bluuebunny/crossref_metadata_2025_split huggingface dataset:
Information silos distort biomedical research
Authors: Rodriguez-Esteban Raul 
Published: July 2021

AbstractInformation silos have been an oft-maligned feature of scientific research for introducing a bias towards knowledge that is produced within a scientist’s own community. The vastness of the scientific literature has been commonly blamed for this phenomenon, despite recent improvements in information retrieval and text mining. Its actual negative impact on scientific progress, however, has never been quantified. This analysis attempts to do so by exploring its effects on biomedical discovery, particularly in the discovery of relations between diseases, genes and chemical compounds. Results indicate that the probability that two scientific facts will enable the discovery of a new fact depends on how far apart these two facts were published within the scientific landscape. In particular, the probability decreases exponentially with the citation distance. Thus, the direction of scientific progress is distorted based on the location in which each scientific fact is published, representing a path-dependent bias in which originally closely-located discoveries drive the sequence of future discoveries. To counter this bias, scientists should open the scope of their scientific work with modern computational approaches.
Molecular Pathophysiology of Cardiac Injury and Cardiac Microthrombi in Fatal COVID-19: Insights from Clinico-histopathologic and Single Nuclei RNA Sequencing Analyses
Authors: Fukuma Nobuaki , Hulke Michelle L. , Brener Michael I. , Golob Stephanie , Zilinyi Robert , Zhou Zhipeng , Tzimas Christos , Russo Ilaria , McGroder Claire , Pfeiffer Ryan , Chong Alexander , Zhang Geping , Burkhoff Daniel , Leon Martin B. , Maurer Mathew , Moses Jeffrey W. , Uhlemann Anne-Catrin , Hibshoosh Hanina , Uriel Nir , Szabolcs Matthias J. , Redfors Björn , Marboe Charles C. , Baldwin Matthew R. , Tucker Nathan R. , Tsai Emily J. 
Published: July 2021

AbstractCardiac injury is associated with critical COVID-19, yet its etiology remains debated. To elucidate the pathogenic mechanisms of COVID-19-associated cardiac injury, we conducted a single-center prospective cohort study of 69 COVID-19 decedents. Of six cardiac histopathologic features, microthrombi was the most commonly detected (n=48, 70%). We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak ESR and CRP during hospitalization were independently associated with higher odds of microthrombi. Using single nuclei RNA-sequence analysis, we discovered an enrichment of pro-thrombotic/anti-fibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling amongst cardiac fibroblasts in microthrombi-positive COVID-19 hearts relative to microthrombi-negative COVID-19. Non-COVID-19 non-failing hearts were used as reference controls. Our cumulative findings identify the specific transcriptomic changes in cardiac fibroblasts as salient features of COVID-19-associated cardiac microthrombi.
Deep learning-based segmentation of high-resolution computed tomography image data outperforms commonly used automatic bone segmentation methods
Authors: Patton Daniella M. , Henning Emilie N. , Goulet Rob W. , Carroll Sean K. , Bigelow Erin M.R. , Provencher Benjamin , Piché Nicolas , Marsh Mike , Jepsen Karl J. , Bredbenner Todd L. 
Published: July 2021

