bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial Genome Diversity across the Subphylum Saccharomycotina
Authors: Wolters John F. , LaBella Abigail L. , Opulente Dana A. , Rokas Antonis , Hittinger Chris Todd 
Published: July 2023

AbstractEukaryotic life depends on the functional elements encoded by both the nuclear genome and organellar genomes, such as those contained within the mitochondria. The content, size, and structure of the mitochondrial genome varies across organisms with potentially large implications for phenotypic variance and resulting evolutionary trajectories. Among yeasts in the subphylum Saccharomycotina, extensive differences have been observed in various species relative to the model yeastSaccharomyces cerevisiae, but mitochondrial genome sampling across many groups has been scarce, even as hundreds of nuclear genomes have become available. By extracting mitochondrial assemblies from existing short-read genome sequence datasets, we have greatly expanded both the number of available genomes and the coverage across sparsely sampled clades. Comparison of 353 yeast mitochondrial genomes revealed that, while size and GC content were fairly consistent across species, those in the generaMetschnikowiaandSaccharomycestrended larger, while several species in the order Saccharomycetales, which includesS. cerevisiae, exhibited lower GC content. Extreme examples for both size and GC content were scattered throughout the subphylum. All mitochondrial genomes shared a core set of protein-coding genes for Complexes III, IV, and V, but they varied in the presence or absence of mitochondrially-encoded canonical Complex I genes. We traced the loss of Complex I genes to a major event in the ancestor of the orders Saccharomycetales and Saccharomycodales, but we also observed several independent losses in the orders Phaffomycetales, Pichiales, and Dipodascales. In contrast to prior hypotheses based on smaller-scale datasets, comparison of evolutionary rates in protein-coding genes showed no bias towards elevated rates among aerobically fermenting (Crabtree/Warburg-positive) yeasts. Mitochondrial introns were widely distributed, but they were highly enriched in some groups. The majority of mitochondrial introns were poorly conserved within groups, but several were shared within groups, between groups, and even across taxonomic orders, which is consistent with horizontal gene transfer, likely involving homing endonucleases acting as selfish elements. As the number of available fungal nuclear genomes continues to expand, the methods described here to retrieve mitochondrial genome sequences from these datasets will prove invaluable to ensuring that studies of fungal mitochondrial genomes keep pace with their nuclear counterparts.
Low-barrier hydrogen bond determines target-binding affinity and specificity of the antitubercular drug bedaquiline
Authors: Słabońska Joanna , Sappati Subrahmanyam , Marciniak Antoni , Czub Jacek 
Published: July 2023

AbstractThe role of short strong hydrogen bonds (SSHB) in ligand-target binding remains largely unexplored, thereby hindering a potentially important avenue in the rational drug design. Here, we investigate the interaction between bedaquiline (Bq), a potent anti-tuberculosis drug, and the mycobacterial ATP synthase, to unravel the role of a specific hydrogen bond to a conserved acidic residue in the target affinity and specificity. Our ab initio molecular dynamics simulations reveal that this bond belongs to the SSHB category and accounts for a substantial fraction of the target binding energy. We also demonstrate that the presence of an extra acidic residue (D32), found exclusively in mycobacteria, cooperatively enhances the HB strength ensuring the specificity for the mycobacterial target. Consistently, we show that the removal of D32 markedly weakens the affinity, leading to Bq resistance associated with mutations of D32 to non-acidic residues. By designing simple Bq analogs, we then explore the possibility to overcome the resistance and potentially broaden the Bq antimicrobial spectrum by making the SSHB independent on the presence of the extra acidic residue.
Barriers to and enablers of quality improvement in primary health care in low- and middle-income countries: a systematic review
Authors: Odhus¹ Camlus , Kapanga² Ruth , Oele³ Elizabeth 
Published: July 2023

