Auswahl der wissenschaftlichen Literatur zum Thema „IPS-CM“

Myocardial hypertrophy is present in many heart diseases, representing a strong predictor of adverse cardiovascular outcomes. Regarding therapeutic intervention, mesenchymal stem cells (MSCs) have been suggested to significantly reduce cardiac hypertrophy and progression to heart failure. Preconditioning of MSCs was previously demonstrated to highly improve their paracrine activity resulting in modulation of immune responses and the progression of diseases. Here, we studied the effects of bone marrow-derived preconditioned MSCs on hypertrophied induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) and also sought to identify MSC-derived antihypertrophic molecules. Phenylephrine (PE) was used to induce hypertrophy in murine iPS-CM, and markers of hypertrophy were identified by microarray analysis. Murine MSCs were treated with IFN-γ and IL-1β to enhance their paracrine activity, and transcriptional profiling was performed by microarray analysis. Hypertrophied iPS-CM were subsequently cocultured with preconditioned MSCs or MSC-conditioned medium (CM), respectively. Effects on hypertrophied iPS-CM were studied by cell area quantification, real-time PCR, and western blot. In some experiments, cells were incubated with fractions of MSC-CM obtained by ultrafiltration or by MSC-CM supplemented with inhibitory antibodies. Intracellular and extracellular levels of vascular endothelial growth factor (VEGF) were evaluated by western blot and ELISA. PE-induced hypertrophy in iPS-CM was associated with an upregulation of neuron-derived orphan receptor (Nor1) expression, activation of Akt, and inhibition of both strongly prevented hypertrophy induction in iPS-CM. VEGF secreted by preconditioned MSCs provoked hypertrophy regression in iPS-CM, and a negative correlation between Nor1 expression and hypertrophic growth could be evidenced. Our results demonstrate that Nor1 expression strongly supports hypertrophy in iPS-CM. Moreover, the secretome of preconditioned MSCs triggered regression of hypertrophy in iPS-CM in a VEGF-dependent manner. We suggest that the delivery of the MSC-derived secretome may represent a therapeutic strategy to limit cardiac hypertrophy. However, additional in vivo studies are needed to prove this hypothesis.

Abstract Introduction/Objective Inflammatory pseudopolyps (IPs) often develop in response to chronic active inflammation in patients with inflammatory bowel disease (IBD). IPs can be diffuse and numerous in severe IBD. IPs can also occur from other chronic active injuries, such as ulcers, persistent infection, ischemic colitis, anastomotic site and diverticulitis. IPs arising from diverticulitis is uncommon and generally few in numbers. We report a rare case of a patient with segmental diffuse IPs associated with diverticulitis in the absence of IBD. Methods A 59-year-old male patient with a history of sigmoid diverticulitis presented with abdominal pain and was treated with antibiotics. Three months later he had severe recurrent diverticulitis. CT scan showed wall thickening of the sigmoid colon and multiple sigmoid diverticula. Colonoscopy showed extremely severe inflammatory colitis in the area of diverticulitis between 25.0 and 35.0 cm from the anal verge. Biopsies revealed cryptitis, crypt abscesses, crypt architecture distortion and Paneth cell metaplasia. The patient underwent laparoscopic left colectomy. Results The rectosigmoid colon specimen is 18.0 cm in length and 6.0 cm in diameter. There was a 7.5 cm segment with numerous polyps. Multiple diverticula with diverticulitis were also identified in this region. The rest of the colon was unremarkable. Microscopic examination revealed numerous IPs and multiple diverticulitis. No evidence of IBD was identified. Conclusion To our knowledge, this is the first time that segmental and diffuse IPs are described with associated diverticulitis in the absence of IBD. The pathogenesis of IPs in non-inflammatory bowel disease is not well described. Previously, it was reported that diverticulosis and subsequent diverticulitis has no significant impact on the development of IPs, and IPs may arise independent of location and time of diverticulitis. Sporadic IPs may also appear without any underlying pathology. In the current case, there were multiple diverticula and diffuse diverticulitis, which may have contributed to the diffuse IPs. Further clinical inquiries revealed no clinical signs and symptoms of IBD.

