bluuebunny/crossref_metadata_2025_split huggingface dataset:
A robust workflow to benchmark deconvolution of multi-omic data
Authors: Amblard Elise , Bertrand Vadim , Pena Luis Martin , Karkar Slim , Chuffart Florent , Ayadi Mira , Baurès Aurélia , Armenoult Lucile , Kermezli Yasmina , Cros Jérôme , Blum Yuna , Richard Magali 
Published: November 2024

AbstractTumour heterogeneity significantly affects cancer progression and therapeutic response, yet quantifying it from bulk molecular data remains challenging. Deconvolution algorithms, which estimate cell-type proportions in bulk samples, offer a potential solution. However, there is no consensus on the optimal algorithm for transcriptomic or methylomic data. Here, we present an unbiased evaluation framework for the first comprehensive comparison of deconvolution algorithms across both omic types, including reference-based and -free approaches. Our evaluation covers raw performance, stability, and computational efficiency under varying conditions, such as missing or additional cell types and diverse sample compositions. We apply this framework across multiple benchmark datasets, including a novel multi-omics dataset generated specifically for this study. To ensure transparency and re-usability, we have designed a reproducible work-flow using containerization and publicly available code. Our results highlight the strengths and limitations of various algorithms, and provides practical guidance for selecting the best method based on data type and analysis context. This benchmark sets a new standard for evaluating deconvolution methods and analysing tumour heterogeneity.
Transfer learning and DNA language models enhance transcription factor binding predictions
Authors: Aksu Ekin Deniz , Vingron Martin 
Published: November 2024

AbstractIdentification ofin vivotranscription factor (TF) binding sites is crucial to understand gene regulatory networks, but the lack of scalability in the methods for their experimental identification directs researchers towards computational models. TF binding site prediction models are often specific for a given TF, which also hinders the generalizability of models to previously unseen TFs. Here, we present an approach to predictin vivoTF binding sites using DNA accessibility, TF RNA expression and TF binding motifs. Our novel method leverages DNA language model embeddings and transfer learning to improve its accuracy and generalizability, achieving a mean area under the precision-recall curve (AUPR) of 0.51 in held-out cell types and chromosomes in the ENCODE-DREAMin vivoTFBS prediction challenge, outperforming the top-ranked methods. Furthermore, we show that prediction accuracy increases when TFs are highly active and exhibit cell-type specific expression. We finally test our models in an independent dataset on previously unseen TFs, and report a mean AUPR of 0.36, which is state-of-the-art in a cross-TF, cross-cell type and cross-chromosomal setting.
Cytoplasmic lncRNAs nucleate signalling pathways to define metastable state dynamics and determine phenotypic output
Authors: Shlyakhtina Y , Bloechl B , Moran KL , Maslakova A , Munro AF , Carragher NO , Portal MM 
Published: November 2024

AbstractCell plasticity, the ability that cells display to rapidly adapt to environmental cues, is thought to be encoded in non-genetic information reservoirs. Although the concept is widely acknowledged, the molecular mechanisms underlying this phenomenon remain largely undiscovered. Herein, we describe that clonal cell populations inherently display multiple co-existing metastable gene expression states that co-segregate with various phenotypic outputs. We show that transcriptome states are readily inherited and dynamically interconvert; not due to a shift in transcriptional programmes, but rather through yet unidentified post-transcriptional regulatory mechanisms. Remarkably, among phenotypically divergent clonal cell populations enriched in subsets of transcriptome states, we identified a peri-nuclear cytoplasmic structure (Signal Integration Portal – SIP) where state-specific lncRNAs, proteins containing intrinsically disordered regions and diverse active signalling pathways converge. Herein, we propose the SIP as a nucleating reservoir of non-genetic information at the crossroads of cell plasticity and non-genetic heterogeneity where it integrates intra- and extracellular signalling pathways buffering phenotypic output.
Afat-2(wa17)suppressor screen inC. elegansreveals genetic adaptations to polyunsaturated fatty acid deficiency
Authors: Kaper Delaney , Radović Uroš , Bergh Per-Olof , Qvist August , Henricsson Marcus , Borén Jan , Pilon Marc 
Published: November 2024