AbstractThe quality of health care remains generally poor across primary health care settings, especially in low- and middle-income countries where tertiary care tends to take up much of the limited resources despite primary health care being the first (and often the only) point of contact with the health system for nearly 80 per cent of people in these countries. Evidence is needed on barriers and enablers of quality improvement initiatives. This systematic review sought to answer the question: What are the enablers of and barriers to quality improvement in primary health care in low- and middle-income countries? It adopted an integrative review approach with narrative evidence synthesis, which combined qualitative and mixed methods research studies systematically. Using a customized geographic search filter for LMICs developed by the Cochrane Collaboration, Scopus, Academic Search Ultimate, MEDLINE, CINAHL, PSYCHINFO, EMBASE, ProQuest Dissertations and Overton.io (a new database for LMIC literature) were searched in January and February 2023, as were selected websites and journals. 7,077 reports were retrieved. After removing duplicates, four reviewers screened titles, abstracts, and full texts, and performed quality appraisal and data extraction and synthesis. 50 reports from 47 studies were included, covering 52 LMIC settings. Six themes related to barriers and enablers of quality improvement were identified and organized using the model for understanding success in quality (MUSIQ) and the consolidated framework for implementation research (CFIR). These were: microsystem of quality improvement, intervention attributes, implementing organization and team, health systems support and capacity, external environment and structural factors, and execution. Decision makers, practitioners, funders, implementers, and other stakeholders can use the evidence from this systematic review to minimize barriers and amplify enablers to better the chances that quality improvement initiatives will be successful in resource-limited settings. PROSPERO registration: CRD42023395166.
Conserved long noncoding RNATILAMpromotes liver fibrosis through interaction with PML in hepatic stellate cells
Authors: Sun Cheng , Zhou Chan , Daneshvar Kaveh , Kratkiewicz Arcadia J. , Saad Amel Ben , Hess Anja , Chen Jennifer Y. , Pondick Joshua V. , York Samuel R. , Li Wenyang , Moran Sean , Gentile Stefan , Rahman Raza Ur , Li Zixiu , Sparks Robert , Habboub Tim , Kim Byeong-Moo , Choi Michael Y. , Affo Silvia , Schwabe Robert F. , Popov Yury V. , Mullen Alan C. 
Published: July 2023

Background & AimsFibrosis is the common endpoint for all forms of chronic liver injury, and progression of fibrosis leads to the development of end-stage liver disease. Activation of hepatic stellate cells (HSCs) and their transdifferentiation to myofibroblasts results in the accumulation of extracellular matrix (ECM) proteins that form the fibrotic scar. Long noncoding (lnc) RNAs regulate the activity of HSCs and may provide targets for fibrotic therapies.MethodsWe identified lncRNATILAMas expressed nearCOL1A1in human HSCs and performed loss-of-function studies in human HSCs and liver organoids. Transcriptomic analyses of HSCs isolated from mice defined the murine ortholog ofTILAM. We then generatedTilam-deficient GFP reporter mice and quantified fibrotic responses to carbon tetrachloride (CCl4) and choline-deficient L-amino acid defined high fat diet (CDA-HFD). Co-precipitation studies, mass spectrometry, and gene expression analyses identified protein partners ofTILAM.ResultsTILAMis conserved between human and mouse HSCs and regulates expression of ECM proteins, including collagen.Tilamis selectively induced in HSCs during the development of fibrosisin vivo. In both male and female mice, loss ofTilamresults in reduced fibrosis in the setting of CCl4and CDA-HFD injury models.TILAMinteracts with promyelocytic leukemia protein (PML) to stabilize PML protein levels and promote the fibrotic activity of HSCs.ConclusionTILAMis activated in HSCs and interacts with PML to drive the development of liver fibrosis. Depletion ofTILAMmay serve as a therapeutic approach to combat the development of end stage liver disease.
Neural division of labor: the gastropodBerghiadefends against attack using its PNS to retaliate and its CNS to erect a defensive screen
Authors: Brown Jeffrey W. , Berg Ondine H. , Boutko Anastasiya , Stoerck Cody , Boersma Margaret A. , Frost William N. 
Published: July 2023