Aim: This study aimed at evaluating the impact of different adjustments and artificial aging on the color change (ΔE) and surface roughness (Ra) of monolithic zirconia (MLZ) and lithium disilicate (LD) ceramics. Materials and methods: Forty discs were prepared from two types of MLZs, including ceramill monolithic Zr (CM-Zr) and Prettau PSZ Zr (PP-Zr), and one LD (IPS e.max-LD, IPS-LD). After different clinical adjustments (performed with glazing, bur, bur + glazing, and bur + polishing) and artificial aging (in-vitro coffee immersion), the ΔE was assessed using a spectrophotometer. The roughness (Ra) was also evaluated after these adjustments. The ANOVA and multiple com-parisons test were used to compare the groups statisitcally and the level of significance was set at 5%. Results: In the CM-Zr group, the greatest ΔE was observed after bur adjustment (3.32, p < 0.05) while the lowest ΔE was seen after the glaze treatment (2.11, p < 0.05). In the PP-Zr group, the highest ΔE was observed after bur treatment (2.70, p < 0.05) while the lowest ΔE was seen after the glaze treatment (1.25, p < 0.05). Lastly, for the IPS-LD group, the highest ΔE was again observed after bur treatment (2.91, p < 0.05) while the lowest ΔE was seen after glaze treatment (1.0, p < 0.05). After coffee immersion, it was observed that the highest overall ΔE was observed for CM-Zr after the bur and polish treatment (3.45), while the lowest overall ΔE was observed in IPS-LD after the glaze treatment (2.10). All the ΔE values were within the clinical acceptable range. The highest overall Ra was witnessed for CM-Zr after bur adjustment (1.64), while the lowest overall Ra was seen for IPS-LD after glaze treatment (0.26). Different clinical adjustments and artificial aging influence the colour stability of different ceramic materials (CM-Zr, PP-Zr, and IPS-LD). Compared to the MLZ, IPS-LD ceramics were more stable as they presented with lower ΔE after surface adjustments and coffee immersion. Conclusions: The surface adjustment that minimally affected the colour of these ceramics was glaze treatment, while the ceramics were most affected by bur adjustments. Coffee aging affected colour stability of all ceramic materials. IPS-LD ceramics presented the lowest Ra values after different clinical adjustments.

