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Abstract Wildlife conservation in Andean countries is a global priority because of the high levels of biodiversity and endemism. Historically, these countries have had limited resources to monitor wildlife (e.g., through genetic tools) and establish conservation programs. Focusing on the study and emblematic use of a few charismatic species has been a strategic approach to direct efforts for conservation and development planning. Consequently, the Andean bear is a flagship and umbrella species for highly biodiverse Andean countries like Ecuador. The few studies exploring the population genetics of this species have concluded that it has low genetic diversity and few units for conservation as populations appear to be well connected. However, these results might be attributed to ascertainment bias as studies have been performed with heterologous molecular markers. Here, using both mtDNA sequences and species-specific microsatellite markers, we show that Andean bears in Ecuador have population structure. Additionally, we found through the study of three Ecuadorian populations that the species might have a higher genetic diversity than we previously thought. These results could support the revision of research priorities, conservation, and planning strategies to improve connectivity for this species which occurs in crucial biodiversity hotspots.

T-cell specificity to differentiate between self and non-self relies on T-cell receptor (TCR) recognition of peptides presented by the Major Histocompatibility Complex (MHC). Investigations into the three-dimensional (3D) structures of peptide:MHC (pMHC) complexes have provided valuable insights of MHC functions. Given the limited availability of experimental pMHC structures and considerable diversity of peptides and MHC alleles, it calls for the development of efficient and reliable computational approaches for modeling pMHC structures. Here we present an update of PANDORA and the systematic evaluation of its performance in modelling 3D structures of pMHC class II complexes (pMHC-II), which play a key role in the cancer immune response. PANDORA is a modelling software that can build low-energy models in a few minutes by restraining peptide residues inside the MHC-II binding groove. We benchmarked PANDORA on 136 experimentally determined pMHC-II structures covering 44 unique αβ chain pairs. Our pipeline achieves a median backbone Ligand-Root Mean Squared Deviation (L-RMSD) of 0.42 Å on the binding core and 0.88 Å on the whole peptide for the benchmark dataset. We incorporated software improvements to make PANDORA a pan-allele framework and improved the user interface and software quality. Its computational efficiency allows enriching the wealth of pMHC binding affinity and mass spectrometry data with 3D models. These models can be used as a starting point for molecular dynamics simulations or structure-boosted deep learning algorithms to identify MHC-binding peptides. PANDORA is available as a Python package through Conda or as a source installation at https://github.com/X-lab-3D/PANDORA.

Macrophages have been reported to regulate thermogenic, sympathetic neuron-mediated norepinephrine signaling in adipose tissues. Here the authors report that male mice lacking the allograft inflammatory factor-1 protein are resistant to diet-induced obesity, in association with higher adipose norepinephrine levels and lower expression of the norepinephrine catabolic enzyme monoamine oxidase A.

Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a secreted protein of incompletely understood physiological function. Here the authors show that scEMC10 is upregulated in people with obesity, and that that genetic EMC10 deletion or antibody-based neutralization of EMC10 prevents diet-induced obesity in mice.

Theobroma cacao L. species, cultivated worldwide for its valuable beans, generates up to 72% weight of the fruit as waste. The lack of reutilization technologies in the cocoa agroindustry has hindered the exploitation of valuable bio-components applicable to the generation of high value added bioproducts. One such bioproduct is microfibrillated cellulose (MFC), a biopolymer that stands out for its desirable mechanical properties and biocompatibility in biomedical, packing, 3D printing, and construction applications. In this study, we isolated microfibrillated cellulose (MFC) from cocoa pod husk (CPH) via oxalic acid hydrolysis combined with a steam explosion. MFC isolation started with the Solid/Liquid extraction via Soxhlet, followed by mild citric acid hydrolysis, diluted alkaline hydrolysis, and bleaching pre-treatments. A Response Surface Methodology (RSM) was used to optimize the hydrolysis reaction at levels between 110 and 125 °C, 30–90 min at 5–10% (w/v) oxalic acid concentration. The cellulose-rich fraction was characterized by Fourier-Transform Infrared Spectroscopy (FTIR), Thermogravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD), and Scanning Electron Microscopy (SEM) analyses. Characterization analyses revealed a cellulose-rich polymer with fibers ranging from 6 to 10 μm, a maximum thermal degradation temperature of 350 °C, and a crystallinity index of 63.4% (peak height method) and 29.0% (amorphous subtraction method). The optimized hydrolysis conditions were 125 °C, 30 min, at 5% w/v oxalic acid: with a 75.7% yield. These results compare with MFC obtained through highly concentrated inorganic acid hydrolysis from different biomass sources. Thus, we show a reliable and greener alternative chemical treatment for the obtention of MFC.