ABSTRACTPolyunsaturated fatty acids (PUFAs) are essential for mammalian health and function as membrane fluidizers and precursors for signaling lipids though the primary essential function of PUFAs within organisms has not been established. Unlike mammals who cannot endogenously synthesize PUFAs,C. eleganscande novosynthesize PUFAs starting with the Δ12 desaturase FAT-2 which introduces a second double bond to monounsaturated fatty acids to generate the PUFA linoleic acid. FAT-2 desaturation is essential forC. eleganssurvival sincefat-2null mutants are non-viable; the near-nullfat-2(wa17)allele synthesizes only small amounts of PUFAs and produces extremely sick worms. Using fluorescence recovery after photobleaching (FRAP), we found that thefat-2(wa17)mutant has rigid membranes and can be efficiently rescued by dietarily providing various PUFAs, but not by fluidizing treatments or mutations. With the aim of identifying mechanisms that compensate for PUFA-deficiency, we performed a forward genetics screen to isolate novelfat-2(wa17)suppressors and identified four internal mutations withinfat-2, and six mutations within the HIF-1 pathway. The suppressors increase PUFA levels infat-2(wa17)mutant worms and additionally suppress the activation of thedaf-16, UPRerand UPRmtstress response pathways that are active infat-2(wa17)worms. We hypothesize that the six HIF-1 pathway mutations, found inegl-9,ftn-2, andhif-1all converge on raising Fe2+levels and in this way boost desaturase activity, including that of thefat-2(wa17)allele. We conclude that PUFAs cannot be genetically replaced and that the only genetic mechanism that can alleviate PUFA-deficiency do so by increasing PUFA levels.
Chronic intermittent ethanol produces nociception through endocannabinoid-independent mechanisms in mice
Authors: Miliano C , Dong Y , Proffit M , Corvalan N , Natividad LA , Gregus AM , Buczynski MW 
Published: November 2024

AbstractAlcohol use disorder (AUD) affects millions of people and represents a significant health and economic burden. Pain represents a frequently under-treated aspect of hyperkatifeia during alcohol withdrawal, yet to date no drugs have received FDA approval for the treatment of this indication in AUD patients. This study aims to evaluate the potential of targeting bioactive lipid signaling pathways as a therapeutic approach for treating alcohol withdrawal-related pain. We utilized a chronic intermittent ethanol (CIE) vapor exposure model in C57BL/6J mice of both sexes to establish alcohol dependence, and demonstrated that CIE mice developed robust tactile allodynia and thermal hyperalgesia during withdrawal that was independent of prior blood alcohol levels. Next, we evaluated four drugs for their efficacy in reversing tactile allodynia during abstinence from CIE using a cross-over treatment design that included FDA-approved naltrexone as well as commercially available inhibitors targeting inflammatory lipid signaling enzymes including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and 15-Lipoxygenase (LOX). None of these compounds produced significant therapeutic benefit in reversing established CIE-induced tactile allodynia, despite attenuating pain-like behaviors at these doses in other chronic pain models. Additionally, we assessed plasma endocannabinoid levels in both sexes during withdrawal. We found that there is an inherent sex difference in the endogenous anti-inflammatory endocannabinoid tone in naive mice and CIE treatment affected endocannabinoids levels in female mice only. These findings underscore the need to better understand the driving causes of AUD induced pain and to develop novel therapeutic approaches to mitigate pain in AUD patients.
ADP-MoA: a platform for screening antibiotic activity and their mechanism of action inPseudomonas aeruginosa
Authors: Valencia Morante Estela Ynés , Nunes Viviane Abreu , Chambergo Felipe S , Spira Beny 
Published: November 2024

ABSTRACTThe emergence and proliferation of multidrug-resistant bacteria pose a major threat to global public health. To address an imminent crisis, it is essential to identify and characterize new antibacterial molecules. With that in mind, we developed the ADP-MoA platform, that facilitates the discovery of new antibiotics and provides preliminary insights into their mechanisms of action. The basic idea is to simultaneously visualize antibiotic activity – growth inhibition, along with one of the three classic antibiotics mechanisms of action: DNA damage/inhibition of DNA replication, protein synthesis inhibition and cell wall damage. The platform consists of three different chromosomal fusions between the promoters ofrecA, ampCorarmZand theluxCDABEoperon. The platform was constructed and hitherto tested in the pathogenic opportunistic bacteriumPseudomonas aeruginosa. As a proof of concept we showed that the promoter fusions were each activated by the expected antibiotics with known mechanisms of action. ThearmZ::luxCDABEfusion responded to antibiotics that inhibit protein synthesis (macrolides, chloramphenicol, tetracyclines and aminoglycosides),ampC::luxCDABEwas induced by β-lactams andrecA::luxCDABEwas induced by quinolones. Interestingly, ciprofloxacin induced PampCand ParmZas well, albeit at a lower level. The ADP-MoA platform offers a readily implementable, low-cost approach with significant potential for high-throughput screening of antimicrobials againstP. aeruginosaand other bacterial species.
Offset mass carrier proteome improves quantification of multiplexed single cell proteomics
Authors: Cheung Tommy K. , Zhu Ying , Rose Christopher M. 
Published: November 2024