Introduction: Nowadays, treatment decision making in advanced Hodgkin lymphoma (ad-HL) is based on pre-therapy risk factors and interim PET/CT (PET-2) results, used as a platform for therapy modification. In the past, a bulky mediastinal mass (BMM) was not found to be a significant risk factor and was not included in the final version of the International Prognostic Score (IPS) system (Hasenclever, NEJM 1998). The current study aimed to assess the effect of BMM presence on relapse-free survival (RFS) in patients (pts) with ad-HL and to determine the optimal cutoff of the mass size for outcome prediction in the PET/CT era. Methods: The Israeli Hodgkin Lymphoma Study Group selected to initiate therapy with standard BEACOPP (SB: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) or ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) in HL pts with IPS 0-2 and with intensified therapy using escalated BEACOPP (EB: bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) in pts with IPS ≥3. Treatment was modified according to PET-2 results. To pts with negative PET-2 another 4 cycles of SB/ABVD were administered. PET-2 positive pts received 4 EB cycles followed by radiation therapy (Dann, Blood 2007). In the present study, disease bulkiness, assessed using baseline PET/CT, was retrospectively evaluated in a cohort of HL pts. The data included measurements of the longest diameter of either the biggest single mass or a conglomerate of lymph node masses in the transverse or coronal plane in the PET/CT image. Prognostic values of mediastinal mass cutoffs of ≥5 cm, ≥7 cm, >10 cm for RFS and progression-free survival (PFS) were compared. Results: One hundred and ninety six pts (female/male: 46/54%) with ad-HL [stage IIB - 28, stage III - 74, stage IV - 94; IPS 0-2 - 104; IPS 3-7 - 92; median age 31 years (16-85)] treated at the Rambam Health Care Campus (n=121) and Memorial Sloan Kettering Cancer Center (n=75) between 2000-2016 were included in the analysis. Mediastinal masses ≥5 cm, ≥7 cm and >10 cm were observed in 125 (63%), 82 (42%), 36 (18%) pts, respectively. PET-2 was negative in 79% of pts. At a median follow-up of 66.5 (1-222) months [80 (4-222) for pts without disease progression and 12 (1-62) for those with relapse or progression], estimated 5-year RFS and PFS for the entire group were 82% and 79%, respectively. A mass of up to 7 cm was found in 62 % of pts (n=123); 22% (n=44) had a mass measuring between 7 and 9.9 cm and 15% (n=29) had a mass ≥10 cm. Mediastinal masses were prevalent in 126/196 (64%) pts; in 58 (30%) of them the mediastinal mass, while being biggest, did not exceed 7 cm, and 68 (34%) had BMM of ≥7 cm. We found no effect of bulky disease, either mediastinal or non-mediastinal, on the outcome of the PET-2 positive group. Univariate analysis showed that in pts with negative PET-2, BMM ≥7 cm was a significant adverse prognostic factor for both 5-year RFS and PFS (HR 2.85; 95% CI 1.09-7.41; p=0.032 and HR 2.86; 95% CI 1.1-7.45; p=0.032, respectively). Outcome comparison of PET-2 negative pts with BMM (≥7 cm) to pts with negative PET-2 and either non-mediastinal or mediastinal non-bulky (<7cm) masses (reference group) revealed an inferior 5-year RFS of 73% versus 89% (HR 2.97; 95% CI 1.37-6.42; p=0.006) in the former group. Of note, both groups received an ABVD/SB regimen. HR for RFS was insignificant when a mass size cutoff of ≥5 cm or >10 cm was used. The HR for RFS was particularly high in the comparison between the subgroup of PET-2 negative pts with IPS 0-2 and BMM (≥7 cm) and those with IPS 0-2 in the reference group, demonstrating a 5-year RFS of 59% versus 89% with HR of 4.20 (95% CI 1.59-11.05; p=0.004). PET-2 negative pts with IPS 3-7 and BMM (≥7 cm) did not have an inferior outcome compared to pts with IPS 3-7 from the reference group (5-year RFS of 82% versus 89%). Notably, the two groups were treated with an EB-containing regimen. Our results indicate that BMM is an important adverse prognostic factor predominantly for pts with IPS 0-2. Multivariate Cox regression analysis identified BMM ≥7 cm as the most significant adverse prognostic factor for RFS (Table 1; Fig. 1). Conclusions: In PET-2 negative pts with ad-HL, mediastinal masses ≥7 cm in any plane are associated with the highest risk for HL progression. These findings should be incorporated in a new prognostic scoring system upon more extensive evaluation in a larger cohort. Disclosures No relevant conflicts of interest to declare.

Background Cardiac injury associated with cytokine release frequently occurs in SARS-CoV-2 mediated coronavirus disease (COVID19) and mortality is particularly high in these patients. The mechanistic role of the COVID19 associated cytokine-storm for the concomitant cardiac dysfunction and associated arrhythmias is unclear. Moreover, the role of anti-inflammatory therapy to mitigate cardiac dysfunction remains elusive. Aims and methods We investigated the effects of COVID19-associated inflammatory response on cardiac cellular function as well as its cardiac arrhythmogenic potential in rat and induced pluripotent stem cell derived cardiomyocytes (iPS-CM). In addition, we evaluated the therapeutic potential of the IL-1β antagonist Canakinumab using state of the art in-vitro confocal and ratiometric high-throughput microscopy. Results Isolated rat ventricular cardiomyocytes were exposed to control or COVID19 serum from intensive care unit (ICU) patients with severe ARDS and impaired cardiac function (LVEF 41±5%; 1/3 of patients on veno-venous extracorporeal membrane oxygenation; CK 154±43 U/l). Rat cardiomyocytes showed an early increase of myofilament sensitivity, a decrease of Ca2+ transient amplitudes and altered baseline [Ca2+] upon exposure to patient serum. In addition, we used iPS-CM to explore the long-term effect of patient serum on cardiac electrical and mechanical function. In iPS-CM, spontaneous Ca2+ release events were more likely to occur upon incubation with COVID19 serum and nuclear as well as cytosolic Ca2+ release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca2+ release or Ca2+ signaling during excitation-contraction coupling, nor significantly influenced cellular automaticity. Conclusion Serum derived from COVID19 patients exerts acute cardio-depressant and chronic pro-arrhythmogenic effects in rat and iPS-derived cardiomyocytes. Canakinumab had no beneficial effect on cellular Ca2+ signaling during excitation-contraction coupling. The presented method utilizing iPS-CM and in-vitro Ca2+ imaging might serve as a novel tool for precision medicine. It allows to investigate cytokine related cardiac dysfunction and pharmacological approaches useful therein.