The authors present DeepRank, a deep learning framework for the data mining of large sets of 3D protein-protein interfaces (PPI). They use DeepRank to address two challenges in structural biology: distinguishing biological versus crystallographic PPIs in crystal structures, and secondly the ranking of docking models.

Summary: Prevention or amelioration of declining β cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by β cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961-induced β cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks β-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of β cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables β cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential therapeutic target, to promote β cell compensation.

Summary: Mouse models enable the study of genetic factors affecting the complex pathophysiology of metabolic disorders. Here, we identify reductions in leptin levels, food intake, and obesity due to high-fat diet, accompanied by increased leptin sensitivity, in mice that harbor the E2a-Cre transgene within Obrq2, an obesity quantitative trait locus (QTL) that includes the leptin gene. Interestingly, loss of allograft inflammatory factor-1-like (AIF1L) protein in these transgenic mice leads to similar leptin sensitivity, yet marked reversal of the obesity phenotype, with accelerated weight gain and increased food intake. Transgenic mice lacking AIF1L also have low circulating leptin, which suggests that benefits of enhanced leptin sensitivity are lost with further impairment of leptin expression due to loss of AIF1L. Together, our results identify AIF1L as a genetic modifier of Obrq2 and leptin that affects leptin levels, food intake, and obesity during the metabolic stress imposed by HFD.

Vascular smooth muscle cells (VSMCs) are normally quiescent and non-migratory, regulating the contraction and relaxation of blood vessels to control the vascular tone. In response to arterial injury, these cells become active; they proliferate, secrete matrix proteins, and migrate, and thereby contribute importantly to the progression of several cardiovascular diseases. VSMC migration specifically supports atherosclerosis, restenosis after catheter-based intervention, transplant vasculopathy, and vascular remodeling during the formation of aneurysms. The atypical cadherin FAT1 is expressed robustly in activated VSMCs and promotes their migration. A positive role of FAT1 in the migration of other cell types, including neurons, fibroblasts, podocytes, and astrocyte progenitors, has also been described. In cancer biology, however, the effect of FAT1 on migration depends on the cancer type or context, as FAT1 either suppresses or enhances cancer cell migration and invasion. With this review, we describe what is known about FAT1’s effects on cell migration as well as the factors that influence FAT1-dependent migration. In VSMCs, these factors include angiotensin II, which activates FAT1 expression and cell migration, and proteins of the Atrophin family: Atrophin-1 and the short isoform of Atrophin-2, which promote VSMC migration, and the long isoform of Atrophin-2, which exerts negative effects on FAT1-dependent VSMC migration.

Deeper understanding of T-cell-mediated adaptive immune responses is important for the design of cancer immunotherapies and antiviral vaccines against pandemic outbreaks. T-cells are activated when they recognize foreign peptides that are presented on the cell surface by Major Histocompatibility Complexes (MHC), forming peptide:MHC (pMHC) complexes. 3D structures of pMHC complexes provide fundamental insight into T-cell recognition mechanism and aids immunotherapy design. High MHC and peptide diversities necessitate efficient computational modelling to enable whole proteome structural analysis. We developed PANDORA, a generic modelling pipeline for pMHC class I and II (pMHC-I and pMHC-II), and present its performance on pMHC-I here. Given a query, PANDORA searches for structural templates in its extensive database and then applies anchor restraints to the modelling process. This restrained energy minimization ensures one of the fastest pMHC modelling pipelines so far. On a set of 835 pMHC-I complexes over 78 MHC types, PANDORA generated models with a median RMSD of 0.70 Å and achieved a 93% success rate in top 10 models. PANDORA performs competitively with three pMHC-I modelling state-of-the-art approaches and outperforms AlphaFold2 in terms of accuracy while being superior to it in speed. PANDORA is a modularized and user-configurable python package with easy installation. We envision PANDORA to fuel deep learning algorithms with large-scale high-quality 3D models to tackle long-standing immunology challenges.

