bluuebunny/crossref_metadata_2025_split huggingface dataset:
On quality thresholds for the clustering of molecular structures
Authors: Daura Xavier , Conchillo-Solé Oscar 
Published: September 2022

AbstractIt has been recently suggested that diametral (so-called quality) similarity thresholds are superior to radial ones for the clustering of molecular three-dimensional structures. 1 The argument has been made for two clustering algorithms available in various software packages for the analysis of molecular structures from ensembles generated by computer simulations, attributed to Daura et al. 2,3 (radial threshold) and Heyer et al. 4 (diametral threshold). Here, we compare these two algorithms using the root-mean-squared-difference between the Cartesian coordinates of selected atoms as pairwise similarity metric. We discuss formally the relation between these two methods and illustrate their behavior with two examples, a set of points in two dimensions and the coordinates of the tau polypeptide along a trajectory extracted from a replica-exchange molecular-dynamics simulation. 1,5 We show that the two methods produce equally-sized clusters as long as adequate choices are made for the respective thresholds. The real issue is not whether the threshold is radial or diametral, but how to choose in either case a threshold value that is physically meaningful. We will argue that, when clustering molecular structures with the RMSD as metric, the simplest best guess for a threshold is actually radial in nature.
Decoding spatiotemporal gene expression of the developing human spinal cord and implications for ependymoma origin
Authors: Li Xiaofei , Andrusivova Zaneta , Czarnewski Paulo , Langseth Christoffer Mattsson , Andersson Alma , Liu Yang , Gyllborg Daniel , Braun Emelie , Larsson Ludvig , Hu Lijuan , Alekseenko Zhanna , Lee Hower , Avenel Christophe , Kallner Helena Kopp , Åkesson Elisabet , Adameyko Igor , Nilsson Mats , Linnarsson Sten , Lundeberg Joakim , Sundström Erik 
Published: September 2022

AbstractThe human spinal cord contains diverse cell types, governed by a series of spatiotemporal events for tissue assembly and functions. However, the spatiotemporal regulation of cell fate specification in the human developing spinal cord remains largely unknown. Single-cell RNA sequencing and spatial transcriptomics techniques have advanced the understanding of human organ development considerably. By performing integrated analysis of single-cell and spatial multi-omics methods, we created a comprehensive developmental cell atlas of the first trimester human spinal cord. Our data revealed that the cell fate commitment of neural progenitor cells and their spatial positioning are spatiotemporally regulated by specific gene sets. Beyond this resource, we unexpectedly discovered unique events in human spinal cord development compared to rodents, including earlier quiescence of active neural stem cells, different regulation of stem cell differentiation, and distinct spatiotemporal genetic regulations of cell fate choices. In addition, using our atlas we identified specific gene expression in cancer stem cells in ependymomas. Thus, we demonstrate spatiotemporal genetic regulation of human spinal cord development as well as its potential to understand novel disease mechanisms and to inspire new therapies.
Accumulated metagenomic studies reveal recent migration, whole genome evolution, and undiscovered diversity of orthomyxoviruses
Authors: Dudas Gytis , Batson Joshua 
Published: September 2022