AbstractPitch canker, caused by Fusarium subglutinans (Wollenw. and Reink.) Nelson, Toussoun, and Marasas, a pine pathogen recently identified in California, may increase the distribution and abundance of Ips spp. on Monterey pines in Santa Cruz Co., CA. In all pine stands, Ips spp. tunneled into healthy branches and boles. Ips mexicanus (Hopkins) was the most abundant engraver beetle observed, followed by I. paraconfusus Lanier; I. plastographus (LeConte) was rare. Ips mexicanus was routinely captured in traps baited with racemic I. paraconfusus pheromone. During die winter, I. mexicanus excavated mass feeding cavities in shade-suppressed branches. In uninfected stands, 3% of the trees and only 0.3% of the branches were mass-attacked. In severely infected stands, 47% of the top one-third of the trees, 3% of all branches, and 91% of the branches declining due to infection by F. subglutinans were mass-attacked by Ips spp. On pitch canker-infected trees, I. mexicanus attacked cones and stems <1 cm in diameter. Sixty percent of the attacks on logs occurred inside or within 5 cm of the area covered with pitch canker-induced resin. When confined with logs, 45% of I. paraconfusus tunneled in or near pitch canker-induced resinous areas,21% near fresh chisel wounds, and 19% near resinous material produced by the Sequoia pitch moth. Synanthedon sequoiae (Hy. Edwards).

Novel polysilanes, antimony-substituted polysilanes (APS) and iron-substituted polysilanes (IPS), were synthesized and characterized in this paper. To prepare these new metal-containing polymers, high reactive polymers, polymethylsilane (PMS) and polychloromethylsilane (PCMS) were used as mother polymers. The APS was synthesized directly by the reaction of PMS with SbCl3, while IPS was obtained from the reaction of PCMS with Na2Fe(CO)4 in the solvent of n-hexane. The polymers were characterized by elemental analysis, FT-IR, 1H-NMR, 29Si CP/MAS NMR, GPC, and UV. The number average molecular weights of these two polymers are between 1400 and 1600. These polymers show good semiconductive properties, whose intrinsic conductivities are in the range of 10-8~10-7S/cm, and can be increased to10-5S/cm after being doped with iodine.

AbstractDual-frequency, multi-polarization airborne synthetic aperture radar (Pi-SAR; developed by the Communications Research Laboratory and National Space Development Agency of Japan) observations of the seasonal sea-ice region off the Okhotsk coast of Hokkaido, Japan, were carried out in February 1999 using X- and L-band radar frequencies with a resolution of 1.5 and 3.0 m. In conjunction with the SAR observations, the sea-ice thickness (draft) and velocity were measured by a moored Ice Profiling Sonar (IPS) and an Acoustic Doppler Current Profiler (ADCP). Tracks of the sea ice passing over the IPS were estimated from the time series of the ADCP ice-velocity and -direction data. Along these tracks, the SAR backscattering coefficient profiles were compared with the IPS ice-draft profiles. The results showed that the L-band SAR backs cattering profiles correlated well with the IPS ice-draft data, particularly in the thicker part (a few meters thick) of the rim of first-year ice, which had a large backscattering coefficient. Although the X-band SAR backscattering profiles did not correlate well with the IPS data, thin ice (<10 cm thick) showed a large backscattering coefficient. The L-band SAR and IPS data did not distinguish thin ice from open water.