SummaryRelatively little is known about how the peripheral nervous system (PNS) contributes to the patterning of behavior, in which its role transcends the simple execution of central motor commands or mediation of reflexes. We sought to draw inferences to this end in the aeolid nudibranchBerghia stephanieae, which generates a rapid, dramatic defense behavior, “bristling.” This behavior involves the coordinated movement of cerata, dozens of venomous appendages emerging from the animal’s mantle. Our investigations revealed that bristling constitutes a stereotyped but non-reflexive two-stage behavior: an initial adduction of proximate cerata to sting the offending stimulus (Stage 1), followed by a coordinated radial extension of remaining cerata to create a pincushion-like defensive screen around the animal (Stage 2). In decerebrated specimens, Stage 1 bristling was preserved, while Stage 2 bristling was replaced by slower, uncoordinated, and ultimately maladaptive ceratal movements. We conclude from these observations that 1) the PNS and central nervous system (CNS) mediate Stages 1 and 2 of bristling, respectively; 2) the behavior propagates through the body utilizing both peripheral- and central-origin nerve networks that support different signaling kinetics; and 3) the former network inhibits the latter in the body region being stimulated. These findings extend our understanding of the PNS’s computational capacity and provide insight into a neuroethological scheme that may generalize across cephalized animals, in which the CNS and PNS both independently and interactively pattern different aspects of non-reflexive behavior.
Fish on the platter! Investigating the dietary habits of fishing cats (Prionailurus viverrinus) in the Godavari Delta, India
Authors: Malla Giridhar , Ray Paromita , Srinivas Yellapu , Malla Sudhakar , Reddy Byragi T. , Hayward Matt , Sivakumar Kuppusamy 
Published: July 2023

ABSTRACTThe threatened fishing cat (Prionailurus viverrinus) is an elusive and medium-sized cat that is adapted to mangroves, swamps, wetlands, and riverine habitats. A close look at the literature indicates that fishing cats are piscivorous, however this is based on very few studies. Understanding the patterns of resource utilisation by species is crucial for assessing their role in ecosystems and in ensuring their conservation. Therefore, our study presents insights into fishing cat feeding patterns from mangroves of the Godavari delta, Andhra Pradesh, India. We collected 303 putative fishing cat scats and conducted analysis using 120 genetically identified scats. Our analysis revealed that fish was the most important prey by fishing cats in the study area, followed by crabs and rodents. The prey composition did not vary significantly between the three seasons but there were differences between the survey years. The niche breadth also varied across the three seasons, from being a generalist in winters to a specialist in summers. Our results suggest that long term conservation and survival of the fishing cats depends on fish populations, which are the main prey of the species and thus recommend the need to protect the fish populations in the Godavari delta and the surrounding riverine habitats. Given the importance of fish to the diet of the fishing cat, the health of waterways throughout their distribution must be one of the focal strategies of conservation action.
Investigating the mechanisms underlying Bortezomib resistance
Authors: Zafeiropoulou Kalliopi , Kalampounias Georgios , Alexis Spyridon , Anastasopoulos Daniel , Symeonidis Argiris , Katsoris Panagiotis 
Published: July 2023

AbstractProteasome inhibitors such as Bortezomib, represent an established type of targeted treatment for several types of hematological malignancies, including multiple myeloma, Waldenstrom’s macroglobulinemia and mantle cell lymphoma, based on the cancer cell’s susceptibility upon impairment of the proteasome-ubiquitin system. However, a major problem limiting their efficacy is the emergence of resistance. Their application on solid tumors is currently being studied, while simultaneously, a wide spectrum of hematological cancers, such as Myelodysplastic Syndromes show minimal or no response to Bortezomib treatment. In this study, we utilize the prostate cancer cell line DU-145 to establish a model of Bortezomib resistance, studying the underlying mechanisms. Evaluating the resulting resistant cell line, we observed restoration of proteasome chymotrypsin-like activity, regardless of drug presence, an induction of pro-survival pathways, and the substitution of the Ubiquitin-Proteasome System role in proteostasis by induction of autophagy. Finally, an estimation of the oxidative condition of the cells, indicated that the resistant clones reduce the generation of reactive oxygen species induced by Bortezomib, to levels even lower than those induced in non-resistant cells. Our findings elucidate key proteins of survival and stress regulation pathways as potential pharmaceutical targets, which could increase the efficiency of the proteasome-targeting therapies, thus expanding the group of molecular targets for neoplastic disorders.
A developmentally-inspired hypoxia condition promotes kidney organoid differentiation from human pluripotent stem cells
Authors: Lim Hyeonji , Kim Dohui , Yoon Haejin , Kang Joo H. , Kim Dong Sung , Park Tae-Eun 
Published: July 2023