AbstractSegmenting bone from background is required to quantify bone architecture in computed tomography (CT) image data. A deep learning approach using convolutional neural networks (CNN) is a promising alternative method for automatic segmentation. The study objectives were to evaluate the performance of CNNs in automatic segmentation of human vertebral body (micro-CT) and femoral neck (nano-CT) data and to investigate the performance of CNNs to segment data across scanners.Scans of human L1 vertebral bodies (microCT [North Star Imaging], n=28, 53μm3) and femoral necks (nano-CT [GE], n=28, 27μm3) were used for evaluation. Six slices were selected for each scan and then manually segmented to create ground truth masks (Dragonfly 4.0, ORS). Two-dimensional U-Net CNNs were trained in Dragonfly 4.0 with images of the [FN] femoral necks only, [VB] vertebral bodies only, and [F+V] combined CT data. Global (i.e., Otsu and Yen) and local (i.e., Otsu r = 100) thresholding methods were applied to each dataset. Segmentation performance was evaluated using the Dice coefficient, a similarity metric of overlap. Kruskal-Wallis and Tukey-Kramer post-hoc tests were used to test for significant differences in the accuracy of segmentation methods.The FN U-Net had significantly higher Dice coefficients (i.e., better performance) than the global (Otsu: p=0.001; Yen: p=0.001) and local (Otsu [r=100]: p=0.001) thresholding methods and the VB U-Net (p=0.001) but there was no significant difference in model performance compared to the FN + VB U-net (p=0.783) on femoral neck image data. The VB U-net had significantly higher Dice coefficients than the global and local Otsu (p=0.001 for both) and FN U-Net (p=0.001) but not compared to the Yen (p=0.462) threshold or FN + VB U-net (p=0.783) on vertebral body image data.The results demonstrate that the U-net architecture outperforms common thresholding methods. Further, a network trained with bone data from a different system (i.e., different image acquisition parameters and voxel size) and a different anatomical site can perform well on unseen data. Finally, a network trained with combined datasets performed well on both datasets, indicating that a network can feasibly be trained with multiple datasets and perform well on varied image data.
Gliding motility of a uranium tolerant Bacteroidetes bacterium Chryseobacterium sp. strain PMSZPI: Insights into the architecture of spreading colonies
Authors: Khare Devanshi , Chandwadkar Pallavi , Acharya Celin 
Published: July 2021

SummaryUranium tolerant soil bacterium Chryseobacterium sp. strain PMSZPI moved over solid agar surfaces by gliding motility thereby forming spreading colonies which is a hallmark of members of Bacteroidetes phylum. PMSZPI genome harbored orthologs of all the gld and spr genes considered as core bacteroidetes gliding motility genes of which gldK, gldL, gldM, and gldN were co-transcribed. Here, we present the intriguing interplay between gliding motility and cellular organization in PMSZPI spreading colonies. While nutrient deficiency enhanced colony spreading, high agar concentrations and presence of motility inhibitor like 5-hydroxyindole reduced the spreading. A detailed in situ structural analysis of spreading colonies revealed closely packed cells forming multiple layers at center of colony while the edges showed clusters of cells periodically arranged in hexagonal lattices interconnected with each other. The cell migration within the colony was visualized as branched structures wherein the cells were buried within extracellular matrix giving rise to ‘fern’ like patterns. PMSZPI colonies exhibited strong iridescence that showed correlation with gliding motility. Presence of uranium reduced motility and iridescence and induced biofilm formation. This is a first report of gliding motility and iridescence in a bacterium from uranium enriched environment that could be of significant interest from an ecological perspective.Originality-Significance StatementThis work provides the first description of the gliding motility and iridescence or structural coloration in a Bacteroidetes soil bacterium from uranium enriched environment. The periodic arrangement of the cell population in the spreading colonies achieved through gliding motility resulted in bright structural coloration of the colonies when illuminated. The study describes the exogenous factors including nutrition, substrate, presence of uranium influencing the motility and iridescence of the bacterium. The highly organized cell population in the gliding and iridescent bacterium may have conferred survival advantage in metal/uranium enriched ecosystem.
Evolution of binding preferences among whole-genome duplicated transcription factors
Authors: Gera Tamar , Jonas Felix , More Roye , Barkai Naama 
Published: July 2021

AbstractThroughout evolution, new transcription factors (TFs) emerge by gene duplication, promoting growth and rewiring of transcriptional networks. How TF duplicates diverge is known for only a few studied cases. To provide a genome-scale view, we considered the 35% of budding yeast TFs, classified as whole-genome duplication (WGD)-retained paralogs. Using high-resolution profiling, we find that ~60% of paralogs evolved differential binding preferences. We show that this divergence results primarily from variations outside the DNA binding domains (DBDs), while DBD preferences remain largely conserved. Analysis of non-WGD orthologs revealed that ancestral preferences are unevenly split between duplicates, while new targets are acquired preferentially by the least conserved paralog (biased sub/neo-functionalization). Dimer-forming paralogs evolved mostly one-sided dependency, while other paralogs interacted through low-magnitude DNA-binding competition that minimized paralog interference. We discuss the implications of our findings for the evolutionary design of transcriptional networks.
Can AlphaFold2 predict protein-peptide complex structures accurately?
Authors: Ko Junsu , Lee Juyong 
Published: July 2021