Smooth muscle cells contribute to cardiovascular disease, the leading cause of death worldwide. The capacity of these cells to undergo phenotypic switching in mature arteries of the systemic circulation underlies their pathogenic role in atherosclerosis and restenosis, among other vascular diseases. Growth factors and cytokines, extracellular matrix components, regulation of gene expression, neuronal influences, and mechanical forces contribute to smooth muscle cell phenotypic switching. Comparatively little is known about cell metabolism in this process. Studies of cancer and endothelial cell biology have highlighted the importance of cellular metabolic processes for phenotypic transitions that accompany tumor growth and angiogenesis. However, the understanding of cell metabolism during smooth muscle cell phenotypic modulation is incipient. Studies of the atypical cadherin FAT1, which is strongly upregulated in smooth muscle cells in response to arterial injury, suggest that it has important and distinctive functions in this context, mediating control of both smooth muscle cell mitochondrial metabolism and cell proliferation. Here we review the progress made in understanding how FAT1 affects the smooth muscle cell phenotype, highlighting the significance of FAT1 as a processed protein and unexpected regulator of mitochondrial respiration. These mechanisms suggest how a transmembrane protein may relay signals from the extracellular milieu to mitochondria to control metabolic activity during smooth muscle cell phenotypic switching.

Pinnipeds found across islands provide an ideal opportunity to examine the evolutionary process of population subdivision affected by several mechanisms. Here, we report the genetic consequences of the geographic distribution of rookeries in Galapagos fur seals (GFS: Arctocephalus galapagoensis) in creating population structure. We show that rookeries across four islands (nine rookeries) are genetically structured into the following major groups: 1) a western cluster of individuals from Fernandina; 2) a central group from north and east Isabela, Santiago, and Pinta; and possibly, 3) a third cluster in the northeast from Pinta. Furthermore, asymmetric levels of gene flow obtained from eight microsatellites found migration from west Isabela to Fernandina islands (number of migrants Nm = 1), with imperceptible Nm in any other direction. Our findings suggest that the marked structuring of populations recovered in GFS is likely related to an interplay between long-term site fidelity and long-distance migration in both male and female individuals, probably influenced by varying degrees of marine productivity.

Despite widespread transcription of LncRNA in mammalian systems, their contribution to metabolic homeostasis at the cellular and tissue level remains elusive. Here Pradas-Juni et al. describe a transcription factor–LncRNA pathway that couples hepatocyte nutrient sensing to regulation of glucose metabolism in mice.

About 6 million adults in the United States have heart failure, and the mortality five years after diagnosis remains high at approximately 50%. Incomplete understanding of disease pathogenesis limits therapeutics, especially in the case of heart failure with preserved ejection fraction, a condition commonly associated with cardiac hypertrophy. Neutrophils, the most abundant leukocyte in blood, have functions beyond antimicrobial activity and participate in both sterile inflammation and disease; however, their role in nonischemic cardiac hypertrophy and heart failure is underexplored. In this issue of the JCI, Tang et al. show that neutrophil extracellular trap (NET) formation contributes to cardiac hypertrophy and dysfunction in a mouse model of angiotensin II–induced cardiomyopathy, and that Krüppel-like factor 2 (KLF2) functions in neutrophils to oppose this process. Whether a neutrophil-centered strategy may benefit patients with cardiac hypertrophy and failure deserves further investigation.

Abstract Epitranscriptome profiling using MeRIP-seq is a powerful technique for in vivo functional studies of reversible RNA modifications. We develop RADAR, a comprehensive analytical tool for detecting differentially methylated loci in MeRIP-seq data. RADAR enables accurate identification of altered methylation sites by accommodating variability of pre-immunoprecipitation expression level and post-immunoprecipitation count using different strategies. In addition, it is compatible with complex study design when covariates need to be incorporated in the analysis. Through simulation and real dataset analyses, we show that RADAR leads to more accurate and reproducible differential methylation analysis results than alternatives, which is available at https://github.com/scottzijiezhang/RADAR.

Summary: The search for higher performance, improved safety, and lifetime of lithium-ion batteries relies on the understanding of degradation mechanisms. Complementary to methods and studies on primary particles or crystalline structure on bulk materials, here we use spatially correlated ptychographic X-ray computed nanotomography with a 35 nm resolution and scanning X-ray diffraction microscopy with 1 μm resolution to visualize in 3D the hidden morphological and structural degradation processes in individual secondary particles of lithium-rich nickel, cobalt, and manganese oxides. From comparative examination of pristine and cycled particles, we suggest that morphological degradation could have radial dependency and secondary particle size dependency. The same particles were examined to correlate the degradation to crystallinity, which shows surprising core-shell structures. This study reveals the inner 3D structure of the secondary particles while opening up questions on the unexpected crystalline structural distributions, which could offer clues for future studies on this promising cathode material for lithium-ion batteries. : Materials Characterization Techniques; Energy Materials; Crystallography Subject Areas: Materials Characterization Techniques, Energy Materials, Crystallography