AbstractMetagenomic studies have uncovered many novel viruses by looking beyond hosts of public health or economic interest. However, the resulting viral genomes are often incomplete, and analyses largely characterize the distribution of viruses over their dynamics. Here, we integrate accumulated data from metagenomic studies to reveal geographic and evolutionary dynamics in a case study ofOrthomyxoviridae, the RNA virus family that includes influenza virus. First, we use sequences of the orthomyxovirid Wǔhàn mosquito virus 6 to track the migrations of its host. We then look at orthomyxovirus genome evolution, finding gene gain and loss across members of the family, especially in the surface proteins responsible for cell and host tropism. We find that the surface protein of Wǔhàn mosquito virus 6 exhibits accelerated non-synonymous evolution suggestive of antigenic evolutioni.e. vertebrate infection, and belongs to a wider quaranjavirid group bearing highly diverged surface proteins. Finally we quantify the progress of orthomyxovirus discovery and forecast that many divergedOrthomyxoviridaemembers remain to be found. We argue that continued metagenomic studies will be fruitful for understanding the dynamics, evolution, ecology of viruses and their hosts, regardless of whether novel viruses are identified or not, as long as study designs allowing for the resolution of complete viral genomes are employed.0.1ImportanceThe number of known virus species has increased dramatically through metagenomic studies, which search genetic material sampled from a host for non-host genes. Here, we focus on an important viral family that includes influenza viruses, theOrthomyxoviridae, with over a hundred recently discovered viruses infecting hosts from humans to fish. We find one virus called Wǔhàn mosquito virus 6, discovered in mosquitoes in China, has spread across the globe very recently. Surface proteins used to enter cells show signs of rapid evolution in Wǔhàn mosquito virus 6 and its relatives which suggests an ability to infect vertebrate animals. We compute the rate at which new orthomyxovirus species discovered add evolutionary history to the tree of life, predict that many viruses remain to be discovered, and discuss what appropriately designed future studies can teach us about how diseases cross between continents and species.
Cell-intrinsic ceramides determine T cell function during melanoma progression
Authors: Hose Matthias , Günther Anne , Naser Eyad , Schumacher Fabian , Schönberger Tina , Falkenstein Julia , Papadamakis Athanassios , Kleuser Burkhard , Becker Katrin Anne , Gulbins Erich , Haimovitz-Friedman Adriana , Buer Jan , Westendorf Astrid M. , Hansen Wiebke 
Published: September 2022

AbstractAcid sphingomyelinase (Asm) and acid ceramidase (Ac) are parts of the sphingolipid metabolism. Asm hydrolyzes sphingomyelin to ceramide, which is further metabolized to sphingosine by Ac. Ceramide generates ceramide-enriched platforms that are involved in receptor clustering within cellular membranes. However, the impact of cell-intrinsic ceramide on T cell function is not well characterized. By using T cell-specific Asm- or Ac-deficient mice, with reduced or elevated ceramide levels in T cells, we identified ceramide to play a crucial role in T cell function in vitro and in vivo. T cell-specific ablation of Asm in Asmflox/flox/CD4cre mice resulted in enhanced tumor progression associated with impaired T cell responses, whereas Acflox/flox/CD4cre mice showed reduced tumor growth rates and elevated T cell activation compared to the respective controls upon tumor transplantation. Further in vitro analysis revealed that decreased ceramide content supports CD4+ regulatory T cell differentiation and interferes with cytotoxic activity of CD8+ T cells. In contrast, elevated ceramide concentration in CD8+ T cells from Acflox/flox/CD4cre mice was associated with enhanced cytotoxic activity. Strikingly, ceramide co-localized with the T cell receptor (TCR) and CD3 in the membrane of stimulated T cells and phosphorylation of TCR signaling molecules was elevated in Ac-deficient T cells. Hence, our results indicate that modulation of ceramide levels, by interfering with the Asm or Ac activity has an effect on T cell differentiation and function and might therefore represent a novel therapeutic strategy for the treatment of T cell-dependent diseases such as tumorigenesis.
Refining Embedding-Based Binding Predictions by Leveraging AlphaFold2 Structures
Authors: Endres Leopold , Olenyi Tobias , Erckert Kyra , Weißenow Konstantin , Rost Burkhard , Littmann Maria 
Published: September 2022

