bluuebunny/crossref_metadata_2025_split huggingface dataset:
Robust and Adaptive Deep Model Ensemble Framework Fine-tuned by Structural Information for Drug-Target Interactions
Authors: Wei Jinhang , Zhuo Linlin , Fu Xiangzheng , Zhang Junmin , Zeng Xiangxiang , Zou Quan 
Published: October 2023

AbstractIn the fields of new drug development and drug repositioning, drug-target interactions (DTI) play a pivotal role. Although deep learning models have already made significant contributions in this domain, the state-of-the-art models still exhibit shortcomings in predictive performance and issues of false-negative errors. Based on these observations, we constructed a streamlined yet effective base learner model. With our designed adaptive feature weight network, the model can capture key features within drugs (targets). Furthermore, by cross-partitioning the training data, multiple base learners are integrated into a powerful ensemble model named EADTN. The performance of the model is further enhanced as the number of base learners increases. Additionally, we employed a single-linkage clustering algorithm to cluster drugs and proteins and leveraged this clustering information to fine-tune the base learners, which elevates the value of EADTN in real-world applications like drug repositioning and targeted drug development. Our designed substructure importance ranking method also demonstrates the model’s exceptional capability to recognize key substructures. Benefiting from the model’s low generalization error capability, we successfully identified false-negative samples within the dataset, revealing new interaction relationships. Experimental results indicate that EADTN consistently outperforms existing state-of-the-art models across multiple datasets. More importantly, the ensemble learning and clustering fine-tuning approaches adopted by our model offer a fresh perspective for related fields.
Ecdysone Orchestrates Notch and Broad Symphony to Craft Epithelial Cell Shape Change
Authors: Ghosh Gaurab , Halder Sudipta , Sahu Aresh , Prasad Mohit 
Published: October 2023

AbstractMorphogenesis in the metazoans relies on cell shape transformations that forms an integral component of organ development, form generation and maintenance of tissue homeostasis. Nevertheless, a comprehensive grasp of how the epithelial morphogenesis is modulated in the metazoans remain still elusive. The Steroid hormones play a pivotal role in morphogenesis spanning several organs including the gonads, urogenital tracts, and mammary glands. Employing theDrosophilaoogenesis model, we investigated the the role of steroid hormone receptor, Ecdysone receptor (EcR) involvement in transforming anterior epithelial follicle cells (AFCs) from cuboidal to squamous shape. Consistent with the fact that the activity of EcR in the AFCs coincides with the timing of cuboidal-to-squamous shape transition, we found that depletion of EcR function impedes the shape transformation of AFCs. We report that EcR doesn’t impair the follicle cell fate, but impedes the morphological change by restricting the remodelling of lateral and adherens junctions. Employing the classical genetic tools and immnohistochemistry, we show that EcR limits the Notch-Broad axis to facilitate alteration of the shape of AFCs. Our study suggests a mechanistic model where Ecdysone signalling, via the Notch pathway, finetunes the activity of non-muscle myosin heavy chain zipper, prompting AFC shape transition. In sum, our work illuminates how Ecdysone signalling orchestrates epithelial follicle cell morphogenesis during metazoan development.
Generation of circulating autoreactive pre-plasma cells fueled by naïve B cells in celiac disease
Authors: Lindeman Ida , Høydahl Lene S. , Christophersen Asbjørn , Risnes Louise F. , Jahnsen Jørgen , Lundin Knut E. A. , Sollid Ludvig M. , Iversen Rasmus 
Published: October 2023