AbstractMultiplexed single cell proteomics by mass spectrometry (scpMS) approaches currently offer the highest throughput as measured by cells analyzed per day. These methods employ isobaric labels and typically a carrier proteome - a sample added at 20-500x the single cell level that improves peptide sampling and identification. Peptides from the carrier and single cell proteomes exist within the same precursor isotopic cluster and are co-isolated for identification and quantification. This represents a challenge as high levels of carrier proteome limit the sampling of peptide ions from single cell samples and can potentially lead to decreased accuracy of quantitative measurements. Here, we address this limitation by introducing a triggered by offset mass acquisition method for scpMS (toma-scpMS) that utilizes a carrier proteome labeled with non-isobaric tags that have the same chemical composition but different mass as the labels used for quantitative multiplexing. Within toma-scpMS the carrier proteome and single cell proteome are separated at the precursor level, enabling separate isolation, fragmentation, and quantitation of the single cell samples. To enable this workflow we implemented a custom data acquisition scheme within inSeqAPI, an instrument application programming interface program, that performed real-time identification of carrier proteome peptides and subsequent triggering of offset single cell quantification scans. We demonstrate that toma-scpMS is more robust to high-levels of carrier proteome and offers superior quantitative accuracy as compared to traditional multiplexed scpMS approaches when similar carrier proteome levels are employed.
Characterizing the rates and patterns ofde novogermline mutations in the aye-aye (Daubentonia madagascariensis)
Authors: Versoza Cyril J. , Ehmke Erin E. , Jensen Jeffrey D. , Pfeifer Susanne P. 
Published: November 2024

ABSTRACTGiven the many levels of biological variation in mutation rates observed to date in primates – spanning from species to individuals to genomic regions – future steps in our understanding of mutation rate evolution will be aided by both a greater breadth of species coverage across the primate clade, but also by a greater depth as afforded by an evaluation of multiple trios within individual species. In order to help bridge these gaps, we here present an analysis of a species representing one of the most basal splits on the primate tree (aye-ayes), combining whole-genome sequencing of seven parent-offspring trios from a three-generation pedigree with a novel computational pipeline that takes advantage of recently developed pan-genome graphs, thereby circumventing the application of (highly subjective) quality metrics that has previously been shown to result in notable differences in the detection ofde novomutations, and ultimately estimates of mutation rates. This deep sampling has enabled both a detailed picture of parental age effects as well as sex dependency in mutation rates which we here compare with previously studied primates, but has also provided unique insights into the nature of genetic variation in one of the most endangered primates on the planet.
Genetic modulation of yield and phenotypic plasticity of yield in winter wheat
Authors: Giordano Nicolas , Sadras Victor O. , Guttieri Mary J. , Cruppe Giovana , Bai Guihua , Fritz Allan , Bernardo Amy , St. Amand Paul , Abbate Pablo , Berger Andres , Boehm Jeffrey , De Oliveira Silva Amanda , Jones-Diamond Sally , Haley Scott , Lingenfelser Jane , Zhang Guorong , Lollato Romulo 
Published: November 2024

AbstractFor winter wheat in the US Central Great Plains, phenotypic plasticity of yield is agronomically adaptive,i.e., genotypes with higher plasticity have higher yield in high yielding environments with no tradeoff in stressful, low yielding environments. Using data from variety trials conducted between 2000 and 2022 and cultivars released between 1967 and 2022, we explored time trends in phenotypic plasticity and heritability of yield. We hypothesize that i) if yield plasticity is agronomically adaptive, then newer cultivars will have higher yield plasticity; ii) heritability of yield is declining in the time series; and iii) genomic regions associated with yield depend on the environment and do not fully overlap with those associated with phenotypic plasticity of yield. Breeding for yield and agronomic adaptation increased phenotypic plasticity of yield at 0.5% year-1; broad sense heritability of yield decreased from 0.23 in 1993 to 0.15 in 2017. Genome-wide-association analysis shows genomic regions associated with yield varied between high yielding and stressful environments and were partially independent of those associated with yield plasticity. Newer cultivars have a higher frequency of alleles associated with yield and its plasticity. We discuss implications for breeding and agronomy aimed to improve wheat phenotypes.
Glioblastoma Drives Protease-Independent Extracellular Matrix Invasion of Microglia
Authors: Chang Chia-Wen , Bale Ashwin , Bhargava Rohit , Harley Brendan A.C. 
Published: November 2024

