembly process, and whether and how cilia biogenesis affects the cell cycle. Appropriate regulation of the functions and/or expressions of ciliary and cell-cycle-associated proteins is pivotal to maintaining bodily homeostasis. Epigenetic mechanisms, including DNA methylation and histone/chromatin modifications, are involved in the regulation of cell cycle progression and cilia biogenesis. In this review, first, we discuss how epigenetic mechanisms regulate cell cycle progression and cilia biogenesis through the regulation of DNA methylation and chromatin structures, to either promote or repress the transcription of genes associated with those processes and the modification of cytoskeleton network, including microtubule and actin. Next, we discuss the crosstalk between the cell cycle and ciliogenesis, and the involvement of epigenetic regulators in this process. In addition, we discuss cilia-dependent signaling pathways in cell cycle regulation. Understanding the mechanisms of how epigenetic regulators contribute to abnormal cell cycle regulation and ciliogenesis defects would lead to developing therapeutic strategies for the treatment of a wide variety of diseases, such as cancers, polycystic kidney disease (PKD), and other ciliopathy-associated disorders.
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Veeranki, Omkara Lakshmi. "A novel patient derived orthotopic xenograft model of gastro-esophageal junction cancer: Key platform for translational discoveries." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 64. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.64.
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64 Background: Mouse models of gastroesophageal junction (GEJ) cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. Current GEJ models have limited applications in tumor microenvironment, immune oncology and metastatic studies. Methods: A novel patient derived tumor orthotopic xenograft (PDOX) was established from GEJ cancer via surgical implantation. Patient tumor was compared to subcutaneously implanted PDX and PDOX by H&E, IHC, and next generation sequencing (T200.1 panel). Drug efficacy studies of 5-flurouracil with and without radiotherapy are being performed. Results: Mechanical abrasion of mouse GEJ prior to implantation of patient derived tumor in situ promotes tumor engraftment (100%, n = 6). Complete PDOX engraftment was observed with rapid intra and extra luminal tumor growth as evidenced by MRI. Patient derived stroma co-engrafts with tumor cells in GEJ-PDOX. PDOXs contain fibroblasts, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJs are recapitulated in GEJ-PDOX mouse model. PDOXs demonstrates tumor invasion into vasculature. GEJ-PDOXs is a clinically relevant model for metastases and immunological studies. Next generation sequencing with the T200.1 revealed that the loss of heterozygosity of NOTCH3, TGFβ1, EZH2, and MLL3 are maintained with similar allelic frequency between the patient tumor and the xenografts. Additional somatic SNVs such as ARID1A, NSD1 (CDS157-158), NSD1 (CDS158-159), KDM6A, XPO1, MAPK1 and EGFR were found to be acquired in xenograft tumor tissues that were not observed in patient tumor. Drug and radiation efficacy studies are ongoing, tumor response to radiation was observed. Conclusions: A GEJ-PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture facilitating it as a novel tool in translating to clinics. This model can be applied to address importance of tumor microenvironment in metastatic and immunological studies, and to develop novel therapeutic approaches for the treatment of GEJ cancer.
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Li, Ai-lan, Yong-mei Zhu, Lai-qiang Gao, Shu-yue Wei, Ming-tao Wang, Qiang Ma, You-you Zheng, Jian-hua Li, and Qing-feng Wang. "Exploration of the Immune-Related Signatures and Immune Infiltration Analysis in Melanoma." Analytical Cellular Pathology 2021 (January 16, 2021): 1–14. http://dx.doi.org/10.1155/2021/4743971.