ABSTRACTAutoantibodies against the enzyme transglutaminase 2 (TG2) are characteristic of celiac disease (CeD), and TG2-specific IgA plasma cells are abundant in gut biopsies of patients. We here describe the corresponding population of autoreactive B cells in blood. Circulating TG2-specific IgA cells were found in untreated patients on a gluten-containing diet but not in controls. They were clonally related to TG2-specific small intestinal plasma cells, and they expressed gut-homing molecules, indicating that they are plasma cell precursors. Unlike other IgA-switched cells, the TG2-specific cells were negative for CD27, placing them in the double negative (IgD-CD27-) category. They had a plasmablast or activated memory B-cell phenotype, and they harbored fewer variable region mutations than other IgA cells. Based on their similarity to naïve B cells, we propose that autoreactive IgA cells in CeD are generated mainly through chronic recruitment of naïve B cells via an extrafollicular response involving gluten-specific CD4+ T cells.
A novel amphibian sex determination candidate gene, evolved by structural variation in the regulatory region between X and Y
Authors: Kuhl Heiner , Tan Wen Hui , Klopp Christophe , Kleiner Wibke , Koyun Baturalp , Ciorpac Mitica , Feron Romain , Knytl Martin , Kloas Werner , Schartl Manfred , Winkler Christoph , Stöck Matthias 
Published: October 2023

AbstractMost vertebrates develop distinct females and males, where sex is determined by repeatedly-evolved environmental or genetic triggers. Undifferentiated sex chromosomes and large genomes have caused major knowledge gaps in amphibians. Only a single master gene is known in >8650 species, thedmrt1-paralogue (dm-w) of female-heterogametic clawed frogs (Xenopus; ZW♀/ZZ♂). Combining a chromosome-scale genome of a non-model amphibian, the European green toad,Bufo(tes)viridis, with ddRAD- and whole genome pool-sequencing revealed a novel candidate master gene (bod1l), governing a male-heterogametic system (XX♀/XY♂). Targeted sequencing across multiple taxa and a male long-read assembly uncovered structural X/Y-variation in the 5’-regulatory region, where a Y-specific non-coding RNA, only expressed in males, suggests regional enhancer-properties. Developmental transcriptomes and RNAin-situhybridization provide evidence for timely and spatially relevant, sex-specificbod1l-gene expression in primordial gonads with coinciding differentialH3K4me-methylation in pre-granulosa/pre-Sertoli cells, pointing to a novel mechanism of amphibian sex determination.
Body-part specificity for learning of multiple prior distributions in human coincidence timing
Authors: Matsumura Yoshiki , Roach Neil W. , Heron James , Miyazaki Makoto 
Published: October 2023

AbstractDuring timing tasks, the brain learns the statistical distribution of target intervals and integrates this prior knowledge with sensory inputs to optimise task performance. Daily events can have different temporal statistics (e.g. fastball/slowball in baseball batting), making it important to learn and retain multiple priors. However, the rules governing this process are not yet understood. Here, we demonstrate that the learning of multiple prior distributions in a coincidence timing task is characterised by body-part specificity. In our experiments, two prior distributions (short and long intervals) were imposed on participants. When using only one body part for timing responses, regardless of the priors, participants learned a single prior by generalising over the two distributions. However, when the two priors were assigned to different body parts, participants concurrently learned the two independent priors. Moreover, body-part specific prior acquisition was faster when the priors were assigned to anatomically distant body parts (e.g. hand/foot) than when they were assigned to close body parts (e.g. index/middle fingers). This suggests that the body-part specific learning of priors is organised according to somatotopy.
ZNF91 is an endogenous repressor of the molecular phenotype associated with X-linked dystonia-parkinsonism (XDP)
Authors: Rosenkrantz Jimi L. , Raghib Sanaz , Brandorff J. Elias , Kapadia Ashni , Vaine Christine A. , Bragg D. Cristopher , Farmiloe Grace , Jacobs Frank M.J. 
Published: October 2023