Objectives: Insulin receptor (IR)-mediated signaling is involved in the regulation of pluripotent stem cells; however, its direct effects on regulating the maintenance of pluripotency and lineage development are not fully understood. The main objective of this study is to understand the role of IR signaling in pluripotency and lineage development. Methods: To explore the role of IR signaling, we generated IR knock-out (IRKO) mouse induced pluripotent stem cells (miPSCs) from E14.5 mouse embryonic fibroblasts (MEFs) of global IRKO mice using a cocktail of four reprogramming factors: Oct4, Sox2, Klf4, cMyc. We performed pluripotency characterization and directed the differentiation of control and IRKO iPSCs into neural progenitors (ectoderm), adipocyte progenitors (mesoderm), and pancreatic beta-like cells (endoderm). We mechanistically confirmed these findings via phosphoproteomics analyses of control and IRKO iPSCs. Results: Interestingly, expression of pluripotency markers including Klf4, Lin28a, Tbx3, and cMyc were upregulated, while abundance of Oct4 and Nanog were enhanced by 4-fold and 3-fold, respectively, in IRKO iPSCs. Analyses of signaling pathways demonstrated downregulation of phospho-STAT3, p-mTor and p-Erk and an increase in the total mTor and Erk proteins in IRKO iPSCs in the basal unstimulated state. Stimulation with leukemia inhibitory factor (LIF) showed a ∼33% decrease of phospho-ERK in IRKO iPSCs. On the contrary, Erk phosphorylation was increased during in vitro spontaneous differentiation of iPSCs lacking IRs. Lineage-specific directed differentiation of the iPSCs revealed that cells lacking IR showed enhanced expression of neuronal lineage markers (Pax6, Tubb3, Ascl1 and Oligo2) while exhibiting a decrease in adipocyte (Fas, Acc, Pparγ, Fabp4, C/ebpα, and Fsp27) and pancreatic beta cell markers (Ngn3, Isl1, and Sox9). Further molecular characterization by phosphoproteomics confirmed the novel IR-mediated regulation of the global pluripotency network including several key proteins involved in diverse aspects of growth and embryonic development. Conclusion: We report, for the first time to our knowledge, the phosphoproteome of insulin, IGF1, and LIF stimulation in mouse iPSCs to reveal the importance of insulin receptor signaling for the maintenance of pluripotency and lineage determination. Keywords: Insulin receptor signaling, Pluripotency, Lineage differentiation, Adipocyte, Beta cells, Neurons, Stem cells, Phosphoproteomics, Reprogramming

ABSTRACT Background: The criterion of Milan (CM) has been used as standard for indication of liver transplantation (LTx) for hepatocellular carcinoma (HCC) worldwide for nearly 20 years. Several centers have adopted criteria expanded in order to increase the number of patients eligible to liver transplantation, while maintaining good survival rates. In Brazil, since 2006, the criterion of Milan/Brazil (CMB), which disregards nodules 2 cm (p=0.028) were associated with relapse. The age (p=0.001), female (p2 cm (p

Background: Pancreatic β-cells adapt to high metabolic demand by expanding their β-cell mass and/or enhancing insulin secretion to maintain glucose homeostasis. Type 2 diabetes (T2D) is typically characterized by β-cell decompensation. Scope of the review: The current review focuses on summarizing the “omics” and “epi-omics” approaches that particularly focus on addressing the β-cell adaptation to insulin resistance and T2D. Major conclusions: The molecular mechanisms underlying successful versus compromised β-cell adaptation to insulin resistance are not entirely understood. The last decade has seen an exponential increase in the use of “omics” and “epi-omics” approaches to dissect pathophysiology of metabolic diseases. One recent example is the emergence of m6A mRNA methylation as a new layer of regulation of gene expression with the potential to impact diverse physiological processes in metabolic cells. Keywords: β-cells, Insulin resistance, Genomics, Transcriptomics, Epigenomics, Epitranscriptomics

How p53 is restrained in arterial maturation during embryonic development is unclear. Here, the authors show that β-catenin C-terminal interactions inhibit CREB binding protein-mediated acetylation and activation of p53 in smooth muscle cells, and that this function is essential for artery formation.

Pancreatic [beta] cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here, we report that succinate receptor 1 (SUCNR1) is expressed in [beta] cells and is upregulated in hyperglycemic states in mice and humans. We found that succinate acted as a hormone-like metabolite and stimulated insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human [beta] cells. Mice with [beta] cell-specific Sucnrl deficiency exhibited impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance showed an enhanced nutrition-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR- mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states., Introduction Insulin secretion by pancreatic [beta] cells is crucial for blood glucose homeostasis and is tightly controlled by a complex network of hormones, nutrients, and neurotransmitters. Impaired [beta] cell function [...]