In this work, we have studied the integration of an optical signal-based Indoor Positioning System (IPS) capable of supporting multi-access discrimination techniques. The research analyzes the different techniques and conditions that can be used to develop an IPS using a microcontroller unit (MCU)-based system-on-chip (SoC) systems. The main goal is to be able to integrate into the MCU both the hardware and software requirements for an IPS detector. In this way, different strategies that can implement multi-access discrimination using Frequency-division multiple access (FDMA) have been tested, such as I/Q demodulation, digital filtering, and discrete Fourier transform (DFT). This analysis has found a good technique to be executed in an MCU-based SoC, the DFT implemented through the Goertzel’s algorithm. The empirical tests carried out concluded that, using only one an MCU with the required HW and tuned SW, 15 position measurements per second were computed, with high accuracy in the 3-D positioning, with errors of less than 1 cm in a test area of 3.5 × 3.5 m 2 . The main contribution of the paper is the implementation of the optical signal based IPS in an MCU-SoC that includes signal acquisition and processing. The digital filtering or spectral processing for up to 16 received signals makes this IPS system very attractive from a design and cost point of view.

Indoor Positioning System (IPS) adalah teknologi untuk mengakomodasi pemetaan objek di dalam ruangan. Sistem ini dibuat tersendiri karena keterbatasan GPS untuk memetakan objek dalam ruangan karena terhalang oleh bangunan sehingga akurasi yang kurang presisi. RFID menjadi salah satu alternatif tag yang digunakan pada IPS karena mampu menghadirkan sistem pemetaan dengan biaya terjangkau dan performa yang tidak kalah jauh dari tag lainnya. Tujuan dari penelitian ini adalah untuk membangun sistem pemetaan dalam ruangan yang ekonomis dengan akurasi yang baik. Pada penelitian ini diajukan sebuah sistem IPS dengan objek pemetaan RFID Passive Tag dengan menggunakan Machine Learning Regresi yang diteruskan ke Multilateration yang selanjutnya dioptimalkan dengan algoritma Nelder Mead. Pada penelitian ini dibandingkan dua model regresi yaitu Support Vector Regression dan Linear Regression, prediksi jarak dari model terbaik akan dimasukkan pada persamaan Multilateration untuk memprediksi koordinat. Untuk meningkatkan akurasi dari teknik Multilateration digunakan optimasi algoritma Nelder Mead untuk mengatasi error dari prediksi jarak. Setelah dilakukan pengujian didapatkan akurasi dari model ini yaitu rerata error sebesar 37.39 cm.