AbstractBackgroundIdentifying residues in a protein involved in ligand binding is important for understanding its function. bindEmbed21DL is a Machine Learning method which predicts protein-ligand binding on a per-residue level using embeddings derived from the protein Language Model (pLM) ProtT5. This method relies solely on sequences, making it easily applicable to all proteins. However, highly reliable protein structures are now accessible through the AlphaFold Protein Structure Database or can be predicted using AlphaFold2 and ColabFold, allowing the incorporation of structural information into such sequence-based predictors.ResultsHere, we propose bindAdjust which leverages predicted distance maps to adjust the binding probabilities of bindEmbed21DL to subsequently boost performance. bindAdjust raises the recall of bindEmbed21DL from 47±2% to 53±2% at a precision of 50% for small molecule binding. For binding to metal ions and nucleic acids, bindAdjust serves as a filter to identify good predictions focusing on the binding site rather than isolated residues. Further investigation of two examples shows that bindAdjust is in fact able to add binding predictions which are not close in sequence but close in structure, extending the binding residue predictions of bindEmbed21DL to larger binding stretches or binding sites.ConclusionDue to its simplicity and speed, the algorithm of bindAdjust can easily refine binding predictions also from other tools than bindEmbed21DL and, in fact, could be applied to any protein prediction task.
Consequences of life-cycle complexity to the potential for evolutionary branching
Authors: Vasconcelos Paula , Saltini Marco , Rueffler Claus 
Published: September 2022

AbstractComplex life-cycles – that is, organismal development that unfolds across ecological niches – are pervasive in nature. In this work we set out to investigate the effects of complex life-cycles on the potential for diversification via evolutionary branching. We did this by analyzing a mathematical model of a consumer with two life-stages, each of which is characterized by a specific feeding efficiency trait that undergoes evolutionary change in response to ecological conditions such as resource competition. We find (i) that life-cycle complexity can favor diversification when compared to simple life-cycles, as there is a larger potential for evolutionary branching in the trait of the life-stage that has a higher population density; (ii) that evolution favors character displacement to minimize intra-stage resource competition; and (iii) that under certain parameters more than one evolutionary branching event can occur.
A Machine Learning and Bioinformatic Analysis Reveals an Associated between Cell Surface Receptor Transcript Levels with Drug Response of Breast Cancer Cells and the Drug Off-Target Effects
Authors: Sinkala Musalula , Naran Krupa , Ramamurthy Dharanidharan , Mungra Neelakshi , Martin Darren , Barth Stefan 
Published: September 2022

AbstractBreast cancer is characterised by varied responses to different anticancer therapies, which may provoke several different off-target effects. We hypothesise that for drugs that target cell surface receptors (CSRs), the different responses of tumours and the adverse events produced by these drugs may be attributed to variations in the transcriptional landscapes of CSRs in both breast tumours and healthy tissues. Here, we use data from various sources to compare the CSR transcriptional landscapes of breast tumours and a range of different non-diseased human tissues. We demonstrate an association between the responses to drug perturbation of breast cancer cell lines and the transcription levels of their targeted CSRs. Furthermore, we reveal important differences in the CSR transcriptional landscapes of primary breast tumour subtypes and the CSR transcriptional landscapes of breast cancer cell lines, which will likely impact the accuracy of drug response predictions. Finally, applying clinical trial data, we expose a link between the expression levels of CSR genes in healthy tissues and adverse reactions of patients to anticancer drugs. Altogether, this approach allows for the isolation of the most suitable CSR target(s) among the expressed transcripts, solely based on the measured dose-responses of cell lines to small molecules, the CSR transcriptional landscape in health patient tissues, and reported adverse responses of patients to drugs targeting CSRs.
Decoy effect in shoaling decision making in zebrafish
Authors: Singh Abhishek , Kumari Kajal , Kalra Sanya , Pal Shubhi , Rajaraman Bittu Kaveri 
Published: September 2022

