Modulation of Apoptosis Pathways by Oxidative Stress and Autophagy in β Cells

Human islets isolated for transplantation are exposed to multiple stresses including oxidative stress and hypoxia resulting in significant loss of functional β cell mass. In this study we examined the modulation of apoptosis pathway genes in islets exposed to hydrogen peroxide, peroxynitrite, hypoxia, and cytokines. We observed parallel induction of pro- and antiapoptotic pathways and identified several novel genes including BFAR, CARD8, BNIP3, and CIDE-A. As BNIP3 is an inducer of autophagy, we examined this pathway in MIN6 cells, a mouse beta cell line and in human islets. Culture of MIN6 cells under low serum conditions increased the levels of several proteins in autophagy pathway, including ATG4, Beclin 1, LAMP-2, and UVRAG. Amino acid deprivation led to induction of autophagy in human islets. Preconditioning of islets with inducers of autophagy protected them from hypoxia-induced apoptosis. However, induction of autophagy during hypoxia exacerbated apoptotic cell death. ER stress led to induction of autophagy and apoptosis in β cells. Overexpression of MnSOD, an enzyme that scavenges free radicals, resulted in protection of MIN6 cells from cytokine-induced apoptosis. Ceramide, a mediator of cytokine-induced injury, reduced the active phosphorylated form of Akt and downregulated the promoter activity of the antiapoptotic gene bcl-2. Furthermore, cytokine-stimulated JNK pathway downregulated the bcl-2 promoter activity which was reversed by preincubation with SP600125, a JNK inhibitor. Our findings suggest that β cell apoptosis by multiple stresses in islets isolated for transplantation is the result of orchestrated gene expression in apoptosis pathway

Violence against doctors is increasing worldwide. will the pandemic revert the trend?

In China the marketisation of health care, media criticism and public shaming led to a spiral of aggressions, write Milo Shaoqing Wang, Mia Raynard and Royston Greenwoo

Multiple Near-Isogenic Lines Targeting a QTL Hotspot of Drought Tolerance Showed Contrasting Performance Under Post-anthesis Water Stress

The complex quantitative nature of drought-related traits is a major constraint to breed tolerant wheat varieties. Pairs of near-isogenic lines (NILs) with a common genetic background but differing in a particular locus could turn quantitative traits into a Mendelian factor facilitating our understanding of genotype and phenotype interactions. In this study, we report our fast track development and evaluation of NILs from C306 × Dharwar Dry targeting a wheat 4BS QTL hotspot in C306, which confers drought tolerance following the heterogeneous inbreed family (HIF) analysis coupled with immature embryo culture-based fast generation technique. Molecular marker screening and phenotyping for grain yield and related traits under post-anthesis water stress (WS) confirmed four isoline pairs, viz., qDSI.4B.1-2, qDSI.4B.1-3, qDSI.4B.1-6, and qDSI.4B.1-8. There were significant contrasts of responses between the NILs with C306 QTL (+NILs) and the NILs without C306 QTL (−NILs). Among the four confirmed NIL pairs, mean grain yield per plant of the +NILs and −NILs showed significant differences ranging from 9.61 to 10.81 and 6.30 to 7.56 g, respectively, under WS condition, whereas a similar grain yield was recorded between the +NILs and −NILs under well-watered condition. Isolines of +NIL and −NIL pairs showed similar chlorophyll content (SPAD), assimilation rate (A), and transpiration rate (Tr) at the beginning of the stress. However, the +NILs showed significantly higher SPAD (12%), A (66%), stomatal conductance (75%), and Tr (97%) than the −NILs at the seventh day of stress. Quantitative RT-PCR analysis targeting the MYB transcription factor gene Triticum aestivum MYB 82 (TaMYB82), within this genomic region which was retrieved from the wheat reference genome TGACv1, also revealed differential expression in +NILs and –NILs under stress. These results confirmed that the NILs can be invaluable resources for fine mapping of this QTL, and also for cloning and functional characterization of the gene(s) responsible for drought tolerance in wheat