La myopathie de Duchenne est une maladie génétique rare caractérisée par une dégénération progressive des muscles striés notamment squelettiques et cardiaque. A l’échelle de la cellule, l’absence de dystrophine perturbe l'intégrité de la membrane plasmique, la signalisation cellulaire et par conséquent la contraction musculaire. A l’échelle du tissu, ces changements se traduisent par une faiblesse musculaire et par une perturbation de la matrice extracellulaire qui se rigidifie, perd son organisation anisotrope et devient peu poreuse. La matrice joue un rôle essentiel dans l’évolution de la maladie et est souvent négligée dans les modèles existants. Ainsi, ce projet de thèse a eu pour but de développer un nouveau modèle tissulaire cardiaque et musculaire prenant en compte ces modifications structurelles de la matrice pour améliorer la compréhension de la pathologie et générer un modèle physiologique pour tester des molécules thérapeutiques. Tout d’abord, un modèle de matrice extracellulaire saine a été généré par impression 3D de collagène de type I dense. Les paramètres ont été ajustés pour reproduire la matrice physiologique, à savoir une rigidité de 10 kPa, de l’anisotropie et de la porosité. L’impression de collagène dense permet à la fois d’aligner les molécules de collagène et de générer une porosité intrinsèque dans l’hydrogel de collagène. Ensuite, son pendant pathologique a pu être développé en modifiant les paramètres d’impression et de gélification du collagène pour obtenir une matrice de rigidité 50 kPa, isotrope et non poreuse. In vivo, les cellules musculaires et cardiaques sont physiologiquement agencées sous forme de fuseaux. Cette morphologie particulière a été reproduite au sein des matrices développées en créant un pore cylindrique par moulage qui a été colonisé par les cellules. L’enjeu est de recréer au sein de ces pores un microtissu jointif pour mimer les conditions physiologiques. En utilisant des cardiomyocytes dérivés de cellules souches pluripotentes induites humaines ou des myoblastes murins, nous avons respectivement obtenu des microtissus cardiaques et musculaires au contact de matrices saines ou pathologiques. Pour le microtissu musculaire, les cellules saines ensemencées dans la matrice pathologique montrent un stress du à l’hypoxie, associé à un ralentissement du cycle cellulaire et une moins bonne différentiation en myotubes. Pour le microtissu cardiaque, les cellules ensemencées dans le modèle pathologique ont montré une moins bonne contraction sous stimulation. Par ailleurs, les matrices ont été adaptées à une puce microfluidique pour assurer la perfusion de milieu de culture par les pores créés par l’impression 3D. Cette perfusion permet d’améliorer la diffusion de l’oxygène et des nutriments au sein du modèle. Ces nouveaux modèles de tissu cardiaque et musculaire permettent de prendre en compte les interactions cellule/cellule mais aussi cellule/matrice dans l’évolution de la pathologie. Ainsi, les différentes combinaisons entre matrice saine/pathologique et cellules saines/mutées permettrait à l’avenir de mieux comprendre la pathologie et de trouver des stratégies thérapeutiques adaptées
Duchenne Muscular Dystrophy is a rare genetic disease characterized by progressive degeneration of striated muscles, notably skeletal and cardiac. At the cellular level, the absence of dystrophin disturbs the integrity of the plasma membrane, cell signaling, and consequently muscle contraction. At the tissue level, these changes result in muscle weakness and a disturbance of the extracellular matrix which becomes rigid and loses its anisotropic organization with reduced porosity. The matrix plays a crucial role in the evolution of the disease and is often neglected in existing models. The matrix plays a crucial role in the evolution of the disease and is often neglected in existing models. This project aims to develop a new tissue model that considers these structural changes in ECM to improve our understanding of the pathology and discover novel therapeutic solutions. First, the 3D printing of dense type I collagen generated a healthy extracellular matrix model. Its parameters were adjusted to reproduce the physiological matrix, i.e., a stiffness of 10 kPa, anisotropy, and porosity. Dense collagen printing allows collagen molecules alignment and generates porosity. Then, its pathological counterpart could be synthesized by modifying the printing and gelling parameters of collagen to get a matrix with a 50 kPa stiffness, isotropic, and non-porous. In vivo, the muscle and heart cells are physiologically arranged in bundles. A cellularized cylindrical pore generated by molding reproduced this morphology within the matrices. To mimic the physiological conditions, the challenge was to recreate a joined microtissue with densely-packed cells within these pores. We obtained a cardiac and a muscular microtissue with both types of matrices (healthy or pathological) using human cardiomyocytes derived from induced pluripotent stem cells or murine myoblasts. For the muscle microtissue, the healthy cells seeded in the pathological matrix showed high stress due to hypoxia, associated with cell cycle arrest and weak differentiation into myotubes. For the cardiac microtissue, cells seeded in the pathological model had irregular beatings when stimulated. In addition, the matrices were adapted to a microfluidic chip to ensure the perfusion of the culture medium through the pores created by the 3D printing. This perfusion enhances nutrient and oxygen diffusion in the model. These new cardiac and muscular tissue models take into account cell/cell and cell/matrix interactions in the evolution of the pathology. Thus, the different combinations between healthy/pathological matrix and healthy/mutated cells will allow us a better understanding of the pathology to discover novel and adapted therapeutic strategies