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In the present study, we aimed to investigate immune-related signatures and immune infiltration in melanoma. The transcriptome profiling and clinical data of melanoma were downloaded from The Cancer Genome Atlas database, and their matched normal samples were obtained from the Genotype-Tissue Expression database. After merging the genome expression data using Perl, the limma package was used for data normalization. We screened the differentially expressed genes (DEGs) and obtained immune signatures associated with melanoma by an immune-related signature list from the InnateDB database. Univariate Cox regression analysis was used to identify potential prognostic immune genes, and LASSO analysis was used to identify the hub genes. Next, based on the results of multivariate Cox regression analysis, we constructed a risk model for melanoma. We investigated the correlation between risk score and clinical characteristics and overall survival (OS) of patients. Based on the TIMER database, the association between selected immune signatures and immune cell distribution was evaluated. Next, the Wilcoxon rank-sum test was performed using CIBERSORT, which confirmed the differential distribution of immune-infiltrating cells between different risk groups. We obtained a list of 91 differentially expressed immune-related signatures. Functional enrichment analysis indicated that these immune-related DEGs participated in several areas of immune-related crosstalk, including cytokine-cytokine receptor interactions, JAK–STAT signaling pathway, chemokine signaling pathway, and Th17 cell differentiation pathway. A risk model was established based on multivariate Cox analysis results, and Kaplan-Meier analysis was performed. The Kruskal-Wallis test suggested that a high risk score indicated a poorer OS and correlated with higher American Joint Committee on Cancer-TNM (AJCC-TNM) stages and advanced pathological stages ( P < 0.01 ). Furthermore, the association between hub immune signatures and immune cell distribution was evaluated in specific tumor samples. The Wilcoxon rank-sum test was used to estimate immune infiltration density in the two groups, and results showed that the high-risk group exhibited a lower infiltration density, and the dominant immune cells included M0 macrophages ( P = 0.023 ) and activated mast cells ( P = 0.005 ).
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Aslam, Mohammad, Kenji Sugita, Yuan Qin, and Abidur Rahman. "Aux/IAA14 Regulates microRNA-Mediated Cold Stress Response in Arabidopsis Roots." International Journal of Molecular Sciences 21, no. 22 (November 10, 2020): 8441. http://dx.doi.org/10.3390/ijms21228441.
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The phytohormone auxin and microRNA-mediated regulation of gene expressions are key regulators of plant growth and development at both optimal and under low-temperature stress conditions. However, the mechanistic link between microRNA and auxin in regulating plant cold stress response remains elusive. To better understand the role of microRNA (miR) in the crosstalk between auxin and cold stress responses, we took advantage of the mutants of Arabidopsis thaliana with altered response to auxin transport and signal. Screening of the mutants for root growth recovery after cold stress at 4 °C revealed that the auxin signaling mutant, solitary root 1 (slr1; mutation in Aux/IAA14), shows a hypersensitive response to cold stress. Genome-wide expression analysis of miRs in the wild-type and slr1 mutant roots using next-generation sequencing revealed 180 known and 71 novel cold-responsive microRNAs. Cold stress also increased the abundance of 26–31 nt small RNA population in slr1 compared with wild type. Comparative analysis of microRNA expression shows significant differential expression of 13 known and 7 novel miRs in slr1 at 4 °C compared with wild type. Target gene expression analysis of the members from one potential candidate miR, miR169, revealed the possible involvement of miR169/NF-YA module in the Aux/IAA14-mediated cold stress response. Taken together, these results indicate that SLR/IAA14, a transcriptional repressor of auxin signaling, plays a crucial role in integrating miRs in auxin and cold responses.
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De Vos, Joeri, Koen De Munck, Mehmet Akif Erismis, Padmakumar Ramachandra Rao, Kiki Minoglou, Wenqi Zhang, Deniz S. Tezcan, Piet De Moor, and Philippe Soussan. "Processing aspects to achieve high-end hybrid backside illuminated imagers." International Symposium on Microelectronics 2010, no. 1 (January 1, 2010): 000372–77. http://dx.doi.org/10.4071/isom-2010-wa1-paper4.
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We present a successful integration scheme of a backside illuminated 1024×1024 pixel sensor array, flip chipped on top of a ROIC with 10μm diameter Indium micro bumps, where the pixel pitch is 22.5μm. Backside illumination results, as compared to front side illumination, in a large gain in quantum efficiency because no incoming light is lost in the metal and dielectric layers. At the other side however, backside illuminated imagers requires more complex post processing because the detector array has to be thinned down to 30μm or less. Surface treatment reduces surface combination and lead to an improvement of the quantum efficiency of the device. Any damage induced at the backside of the imager is detrimental for the quantum efficiency since defects act as recombination centers for the light generated electron-hole pairs. In the end, all process optimizations on the hybrid backside illuminated imager device lead towards a quantum efficiency of 80–90% (over the visible spectrum). Next to the discussion on the critical steps (such as wafer thinning on carrier, wafer flip, cleaning), we introduce a novel backside alignment strategy to avoid using pyrex substrate as temporary carrier for thinning. Pyrex is namely not compatible in a high-end Si process environment due to its fragile nature. It is also shown that through introduction of a high aspect ratio pixel separating trenches, inter pixel electrical crosstalk can be avoided. Finally an alternative micro bump formation by means of CuSn bumps is presented.