AbstractBackgroundX-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder resulting from the insertion of an intronic SINE-Alu-VNTR (SVA) retrotransposon in theTAF1gene. Recent research has revealed that the pathogenic XDP-SVA insertion leads to dysregulation ofTAF1transcription, including increased intron retention and decreased expression of exons surrounding the insertion. The Krüppel-associated box (KRAB) zinc finger protein, ZNF91, is a critical repressor of SVA retrotransposons. However, it remains unclear whether ZNF91 is able to repress the XDP-SVA insertion and how this influences the XDP-associated molecular phenotype. In this study, we investigate the role of ZNF91 in repressing the XDP-SVA insertion and its impact on the molecular phenotype associated with XDP.MethodsHere, we used CRISPR/Cas9 to genetically delete ZNF91 in induced pluripotent stem cell (iPSC) lines derived from XDP patients, as well as isogenic control iPSC lines that lack the XDP-SVA insertion. Total RNA sequencing and capture RNA-sequencing were used to confirm ZNF91 deletion and to assessTAF1transcriptional changes between conditions. Furthermore, publicly available transcriptomic data from whole blood and different brain regions were used to assess ZNF91 expression levels across ages.ResultsWe found that genetic deletion of ZNF91 exacerbates the molecular phenotype associated with the XDP-SVA insertion in patient cells, while no difference was observed when ZNF91 was deleted from isogenic control cells. Additionally, we observed a significant age-related reduction in ZNF91 expression in whole blood and brain, indicating a potential role of ZNF91 in the age-dependent onset of XDP.ConclusionsThese findings indicate that ZNF91 plays a crucial role in controlling the molecular phenotype associated with XDP. Since ZNF91 is a critical epigenetic repressor of SVAs, this suggests that epigenetic silencing of the XDP-SVA minimizes the severity of the molecular phenotype. Our results showing that ZNF91 expression levels significantly decrease with age provide a potential explanation for the age-related progressive neurodegenerative character of XDP. Collectively, our study provides important insights into the protective role of ZNF91 in XDP pathogenesis and suggests that modulating ZNF91 levels or targeted repression of the XDP-SVA could be novel therapeutic strategies worth exploring.
Changes in reward-induced neural activity upon Cafeteria Diet consumption
Authors: Heijkoop R. , Lalanza J.F. , Solanas M. , Álvarez-Monell A. , Subias-Gusils A. , Escorihuela R.M. , Snoeren E.M.S. 
Published: October 2023

AbstractExcessive consumption of highly palatable foods rich in sugar and fat, often referred to as “junk” or “fast” foods, plays a central role in the development of obesity. The highly palatable characteristics of these foods activate hedonic and motivational mechanisms to promote food-seeking behavior and overeating, which is largely regulated by the brain reward system. Excessive junk food consumption can alter the functioning of this reward system, but exact mechanisms of these changes are still largely unknown. This study investigated whether long-term junk food consumption, in the form of Cafeteria (CAF) diet, can alter the reward system in adult, female Long-Evans rats, and whether different regimes of CAF diet influence the extent of these changes. To this end, rats were exposed to a 6-week diet with either standard chow, orad libitumdaily access to CAF diet, 30% restricted but daily access to CAF diet, or one-day-a-week (intermittent)ad libitumaccess to CAF diet, after which c-Fos expression in the Nucleus Accumbens (NAc), Prefrontal Cortex (PFC), and Ventral Tegmental Area (VTA) following consumption of a CAF reward of choice was examined. We found that all CAF diet regimes decreased c-Fos expression in the NAc-shell when presented with a CAF reward, while no changes in c-Fos expression upon the different diet regimes were found in the PFC, and possibly the VTA. Our data suggests that long-term junk food exposure can affect the brain reward system, resulting in an attenuated activity of the NAc-shell.
DrugMap: A quantitative pan-cancer analysis of cysteine ligandability
Authors: Takahashi Mariko , Chong Harrison B. , Zhang Siwen , Lazarov Matthew J. , Harry Stefan , Maynard Michelle , White Ryan , Murrey Heather E. , Hilbert Brendan , Neil Jason R. , Gohar Magdy , Ge Maolin , Zhang Junbing , Durr Benedikt R. , Kryukov Gregory , Tsou Chih-Chiang , Brooijmans Natasja , Alghali Aliyu Sidi Omar , Rubio Karla , Vilanueva Antonio , Harrison Drew , Koglin Ann-Sophie , Ojeda Samuel , Karakyriakou Barbara , Healy Alexander , Assaad Jonathan , Makram Farah , Rachman Inbal , Khandelwal Neha , Tien Pei-Chieh , Popoola George , Chen Nicholas , Vordermark Kira , Richter Marianne , Patel Himani , Yang Tzu-yi , Griesshaber Hanna , Hosp Tobias , van den Ouweland Sanne , Hara Toshiro , Bussema Lily , Dong Rui , Shi Lei , Rasmussen Martin Q. , Domingues Ana Carolina , Lawless Aleigha , Fang Jacy , Yoda Satoshi , Nguyen Linh Phuong , Reeves Sarah Marie , Wakefield Farrah Nicole , Acker Adam , Clark Sarah Elizabeth , Dubash Taronish , Fisher David E. , Maheswaran Shyamala , Haber Daniel A. , Boland Genevieve , Sade-Feldman Moshe , Jenkins Russel , Hata Aaron , Bardeesy Nabeel , Suva Mario L. , Martin Brent , Liau Brian , Ott Christopher , Rivera Miguel N. , Lawrence Michael S. , Bar-Peled Liron 
Published: October 2023

AbstractCysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developedDrugMap, an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NFκB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity.
Open-source instrumented object to study dexterous object manipulation
Authors: Córdova Bulens David , du Bois de Dunilac Sophie , Delhaye Benoit , Lefèvre Philippe , Redmond Stephen J. 
Published: October 2023

Humans use tactile feedback to perform skillful manipulation. When tactile sensory feedback is unavailable, for instance, if the fingers are anesthetized, dexterity is severely impaired. Imaging the deformation of the finger pad skin when in contact with a transparent plate provides information about the tactile feedback received by the central nervous system. Indeed, skin deformations are transduced into neural signals by the mechanoreceptors of the finger pad skin. Understanding how this feedback is used for active object manipulation would improve our understanding of human dexterity. In this paper, we present a new device for imaging the skin of the finger pad of one finger during manipulation performed with a precision grip. The device’s weight (300 g) makes it easy to use during unconstrained dexterous manipulation. Using this device, we reproduced the experiment performed in Delhaye et al. 2021a. We extracted the strains aligned with the object’s movement, i.e., the vertical strains in the ulnar and radial parts of the fingerpad, to see how correlated they were with the grip force (GF) adaptation. Interestingly, parts of our results differed from those in Delhaye et al. 2021a due to weight and inertia differences between the devices, with average GF across participants differing significantly. Our results highlight a large variability in the behavior of the skin across participants, with generally low correlations between strain and GF adjustments, suggesting that skin deformations are not the primary driver of GF adaptation in this manipulation scenario.Significance statementIn this paper, we introduce a new device weighing 300 g and capable of imaging the skin of the finger pad of one finger during manipulation performed with a precision grip. This object is also capable of recording the forces and accelerations applied to the object. We reproduced the experiment performed in Delhaye et al. 2021a using this device. We extracted the strains aligned with the object’s movement to analyze how correlated these strains were with GF adaptation. The behavior of the skin across participants presented a large variability, and we observed low correlations between strain and GF adjustments in most participants. Our results suggest that skin deformations are not the primary driver of GF adaptation in this manipulation scenario.
Photoacoustic Imaging for Non-Invasive Assessment of Physiological Biomarkers of Intestinal Injury in Experimental Necrotizing Enterocolitis
Authors: Weis Jared A. , Rauh Jessica L. , Ellison Maryssa A. , Cruz-Diaz Nildris , Yamaleyeva Liliya M. , Welch Cherrie D. , Zeller Kristen A. , Weis Victoria G. 
Published: October 2023