Le malattie cardiache, ed in particolare i disturbi del ritmo cardiaco, sono una delle principali cause di morte nel mondo, per questo motivo rappresentano una tematica su cui si concentra l’interesse della comunità scientifica. Tuttavia, i meccanismi di regolazione a livello cellulare nell’elettrofisiologia cardiaca sono affetti da una certa variabilità da individuo a individuo che deve essere investigata per la predizione della risposta del tessuto cardiaco a specifiche terapie. Uno dei limiti nell’attuale modellistica matematica risiede proprio nel fatto che non si tiene conto di questa variabilità intercellulare perdendo così informazioni importanti. Per superare questi limiti, sono stati sviluppati modelli in silico che consentono di pianificare nuovi esperimenti e formulare ipotesi con il vantaggio di abbattere sia i costi che i tempi richiesti dagli esperimenti in laboratorio. In particolare, in questo lavoro di tesi ci si è avvalsi dell’approccio delle popolazioni di modelli (PoMs) con lo scopo di descrivere la risposta di cellule hiPS-CSs a due farmaci, E4031 e Nifedipina, che bloccano specifici canali ionici cardiaci. Il primo passo è stato quindi quello di costruire una popolazione di 20000 modelli, randomizzando entro un certo intervallo i parametri corrispondenti alle conduttanze massime delle correnti ioniche cardiache, poi la popolazione è stata raffinata scartando tutti i modelli che non mostravano un potenziale d’azione fisiologico. Il passo successivo è stata la “calibrazione sperimentale”, cioè il confronto tra le simulazioni e i dati sperimentali relativi ai due farmaci. I risultati mostrano come le simulazioni ottenute, seguono in maniera quasi soddisfacente i dati sperimentali per il bloccante della ICaL ma non sono rappresentativi dei dati per il blocco della IKr i quali presentano una morfologia del potenziale d’azione diversa rispetto quello delle cellule virtuali.

Multicellular 3D cardiac microtissues composed of induced pluripotent stem cell (iPSC) derived cardiomyocytes and normal human cardiac fibroblasts (NHCFs) with different contractile performances are presented in this work. The cells were coated with fibronectin-gelatin nanofilm or collagen and then assembled using the developed cell accumulation technique to produce the multi-layered 3D tissues. The mixing ratio of NHCFs was adjusted to 0%, 25%, 50%, and 75% (iPS-CM100, iPS-CM75, iPS-CM50, iPS-CM25) of the total cell number. Using the image correlation analysis (Fig 1a-d), a non-invasive method, the effect of the amount of NHCF and the type of extra cellular matrix (ECM) coating used in the developed technique was determined. After 4 days of incubation, it was observed that the microtissue formed from the cells coated with collagen and with 25% NHCF had the best performance (Fig. 1e-f). However, further tests are still needed to determine if a lower amount of NHCF will have better performance and if it will be compatible with the host myocardium. Other tests are still needed to be done to determine the relationship of the histology to the observed contractile behavior. In addition, the presented data can be utilized in tuning the contractile behavior of the tissue by changing the ratio of iPS-CM and NHCF and cell surface coating depending on the desired behavior. With this, an alternative method for analyzing the engineered tissue and assessing the derived parameters were formulated which can be helpful in realizing the ideal cardiac tissue for transplant.

Studies at the Pacific Northwest National Laboratory (PNNL) in Richland, Washington, were conducted to evaluate nondestructive examinations (NDE) coupled with mechanical testing of butt fusion joints in high-density polyethylene (HDPE) pipe for assessing lack of fusion. The work provided information to the United States Nuclear Regulatory Commission (NRC) on the effectiveness of volumetric inspection techniques of HDPE butt fusion joints in Section III, Division 1, Class 3, buried piping systems in nuclear power plants. This paper describes results from assessments using ultrasonic and microwave nondestructive techniques and mechanical testing with the high-speed tensile impact test and the side-bend test for determining joint integrity. A series of butt joints were fabricated in 3408, 12-inch (30.5-cm) IPS DR-11 HDPE material by varying the fusion parameters to create good joints and joints containing a range of lack-of-fusion conditions. Six of these butt joints were volumetrically examined with time-of-flight diffraction (TOFD), phased-array (PA) ultrasound, and the Evisive microwave system. The outer diameter (OD) weld beads were removed for microwave evaluation and the pipes ultrasonically re-evaluated. In two of the six pipes, both the outer and inner diameter (ID) weld beads were removed and the pipe joints re-evaluated. Some of the pipes were sectioned and the joints destructively evaluated with the high-speed tensile test and the side-bend test. The fusion parameters, nondestructive and destructive evaluation results have been correlated to validate the effectiveness of what each NDE technology detects and what each does not detect based on the limited testing that was conducted. No single NDE method detected all of the lack-of-fusion flaws; further a combination of NDE methods did not detect all of the flaws.