PP-235, a 4-page illustrated fact sheet by Wayne M. Jurick II, Dario F. Narvaez, Carrie L. Harmon, James J. Marois, David L. Wright, and Philip F. Harmon, describes this fungal plant disease new to the US since 2004, its symptoms, causal organism, disease cycle and epidemiology, diagnosis, and management. Includes links to web-based resources and references. Published by the UF Department of Plant Pathology, July 2007.

AbstractThis study systematically reviewed the published literature on the objective characterization of myofascial pain syndrome and myofascial trigger points using imaging methods. PubMed, Embase, Ovid, and the Cochrane Library databases were used, whereas citation searching was conducted in Scopus. Citations were restricted to those published in English and in peer-reviewed journals between 2000 and 2021. Of 1762 abstracts screened, 69 articles underwent full-text review, and 33 were included. Imaging data assessing myofascial trigger points or myofascial pain syndrome were extracted, and important qualitative and quantitative information on general study methodologies, study populations, sample sizes, and myofascial trigger point/myofascial pain syndrome evaluation were tabulated. Methodological quality of eligible studies was assessed based on the Quality Assessment of Diagnostic Accuracy Studies criteria. Biomechanical properties and blood flow of active and latent myofascial trigger points assessed via imaging were found to be quantifiably distinct from those of healthy tissue. Although these studies show promise, more studies are needed. Future studies should focus on assessing diagnostic test accuracy and testing the reproducibility of results to establish the best performing methods. Increasing methodological consistency would further motivate implementing imaging methods in larger clinical studies. Considering the evidence on efficacy, cost, ease of use and time constraints, ultrasound-based methods are currently the imaging modalities of choice for myofascial pain syndrome/myofascial trigger point assessment.

BackgroundA better understanding of the pathophysiology involving coronary artery calcification (CAC) in patients on hemodialysis (HD) will help to develop new therapies. We sought to identify the differences in metabolomics profiles between patients on HD with and without CAC.MethodsIn this case-control study, nested within a cohort of 568 incident patients on HD, the cases were patients without diabetes with a CAC score >100 (n=51), and controls were patients without diabetes with a CAC score of zero (n=48). We measured 452 serum metabolites in each participant. Metabolites and pathway scores were compared using Mann-Whitney U tests, partial least squares-discriminant analyses, and pathway enrichment analyses.ResultsCompared with controls, cases were older (64±13 versus 42±12 years) and were less likely to be Black (51% versus 94%). We identified three metabolites in bile-acid synthesis (chenodeoxycholic, deoxycholic, and glycolithocholic acids) and one pathway (arginine/proline metabolism). After adjusting for demographics, higher levels of chenodeoxycholic, deoxycholic, and glycolithocholic acids were associated with higher odds of having CAC; comparing the third with the first tertile of each bile acid, the OR was 6.34 (95% CI, 1.12 to 36.06), 6.73 (95% CI, 1.20 to 37.82), and 8.53 (95% CI, 1.50 to 48.49), respectively. These associations were no longer significant after further adjustment for coronary artery disease and medication use. Per 1 unit higher in the first principal component score, arginine/proline metabolism was associated with CAC after adjusting for demographics (OR, 1.83; 95% CI, 1.06 to 3.15), and the association remained significant with additional adjustments for statin use (OR, 1.84; 95% CI, 1.04 to 3.27).ConclusionsAmong patients on HD without diabetes mellitus, chenodeoxycholic, deoxycholic, and glycolithocholic acids may be potential biomarkers for CAC, and arginine/proline metabolism is a plausible mechanism to study for CAC. These findings need to be confirmed in future studies.

MXenes, two-dimensional-layered transition metal carbides/nitrides, have emerged as promising candidates as electrode materials for supercapacitors. Especially, the unique layered structure of Ti3C2Tx has active redox sites and can avail ionic transportation to achieve high specific capacitance with charge storage capacity. In this contribution, a simple preparation method for few-layered Ti3C2Tx has been developed by chemical etching and exfoliation by freeze drying to study their structural and morphological properties. The electrochemical behavior of the few-layered Ti3C2Tx electrode were performed on the Ni-foil as a current collector. The pronounced –OH and –F surface terminations in few-layered Ti3C2Tx enhanced its supercapacitor performance reaching a specific capacitance 342.83 F/g at a current density of 1 A/g. A symmetric supercapacitor compact device has been fabricated and tested the charging and discharging performance by realizing a laboratory prototype capacitor through a resistor–capacitor (RC) circuit. Consequently, the exfoliated few-layered Ti3C2Tx demonstrated an enhanced electrochemical behavior thus making it excellent candidates for electrode materials in energy storage devices. [ABSTRACT FROM AUTHOR]