AbstractBackgroundNecrotizing enterocolitis (NEC) is an often-lethal disease of the premature infants’ intestinal tract that is exacerbated by significant difficulties in early and accurate diagnosis. In NEC disease, the intestine often exhibits hypoperfusion and dysmotility, which contributes to advanced disease pathogenesis. However, these physiological features cannot be accurately and quantitively assessed within the current constraints of imaging modalities frequently used in the clinic (plain film X-ray and ultrasound). We have previously demonstrated the ability of photoacoustic imaging (PAI) to non-invasively and quantitively assess intestinal tissue oxygenation and motility in a healthy neonatal rat model. As a first-in-disease application, we evaluated NEC pathogenesis using PAI to assess intestinal health biomarkers in a preclinical neonatal rat experimental model of NEC.MethodsNEC was induced in neonatal rat pups from birth to 4 days old via hypertonic formula feeding, full-body hypoxic stress, and lipopolysaccharide administration to mimic bacterial colonization. Healthy breastfed (BF) controls and NEC rat pups were imaged at 2- and 4-days old. Intestinal tissue oxygen saturation was measured with PAI imaging for oxy- and deoxyhemoglobin levels. To measure intestinal motility, ultrasound and co-registered PAI cine recordings were used to capture intestinal peristalsis motion and contrast agent (indocyanine green) transit within the intestinal lumen. Additionally, both midplane two-dimensional and volumetric three-dimensional imaging acquisitions were assessed for oxygenation and motility.ResultsNEC pups showed a significant decrease of intestinal tissue oxygenation as compared to healthy BF controls at both ages (2-days old: 55.90% +/-3.77% vs 44.12% +/-7.18%; 4-days old: 56.13% +/-3.52% vs 38.86% +/-8.33%). Intestinal motility, assessed using a computational intestinal deformation analysis, demonstrated a significant reduction in the intestinal motility index in both early (2-day) and established (4-day) NEC. Extensive NEC damage was confirmed with histology and dysmotility was confirmed by small intestinal transit assay.ConclusionsThis study presents PAI as a successful emerging diagnostic imaging modality for both intestinal tissue oxygenation and intestinal motility disease hallmarks in a rat NEC model. PAI presents enormous significance and potential for fundamentally changing current clinical paradigms for detecting and monitoring intestinal pathologies in the premature infant.
Assembly of Protein Complexes In and On the Membrane with Predicted Spatial Arrangement Constraints
Authors: Christoffer Charles , Harini Kannan , Archit Gupta , Kihara Daisuke 
Published: October 2023

ABSTRACTMembrane proteins play crucial roles in various cellular processes, and their interactions with other proteins in and on the membrane are essential for their proper functioning. While an increasing number of structures of more membrane proteins are being determined, the available structure data is still sparse. To gain insights into the mechanisms of membrane protein complexes, computational docking methods are necessary due to the challenge of experimental determination. Here, we introduce Mem-LZerD, a rigid-body membrane docking algorithm designed to take advantage of modern membrane modeling and protein docking techniques to facilitate the docking of membrane protein complexes. Mem-LZerD is based on the LZerD protein docking algorithm, which has been constantly among the top servers in many rounds of CAPRI protein docking assessment. By employing a combination of geometric hashing, newly constrained by the predicted membrane height and tilt angle, and model scoring accounting for the energy of membrane insertion, we demonstrate the capability of Mem-LZerD to model diverse membrane protein-protein complexes. Mem-LZerD successfully performed unbound docking on 13 of 21 (61.9%) transmembrane complexes in an established benchmark, more than shown by previous approaches. It was additionally tested on new datasets of 44 transmembrane complexes and 92 peripheral membrane protein complexes, of which it successfully modeled 35 (79.5%) and 15 (16.3%) complexes respectively. When non-blind orientations of peripheral targets were included, the number of successes increased to 54 (58.7%). We further demonstrate that Mem-LZerD produces complex models which are suitable for molecular dynamics simulation. Mem-LZerD is made available athttps://lzerd.kiharalab.org.
Predictably manipulating photoreceptor light responses to reveal their role in downstream visual responses
Authors: Chen Qiang , Ingram Norianne T. , Baudin Jacob , Angueyra Juan M. , Sinha Raunak , Rieke Fred 
Published: October 2023

ABSTRACTComputation in neural circuits relies on the judicious use of nonlinear circuit components. In many cases, multiple nonlinear components work collectively to control circuit outputs. Separating the contributions of these different components is difficult, and this limits our understanding of the mechanistic basis of many important computations. Here, we introduce a tool that permits the design of light stimuli that predictably alter rod and cone phototransduction currents - including stimuli that compensate for nonlinear properties such as light adaptation. This tool, based on well-established models for the rod and cone phototransduction cascade, permits the separation of nonlinearities in phototransduction from those in downstream circuits. This will allow, for example, direct tests of how adaptation in rod and cone phototransduction affects downstream visual signals and perception.