Studies at the Pacific Northwest National Laboratory (PNNL) in Richland, Washington, are being conducted to evaluate nondestructive examinations (NDE) coupled with mechanical testing of butt fusion joints in high density polyethylene (HDPE) pipe for assessing lack of fusion. The work provides information to the United States Nuclear Regulatory Commission (NRC) on the effectiveness of volumetric inspection techniques of HDPE butt fusion joints in Section III, Division 1, Class 3, buried piping systems in nuclear power plants. This paper describes results from preliminary assessments using ultrasonic and microwave nondestructive techniques and mechanical testing with the high speed tensile impact test and the bend test for determining joint integrity. A series of butt joints were fabricated in 3408, 12 inch (30.5 cm) IPS DR-11 HDPE material by varying the fusion parameters to create good joints and joints containing a range of lack of fusion conditions. Six of these butt joints were volumetrically examined with time of flight diffraction (TOFD), phased array (PA) ultrasound, and the Evisive microwave system. The outer diameter (OD) weld beads were removed for microwave evaluation and the pipes ultrasonically re-evaluated. In two of the six pipes both the outer and inner diameter (ID) weld beads were removed and the pipe joints re-evaluated. Several of the pipes were sectioned and the joints destructively evaluated with the following techniques: high speed tensile test, bend test, and focused immersion ultrasound on a joint section removed from the pipe coupled with slicing through the joint and examining the revealed surfaces. The fusion parameters, nondestructive, and destructive evaluation results will be correlated to validate the effectiveness of what each NDE technology detects and what each does not detect. This is an initial limited study which will aid in identifying key future work.

Companies and investors in land-based sectors have a responsibility to respect human rights and the legitimate tenure rights of Indigenous Peoples, local communities, and Afro-descendant Peoples (IPs, LCs, and ADPs). These responsibilities are evident in international frameworks, national laws, emerging regulation, industry best practices, and the social and sustainability policies and commitments made by progressive companies and investors. As a result, comprehensive human rights and environmental due diligence (HREDD) processes are required for companies and investors to proactively assess the potential impacts of their enterprises on collective rightsholders and establish measures to prevent, mitigate, and remedy potential harms tied to their business operations, supply chains, and investments. Secure tenure and the effective engagement of local rightsholders are critical to the success of HREDD, and community monitoring provides a pathway to building reciprocal and rights-based relationships that bridge the divide between communities and companies/investors. Community monitoring (CM) refers to a process in which IPs, LCs, and ADPs assess and collect data on business operations that may affect their lands, territories, resources, rights, cultures, and livelihoods. Communities utilize this data to inform and shape business practices, prevent/address negative human rights and environmental impacts, and hold companies and investors accountable to crucial laws and standards. Where partnerships are developed, CM can help companies and investors improve their compliance with these laws and standards, including their internal policies and commitments, as well as reduce operational and reputational risks. Most importantly, CM supports more direct, balanced, and rights-based partnerships between communities and companies/investors, which are required to continually respect the legitimate tenure rights and self-determination of IPs, LCs, and ADPs—rights that are intrinsically tied to achieving global climate and biodiversity goals and associated corporate sustainability agendas. In response to this burgeoning opportunity, this document shares emerging ideas, principles, and good practices to socialize the concept of CM among companies and investors in land-based sectors, as well as outline steps they can take to meaningfully engage with IPs, LCs, and ADPs to monitor and respond to the potential environmental and human rights impacts of their operations, supply chains, or investments.