ABSTRACTKidney organoids derived from human pluripotent stem cells (hPSCs) lack a contiguous network of collecting ducts, which limits their utility in modeling kidney development and disease. Here, we report the generation of kidney organoids containing ureteric bud (UB)-derived collecting ducts connected to metanephric mesenchyme (MM)-derived nephrons using developmentally-inspired hypoxic differentiation conditions. Hypoxia promotes a reiterative process of branching morphogenesis and nephron induction through reciprocal interactions between co-induced MM and UB, which lead to a higher-order kidney organogenesisin vitro. The resulting kidney organoids demonstrate greater maturity, as indicated by higher levels of functional markers and more realistic micro-anatomy of the tubules and collecting ducts. Additionally, these hypoxic-enhanced kidney organoids show a great potential asin vitromodels for renal cystic diseases, as they efficiently generate cystic formations and display high sensitivity to drugs. This hypoxia approach may open new avenues for an enhanced understanding of kidney development and diseases.
Improved modeling of human vision by incorporating robustness to blur in convolutional neural networks
Authors: Jang Hojin , Tong Frank 
Published: July 2023

AbstractWhenever a visual scene is cast onto the retina, much of it will appear degraded due to poor resolution in the periphery; moreover, optical defocus can cause blur in central vision. However, the pervasiveness of blurry or degraded input is typically overlooked in the training of convolutional neural networks (CNNs). We hypothesized that the absence of blurry training inputs may cause CNNs to rely excessively on high spatial frequency information for object recognition, thereby causing systematic deviations from biological vision. We evaluated this hypothesis by comparing standard CNNs with CNNs trained on a combination of clear and blurry images. We show that blur-trained CNNs outperform standard CNNs at predicting neural responses to objects across a variety of viewing conditions. Moreover, blur-trained CNNs acquire increased sensitivity to shape information and greater robustness to multiple forms of visual noise, leading to improved correspondence with human perception. Our results provide novel neurocomputational evidence that blurry visual experiences are very important for conferring robustness to biological visual systems.
Square beams for optimal tiling in TEM
Authors: Chua Eugene YD , Alink Lambertus M , Kopylov Mykhailo , Johnston Jake , Eisenstein Fabian , de Marco Alex 
Published: July 2023

AbstractImaging large fields of view at a high magnification requires tiling. Transmission electron microscopes typically have round beam profiles; therefore, tiling across a large area is either imperfect or results in uneven exposures, a problem on dose-sensitive samples. Here, we introduce a square electron beam that can be easily retrofitted in existing microscopes and demonstrate its application, showing it can tile nearly perfectly and deliver cryo-EM imaging with a resolution comparable to conventional setups.
Assessing the Generalization Capabilities of TCR Binding Predictors via Peptide Distance Analysis
Authors: Castorina Leonardo V. , Grazioli Filippo , Machart Pierre , Mösch Anja , Errica Federico 
Published: July 2023