AbstractIn this preprint, we investigated whether AlphaFold2, AF2, can predict protein-peptide complex structures only with sequence information. We modeled the structures of 203 protein-peptide complexes from the PepBDB DB and 183 from the PepSet. The structures were modeling with concatenated sequences of receptors and peptides via poly-glycine linker. We found that for more than half of the test cases, AF2 predicted the bound structures of peptides with good accuracy, Cα-RMSD of a peptide < 3.0 Å. For about 40% of cases, the peptide structures were modeled with an accuracy of Cα-RMSD < 2.0 Å. Our benchmark results clearly show that AF2 has a great potential to be applied to various higher-order structure prediction tasks.
CD8+ T-Cell Metabolic Rewiring Defined by Single-Cell RNA-Sequencing Identifies a Critical Role of ASNS Expression Dynamics in T-Cell Differentiation
Authors: Fernández-García Juan , Franco Fabien , Parik Sweta , Pane Antonino A. , Broekaert Dorien , van Elsen Joke , Vermeire Ines , van Brussel Thomas , Schepers Rogier , Modave Elodie , Karakach Tobias K. , Carmeliet Peter , Lambrechts Diether , Ho Ping-Chih , Fendt Sarah-Maria 
Published: July 2021

ABSTRACTCytotoxic T cells dynamically rewire their metabolism during the course of an immune response. While T-cell metabolism has been extensively studied at phenotypic endpoints of activation and differentiation, the underlying dynamics remain largely elusive. Here, we leverage on single-cell RNA-sequencing (scRNA-seq) measurements of in vitro activated and differentiated CD8+ T cells cultured in physiological media to resolve these metabolic dynamics. We find that our scRNA-seq analysis identifies most metabolic changes previously defined in in vivo experiments, such as a rewiring from an oxidative to an anabolism-promoting metabolic program during activation to an effector state, which is later reverted upon memory polarization. Importantly, our scRNA-seq data further provide a dynamic description of these changes. In this sense, our data predict a differential time-dependent reliance of CD8+ T cells on the synthesis versus uptake of various non-essential amino acids during T-cell activation, which we corroborate with additional functional in vitro experiments. We further exploit our scRNA-seq data to identify metabolic genes that could potentially dictate the outcome of T-cell differentiation, by ranking them based on their expression dynamics. Among the highest-ranked hits, we find asparagine synthetase (Asns), whose expression sharply peaks for effector CD8+ T cells and further decays towards memory polarization. We then confirm that these in vitro Asns expression dynamics are representative of an in vivo situation in a mouse model of viral infection. Moreover, we find that disrupting these expression dynamics in vitro, by depleting asparagine from the culture media, delays central-memory polarization. Accordingly, we find that preventing the decay of ASNS by stable overexpression at the protein level in vivo leads to a significant increase in effector CD8+ T-cell expansion, and a concomitant decrease in central-memory formation, in a mouse model of viral infection. This shows that ASNS expression dynamics dictate the fate of CD8+ T-cell differentiation. In conclusion, we provide a resource of dynamic expression changes during CD8+ T-cell activation and differentiation that is expected to increase our understanding of the dynamic metabolic requirements of T cells progressing along the immune response cascade.
Transcriptome-wide in vivo mapping of cleavage sites for the compact cyanobacterial ribonuclease E reveals insights into its function and substrate recognition
Authors: Hoffmann Ute A. , Heyl Florian , Rogh Said N. , Wallner Thomas , Backofen Rolf , Hess Wolfgang R. , Steglich Claudia , Wilde Annegret 
Published: July 2021

ABSTRACTRibonucleases are crucial enzymes in RNA metabolism and post-transcriptional regulatory processes in bacteria. Cyanobacteria encode the two essential ribonucleases RNase E and RNase J. Cyanobacterial RNase E is shorter than homologues in other groups of bacteria and lacks both the chloroplast-specific N-terminal extension as well as the C-terminal domain typical for RNase E of enterobacteria. In order to investigate the function of RNase E in the model cyanobacterium Synechocystis sp. PCC 6803, we engineered a temperature-sensitive RNase E mutant by introducing two site-specific mutations, I65F and spontaneously occurring V94A. This enabled us to perform RNA-seq after the transient inactivation of RNase E by a temperature shift (TIER-seq) and to map 1,472 RNase-E-dependent cleavage sites. We inferred a dominating cleavage signature consisting of an adenine at the -3 and a uridine at the +2 position within a single-stranded segment of the RNA. The data identified putative RNase-E-dependent instances of operon discoordination, mRNAs likely regulated jointly by RNase E and an sRNA, potential 3’ end-derived sRNAs and a dual-acting mechanism for the glutamine riboswitch. Our findings substantiate the pivotal role of RNase E in post-transcriptional regulation and suggest the redundant or concerted action of RNase E and RNase J in cyanobacteria.
Lytic transglycosylases mitigate periplasmic crowding by degrading soluble cell wall turnover products
Authors: Weaver Anna , Alvarez Laura , Rosch Kelly , Ahmed Asraa , Wang Garrett , VanNieuwenhze Michael , Cava Felipe , Dörr Tobias 
Published: July 2021