Content-Based Search for Deep Generative Models

The growing proliferation of customized and pretrained generative models has made it infeasible for a user to be fully cognizant of every model in existence. To address this need, we introduce the task of content-based model search: given a query and a large set of generative models, finding the models that best match the query. As each generative model produces a distribution of images, we formulate the search task as an optimization problem to select the model with the highest probability of generating similar content as the query. We introduce a formulation to approximate this probability given the query from different modalities, e.g., image, sketch, and text. Furthermore, we propose a contrastive learning framework for model retrieval, which learns to adapt features for various query modalities. We demonstrate that our method outperforms several baselines on Generative Model Zoo, a new benchmark we create for the model retrieval task.Comment: Our project page is hosted at https://generative-intelligence-lab.github.io/modelverse

The effect of first step right atrial mapping (FRAM) on ablation duration and fluoroscopy exposure during cavotricuspid isthmus ablation of atrial flutter

AIM To investigate the clinical significance of right atrial mapping prior to cavotricuspid isthmus (CTI) ablation in patients with typical atrial flutter (AFL). METHODS Clinical and ablation parameters were retrospectively assessed and compared in patients undergoing CTI ablation with or without a first-step right atrial mapping (FRAM) by using the CARTO 3D mapping system. RESULTS CTI block by radiofrequency ablation (RFA) was achieved in all 143 patients. In the FRAM group there was a shorter ablation duration and fluoroscopy exposure compared with the non-FRAM group. CHA$_{2}$DS$_{2}$-VASc score was associated with higher ablation durations, more ablation applications and increased fluoroscopy exposure. Body mass index (BMI) was associated with longer ablation duration and more ablation applications. Furthermore, patients with reduced left ventricular ejection fraction (LVEF) had longer ablation durations and more fluoroscopy exposure. One patient in the non-FRAM group developed cardiac effusion after ablation. None of the patients had recurrence after 6 months of follow-up. CONCLUSIONS Patients with high BMI, high CHA$_{2}$DS$_{2}$-VASc score and reduced LVEF may benefit from the FRAM approach by reducing ablation duration, number of ablation applications and fluoroscopy exposure

Practical Policy Optimization with Personalized Experimentation

Many organizations measure treatment effects via an experimentation platform to evaluate the casual effect of product variations prior to full-scale deployment. However, standard experimentation platforms do not perform optimally for end user populations that exhibit heterogeneous treatment effects (HTEs). Here we present a personalized experimentation framework, Personalized Experiments (PEX), which optimizes treatment group assignment at the user level via HTE modeling and sequential decision policy optimization to optimize multiple short-term and long-term outcomes simultaneously. We describe an end-to-end workflow that has proven to be successful in practice and can be readily implemented using open-source software.Comment: 5 pages, 2 figure

Long-Term Rewetting of Three Formerly Drained Peatlands Drives Congruent Compositional Changes in Pro- and Eukaryotic Soil Microbiomes through Environmental Filtering

Drained peatlands are significant sources of the greenhouse gas (GHG) carbon dioxide.Rewetting is a proven strategy used to protect carbon stocks; however, it can lead to increasedemissions of the potent GHG methane. The response to rewetting of soil microbiomes as drivers ofthese processes is poorly understood, as are the biotic and abiotic factors that control communitycomposition. We analyzed the pro- and eukaryotic microbiomes of three contrasting pairs ofminerotrophic fens subject to decade-long drainage and subsequent long-term rewetting. Abiotic soilproperties including moisture, dissolved organic matter, methane fluxes, and ecosystem respirationrates were also determined. The composition of the microbiomes was fen-type-specific, but allrewetted sites showed higher abundances of anaerobic taxa compared to drained sites. Based onmulti-variate statistics and network analyses, we identified soil moisture as a major driver ofcommunity composition. Furthermore, salinity drove the separation between coastal and freshwaterfen communities. Methanogens were more than 10-fold more abundant in rewetted than in drainedsites, while their abundance was lowest in the coastal fen, likely due to competition with sulfatereducers. The microbiome compositions were reflected in methane fluxes from the sites. Our resultsshed light on the factors that structure fen microbiomes via environmental filtering