ABSTRACTThe decoy effect, a bias in choice between two options when a third, inferior option is introduced, has been observed across various organisms, from slime molds to humans. In this study, we investigated whether zebrafish (Danio rerio), a widely used biological model organism, exhibit the decoy effect in their shoaling group choices, specifically examining this effect by varying only shoal size. Using spatial trajectory analysis of freely swimming zebrafish interacting with conspecifics in adjacent display tanks, we tested how shoaling decisions varied between dichotomous (two-option) and trichotomous (three-option) choice sets. Our experiments compared preferences for 4 versus 2 and 6 versus 3 shoal sizes, with a single fish serving as a decoy in the trichotomous sets. The results revealed sex-specific differences in the decoy effect: males exhibited a shift in preference only in the Trichotomous-first condition, where prior exposure to the decoy led to a significant preference for the larger shoal. In contrast, females displayed the decoy effect exclusively in the Dichotomous-first condition, shifting from a significant preference for the larger shoal to showing no clear preference in the presence of the decoy. Notably, our findings demonstrate that the decoy effect can occur even when studied unidimensionally, with both sex and the order of presentation influencing zebrafish shoaling preferences. These results offer new insights into decision-making processes and highlight the importance of considering order effects in studies of choice behavior, with potential methodological implications for research in other species.
A circulating biomarker of facioscapulohumeral muscular dystrophy clinical severity, valid in skeletal muscle and blood
Authors: Banerji Christopher R. S. , Greco Anna , Joosten Leo A. B. , van Engelen Baziel , Zammit Peter S. 
Published: September 2022

AbstractFacioscapulohumeral muscular dystrophy (FSHD) is incurable. DUX4 mis-expression is believed to underlie FSHD pathogenesis, alongside PAX7 target gene repression, yet clinical trials lack robust biomarkers of severity. FSHD entails fatty replacement of muscle, accelerated by inflammation, we thus performed RNA-sequencing on both an MRI guided inflamed (TIRM+) and non-inflamed (TIRM-) muscle biopsies from clinically-characterised FSHD patients, alongside peripheral blood mononucleated cells (PBMCs). PAX7 target gene repression in TIRM-muscle associates with severity. DUX4 target gene biomarkers associate with lower limb fat fraction and D4Z4 repeat length, but not severity. PAX7 target gene repression in muscle correlates with levels in matched PBMCs. A refined biomarker computed in PBMCs associates with severity in FSHD patients, and also validates as a classifier of severity in an independent set of 54 FSHD patient blood samples. In summary, we present a minimally-invasive, circulating, transcriptomic biomarker of FSHD clinical severity valid in muscle and blood.
Salinomycin disturbs Golgi apparatus function and specifically affects cells in epithelial-to-mesenchymal transition
Authors: Marjanović Marko , Dražić Ana-Matea Mikecin , Mioč Marija , Kliček Filip , Novokmet Mislav , Lauc Gordan , Kralj Marijeta 
Published: September 2022

AbstractEpithelial-to-mesenchymal transition (EMT) gives rise to cells with properties similar to cancer stem cells (CSCs). Targeting the EMT program to selectively eliminate CSCs is a promising way to improve cancer therapy. Salinomycin (Sal), a K+/H+ ionophore, was identified as highly selective towards CSC-like cells, but its mechanism of action and selectivity remains elusive. Here we show that Sal, similarly to monensin and nigericin, disturbs the function of the Golgi apparatus (GA). Sal alters the expression of GA-related genes and leads to marked changes in GA morphology, particularly in cells that underwent EMT. Moreover, GA disturbing agents severely affect protein post-translational modifications including protein processing, glycosylation and secretion. We discover that the alterations induced by GA disturbing agents specifically affect the viability of EMT cells. Collectively, our work identifies a new vulnerability related to the EMT, suggesting that targeting the GA is a novel therapeutic approach against CSCs.
CRTC-1 balances histone trimethylation and acetylation to promote longevity
Authors: Silva-García Carlos G. , Láscarez-Lagunas Laura I. , Papsdorf Katharina , Heintz Caroline , Prabhakar Aditi , Morrow Christopher S. , Torres Lourdes Pajuelo , Sharma Arpit , Liu Jihe , Colaiácovo Monica P. , Brunet Anne , Mair William B. 
Published: September 2022