AbstractThe peptidoglycan cell wall is a predominant structure of bacteria, determining cell shape and supporting survival in diverse conditions. Peptidoglycan is dynamic and requires regulated synthesis of new material, remodeling, and turnover – or autolysis – of old material. Despite exploitation of peptidoglycan synthesis as an antibiotic target, we lack a fundamental understanding of how peptidoglycan synthesis and autolysis intersect to maintain the cell wall. Here, we uncover a critical physiological role for a widely misunderstood class of autolytic enzymes, lytic transglycosylases (LTGs). We demonstrate that LTG activity is essential to survival by contributing to periplasmic processes upstream and independent of peptidoglycan recycling. Defects accumulate in Vibrio cholerae LTG mutants due to generally inadequate LTG activity, rather than absence of specific enzymes, and essential LTG activities are likely independent of protein-protein interactions, as heterologous expression of a non-native LTG rescues growth of a conditionally LTG-null mutant. Lastly, we demonstrate that soluble, uncrosslinked, endopeptidase-dependent peptidoglycan chains, also detected in the wild-type, are enriched in LTG mutants, and that LTG mutants are hypersusceptible to the production of diverse periplasmic polymers. Collectively, our results suggest that LTGs prevent toxic crowding of the periplasm with synthesis-derived peptidoglycan polymers and contrary to prevailing models, that this autolytic function can be temporally separate from peptidoglycan synthesis.
Proximity labeling identifies LOTUS domain proteins that promote the formation of perinuclear germ granules in C. elegans
Authors: Price Ian F. , Hertz Hannah L. , Pastore Benjamin , Wagner Jillian , Tang Wen 
Published: July 2021

AbstractThe germline produces gametes that transmit genetic and epigenetic information to the next generation. Maintenance of germ cells and development of gametes require germ granules—well-conserved membraneless and RNA-rich organelles. The composition of germ granules is elusive owing to their dynamic nature and their exclusive expression in the germline. Using C. elegans germ granule, called P granule, as a model system, we employed a proximity-based labeling method in combination with mass spectrometry to comprehensively define its protein components. This set of experiments identified over 200 proteins, many of which contain intrinsically disordered regions. An RNAi-based screen identified factors that are essential for P granule assembly, notably EGGD-1 and EGGD-2, two previously uncharacterized LOTUS-domain proteins. Loss of eggd-1 and eggd-2 results in separation of P granules from nuclear envelope, germline atrophy and reduced fertility. We show that intrinsically disordered regions of EGGD-1 are required to anchor EGGD-1 to the nuclear periphery while its LOTUS domains are required to promote perinuclear localization of P granules. Together, our work expands the repertoire of P granule constituents and provides new insights into the role of LOTUS-domain proteins in germ granule organization.
1,25(OH)2D3 attenuates hepatic insulin resistance in rats with streptozotocin-induced diabetes via antioxidation
Authors: Huang Guoyu , Ding Runrong , Zhang Yujing , Gao Jiaojiao , Xu Ze , Li Wenjie , Li Xing 
Published: July 2021