ABSTRACTUnderstanding the interaction between T Cell Receptors (TCRs) and peptide-bound Major Histocompatibility Complexes (pMHCs) is crucial for comprehending immune responses and developing targeted immunotherapies. While recent machine learning (ML) models show remarkable success in predicting TCR-pMHC binding within training data, these models often fail to generalize to peptides outside of their training distributions, raising concerns about their applicability in therapeutic settings. Understanding and improving the generalization of these models is therefore critical to ensure real-world applications.To address this issue, we evaluate the effect of the distance between training and testing peptide distributions on ML model empirical risk assessments, using sequence-based and 3D structure-based distance metrics. In our analysis we use several state-of-the-art models for TCR-peptide binding prediction: Attentive Variational Information Bottleneck (AVIB), NetTCR-2.0 and -2.2, and ERGO II (pre-trained autoencoder) and ERGO II (LSTM).In this work, we introduce a novel approach for assessing the generalization capabilities of TCR binding predictors: the Distance Split (DS) algorithm. The DS algorithm controls the distance between training and testing peptides based on both sequence and structure, allowing for a more nuanced evaluation of model performance. We show that lower 3D shape similarity between training and test peptides is associated with a harder out-of-distribution task definition, which is more interesting when measuring the ability to generalize to unseen peptides. However, we observe the opposite effect when splitting using sequence-based similarity. These findings highlight the importance of using a distance-based splitting approach to benchmark models. This could then be used to estimate a confidence score on predictions on novel and unseen peptides, based on how different they are from the training ones. Additionally, our results may hint that employing 3D shape to complement sequence information could improve the accuracy of TCR-pMHC binding predictors.
Identification of 5-HT2AReceptor Signaling Pathways Responsible for Psychedelic Potential
Authors: Wallach Jason , Cao Andrew B. , Calkins Maggie M. , Heim Andrew J. , Lanham Janelle K. , Bonniwell Emma M. , Hennessey Joseph J. , Bock Hailey A. , Anderson Emilie I. , Sherwood Alexander M. , Morris Hamilton , de Klein Robbin , Klein Adam K. , Cuccurazzu Bruna , Gamrat James , Fannana Tilka , Zauhar Randy , Halberstadt Adam L. , McCorvy John D. 
Published: July 2023

SummarySerotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2Areceptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and β-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-β-arrestin2 efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT2Apartial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT2A-Gq efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2Aagonists. We also demonstrate that β-arrestin-biased 5-HT2Areceptor agonists induce receptor downregulation and tachyphylaxis, and have an anti-psychotic-like behavioral profile. Overall, 5-HT2Areceptor signaling can be fine-tuned to generate ligands with properties distinct from classical psychedelics.
Quantifying the large-scale chromosome structural dynamics during the mitosis-to-G1 phase transition of cell cycle
Authors: Chu Xiakun , Wang Jin 
Published: July 2023

AbstractCell cycle, essential for various cellular processes, is known to be precisely regulated by the underlying gene network. Accumulating evidence has revealed that the chromosome, which serves as the scaffold for the gene expressions, undergoes significant structural reorganizations during mitosis. Understanding the mechanism of the cell cycle from the molecular chromosome structural perspective remains a grand challenge. In this study, we applied an integrated approach using a data-driven model combined with a nonequilibrium landscape-switching model to investigate large-scale chromosome structural dynamics during the mitosis-to-G1 phase transition. We generated 3D chromosome structural ensembles for the five critical stages in the process. We observed that the chromosome structural expansion and adaptation of the structural asphericity do not occur synchronously. We attributed this asynchronous adaptation behavior in the chromosome structural geometry to the unique unloading sequence of the two types of condensins. Furthermore, we observed that the coherent motions between the chromosomal loci are primarily enhanced within the topologically associating domains (TADs) as cells progress to the G1 phase, suggesting that TADs can be considered as both structural and dynamical units for organizing the 3D chromosome. Our analysis also reveals that the quantified pathways of chromosome structural reorganizations during the mitosis-to-G1 phase transition exhibit high stochasticity at the single-cell level and show non-linear behaviors in changing TADs and contacts formed at the long-range regions. These features underscore the complex nature of the cell-cycle processes. Our findings, which are consistent with the experiments in many aspects, offer valuable insights into the large-scale chromosome structural dynamics after mitosis and contribute to the molecular-level understanding of the cell-cycle process.