SUMMARYLoss of function during ageing is accompanied by transcriptional drift, altering gene expression and contributing to a variety of age-related diseases. CREB-regulated transcriptional coactivators (CRTCs) have emerged as key regulators of gene expression that might be targeted to promote longevity. Here, we define the role of theCaenorhabditis elegansCRTC-1 in the epigenetic regulation of longevity. Endogenous CRTC-1 binds chromatin factors, including components of the COMPASS complex, which trimethylates lysine 4 on histone H3 (H3K4me3). CRISPR editing of endogenous CRTC-1 reveals that the CREB-binding domain in neurons is specifically required for H3K4me3-dependent longevity. However, this effect is independent of CREB but instead acts via the transcription factor AP-1. Strikingly, CRTC-1 also mediates global histone acetylation levels, and this acetylation is essential for H3K4me3-dependent longevity. Indeed, overexpression of an acetyltransferase enzyme is sufficient to promote longevity in wild-type worms. CRTCs, therefore, link energetics to longevity by critically fine-tuning histone acetylation and methylation to promote healthy ageing.
A Camera-Assisted Pathology Microscope to Capture the Lost Data in Clinical Glass Slide Diagnosis
Authors: Ashman Kimberly , Cooper Max S. , Zhuge Huimin , Fox Sharon E. , Epstein Jonathan I. , Wenk Carola , Summa Brian , Brown J. Quincy 
Published: September 2022

AbstractDigital pathology, or the practice of acquiring, managing, and interpreting high-resolution digital images from glass pathology slides, holds much promise in precision medicine, potentially transforming diagnosis and prognosis based on computational image biomarkers derived from digital tissue images. However, for all its promise, digital imaging in pathology has not yet become an integral part of the clinical workflow as it has in radiology due to high cost, workflow disruptions, burdensome data sizes and IT requirements, and additional dedicated personnel requirements. Consequently, pathology retains the 150-year-old analog workflow, and the vast majority of slides used in clinical diagnosis are never digitized. Furthermore, there is a missed opportunity to capture the image information and associated data on search processes that led to the clinical diagnosis, which could serve as the foundation for computational clinical decision support. This paper describes an approach for slide digitization during clinical review using a camera attached to a standard brightfield pathology microscope. While a pathologist reviews a glass slide using the eyepiece oculars, the continuously running camera digitizes a complete record of the slide review, resulting in multi-resolution slide images and spatiotemporal saliency maps of the slide review. Unlike other approaches, the pathologist does not stop to review the video stream or monitor the acquisition of video frames but performs the diagnostic review at the microscope using the standard clinical protocol. This hybrid analog-digital approach combines the benefits of digital slide analysis, including annotation, computation, and the ability to confirm the completeness and quality of the glass slide review with the ease of using the microscope for primary diagnosis. Furthermore, a record of the pathologist’s attention during the review, including their search path, magnification level, and dwell times at each location on the slide, is obtained. In the future, this approach could enable the development and application of new and emerging computational decision-support algorithms in real-time to provide feedback to the pathologist, reduce diagnostic errors, and improve disease diagnosis and prognosis.
STAT3 cooperates with the core transcriptional regulatory circuitry to drive MYC expression and oncogenesis in anaplastic large cell lymphoma
Authors: Prutsch Nicole , He Shuning , Berezovskaya Alla , Durbin Adam D. , Dharia Neekesh V. , Stegmaier Kimberly , Matthews Jamie D. , Hare Lucy , Turner Suzanne D. , Kenner Lukas , Merkel Olaf , Young Richard A. , Abraham Brian J. , Look A. Thomas , Zimmerman Mark W. 
Published: September 2022

AbstractAnaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T-cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here we show that dysregulated STAT3, together with a core transcriptional regulatory circuit consisting of BATF3–IRF4– IKZF1, co-occupies gene enhancers to establish an oncogenic transcription program and maintain the malignant state of ALCL. Critical downstream targets of this network in ALCL cells include the proto-oncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The activity of this auto-regulatory transcription loop is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. These findings provide new insights for understanding how dysregulated signaling pathways hijack cell-type-specific transcriptional machinery to drive tumorigenesis and create therapeutic vulnerabilities in genetically defined tumors.