AbstractAimThis study was conducted to explore the mechanism by which 1,25(OH)2D3 ameliorates hepatic insulin resistance in rats with streptozotocin (STZ)-induced type 2 diabetes.MethodsSprague Dawley (SD) rats were randomly divided into five groups: normal, control, and 1,25(OH)2D3 administered at 0.075, 0.15, and 0.3 μg/kg/d. Tissue and blood samples were obtained from all five groups after 4 and 12 weeks of treatment. Morphological changes in the livers were observed with HE staining. The levels of fasting blood glucose (FBG), insulin, and lipids were determined using an automatic biochemistry analyzer. The levels of hepatic glycogen, superoxide dismutase (SOD), malondialdehyde (MDA), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were analyzed by spectrophotometry. Protein expression of AKT and GLUT2 was examined by western blotting.Results1,25(OH)2D3 treatment reduced the FBG content as well as hepatic MDA, AST, and ALT levels, improved the activity of SOD, and enhanced the expression of GLUT2 and AKT in diabetic rats. These findings suggest that 1,25(OH)2D3, exerts antioxidant effects and ameliorates insulin resistance in the liver.Conclusion1,25(OH)2D3 is a potential agent that could be used in the treatment of insulin resistance in the liver.
Antifungal activity ofConocephalum conicum(L) Dumort. (Marchantiophyta) againstFusarium oxysporumf. sp.lycopersici
Authors: Negi Kavita , Chaturvedi Preeti 
Published: July 2021

AbstractTomato, a high valuevegetable crop, suffers huge production losses in tropics due to a wilt disease caused byFusarium oxysporumf. sp.lycopersici. Present study was undertaken to find an effective biocontrol method to check fusarium wilt in order to curb the losses suffered by the crop growers. Organic extracts(acetone, methanol/ethanol) of thalloid bryophytes (Conocephalumconicum(L.) Dumort. andMarchantiapapillataRaddi subsp.grossibarba(Steph.) Bischl.)were tested againstF. oxysporumf. sp.lycopersiciusing disc diffusion and micro broth dilution assay.Methanol extract ofC.conicum(L.) Dumort. (CCDM) showed significantly high antifungal activity (85.5% mycelial inhibition; 31.25μg/mL MIC and 125μg/mL MFC).Potential of methanol extract was tested in a glasshouse experiment on tomato, which illustrated the efficacy of the plant extract to control the fusarial wilt. Morphological and ultrastructural alterationsin CCDM treated fusarium myceliawere observed in scanning electron microscopy. GC-MS analysis of CCDM extract showed the presence of51 constituents, and the dominant compounds werebis (bibenzyl), acyclic alkanes, fatty acids, sesquiterpenpoids and steroids. The study suggested thatC. conicumbeing an efficient source of Riccardin C like antifungal compounds provides a potent and eco-friendly alternative to conventional fungicides in vegetables.
B Cell Receptor Signaling Drives APOBEC3 Expression Via Direct Enhancer Regulation in Chronic Lymphocytic Leukemia B Cells
Authors: Wang Zhiquan , Yan Huihuang , Boysen Justin C. , Secreto Charla R. , Zhong Jian , Zhou Jiaqi , Gan Haiyun , Yu Chuanhe , Braggio Esteban , Slager Susan L. , Parikh Sameer A. , Kay Neil E. 
Published: July 2021

AbstractConstitutively activated B cell receptor (BCR) signaling is a primary biological feature of chronic lymphocytic leukemia (CLL). The biological events controlled by BCR signaling in CLL are not fully understood and need investigation. To make inroads we obtained blood samples from CLL patients before and after Bruton’s tyrosine kinase inhibitors (BTKi) treatment and used them to study BCR signaling regulated genes. Here, by analysis of the chromatin states and gene expression profiles of CLL B cells from patients before and after BTKi ibrutinib treatment, we show that BTKi treatment leads to a decreased expression of APOBEC3 family genes in an enhancer regulation dependent manner. BTKi treatment reduces enrichment of enhancer markers (H3K4me1, H3K27ac) and chromatin accessibility at putative APOBEC3 enhancers. CRISPR-Cas9 directed deletion or inhibition of the putative APOBEC3 enhancers leads to reduced APOBEC3 expression. We further find that transcription factor NFATc1 couples BCR signaling with the APOBEC3 enhancer activity to control APOBEC3 expression. Importantly, enhancer regulated APOBEC3 expression contributes to replication stress in malignant B cells. We also demonstrate a novel mechanism for BTKi suppression of APOBEC3 expression via direct enhancer regulation in a NFATc1 dependent manner, implicating BCR signaling as a potential regulator of leukemic genomic instability.Key pointsBCR signaling pathway regulates APOBEC3 expression via direct enhancer regulation.AOPEBC3 enhancers are involved in the process of DNA replication stress, implicating a potential role in B cell genomic instability and CLL evolution