ABSTRACTGlioblastoma (GBM) is the most common and lethal form of primary brain cancer. Microglia infiltration into the tumor microenvironment is associated with immunosuppression and poor prognosis. Improved physicochemical understanding of microglia activation and invasion may provide novel GBM therapeutic strategies essential for improving long-term treatment efficacy. Here, we combine microfluidic systems with 3-D collagen hydrogels to systematically investigate microglia activation, invasion, contractility and cytokine secretion in response of GBM-microglia crosstalk. GBM inflammatory biomolecules significantly promote activation and 3D invasion of microglia. Interestingly, microglia invasion is not significantly affected by inhibitors of MMP activity or cellular glycolysis. In contrast, ROCK-pathway inhibition significantly impedes microglia invasion. Infrared microscopy analyses show that GBM co-culture does not significantly alter microglia lipid content. Further, GBM conditioned media resulted in significantly increased collagen hydrogel contraction, suggesting the importance of microglia contractility to physically remodel the local extracellular matrix (ECM). We also identify a panel of soluble proteins that may contribute to microglia chemotaxis, such as TIMP-1 and CXCL12. Taken together, this study suggests that the presence of GBM cells can enhance microglia invasion via increased cellular contractility, independent of MMP activity and cellular glycolysis.
Identification and characterization of vasoactive intestinal peptide receptor antagonists with high-affinity and potent anti-leukemia activity
Authors: Wang Yuou , Sen-Majumdar Anish , Li Jian-Ming , Sarkar Srijon , Passang Tenzin , Li Yiwen , Cohen Jamie , Chen Zihan , Chaudagar Kiranj , Das Pankoj Kumar , Wang Shuhua , Bruk Nabute , Papadantonakis Nikolaos , Giver Cynthia R. , Waller Edmund K. 
Published: November 2024

ABSTRACTVasoactive intestinal peptide (VIP) is a neuropeptide involved in tumor growth and immune modulating functions. Previous research indicated that a VIP antagonist (VIPhyb) enhances T-cell activation and induces T-cell-dependent anti-leukemic activity in mice. We created a combinatorial library of VIPhyb C-terminal sequence variations to develop a more potent VIP-receptor (VIP-R) antagonist, hypothesizing that specific amino acid substitutions would improve receptor binding and plasma stability.In silicoscreening analyses identified sequences with improved docking scores predicting increased binding affinity to human VIP receptors VPAC1 and VPAC2. Fifteen peptides were synthesized and tested for their ability to potentiate activation of purified mouse and human T cells and enhance T cell-dependent anti-leukemia responses in murine models of acute myeloid leukemia. Treating C57Bl/6 mice engrafted with a C1498 myeloid leukemia cell line with daily subcutaneous injections of VIP-R antagonist peptides induced T cell activation resulting in specific anti-leukemia responses. Strikingly, the predicted binding affinity of the VIP-R antagonists to VIP receptors correlated positively with their ability to augment mouse T-cell proliferation and anti-leukemia activity. ANT308 and ANT195 emerged as top candidates due to their high predicted VIP-R binding, low EC50forin vitroT cell activation, and potent anti-leukemia activities. ANT308 decreased CREB phosphorylation, a downstream signaling pathway of the VIP receptor, and stimulated granzyme B and perforin expression in CD8+ T cells from AML patients. Combiningin silicomodeling,in vitroT cell activation properties, andin vivoanti-leukemia activity has identified promising VIP-R antagonist candidates for further development as novel immunotherapies for AML, especially for patients with relapsed disease.
How population control of pests is modulated by density dependence: The perspective of genetic biocontrol
Authors: Butler C. D. , Lloyd A. L. 
Published: November 2024

AbstractManaging pest species relies critically on mechanisms that regulate population dynamics, particularly those factors that change with population size. These density-dependent factors can help or hinder control efforts and are especially relevant considering recent advances in genetic techniques that allow for precise manipulation of the timing and sex-specificity of a control. Despite this importance, density dependence is often poorly characterized owing to limited data and an incomplete understanding of developmental ecology. To address this issue, we construct and analyze a mathematical model of a pest population with a general control under a wide range of density dependence scenarios. Using this model, we investigate how control performance is affected by the strength of density dependence. By modifying the timing and sex-specificity of the control, we tailor our analysis to simulate different pest control strategies, including conventional and genetic biocontrol methods. We pay particular attention to the latter as case studies by extending the baseline model to include genetic dynamics. Finally, we clarify past work on the dynamics of mechanistic models with density dependence. As expected, we find substantial differences in control performance for differing strengths of density dependence, with populations exhibiting strong density dependence being most resilient to suppression. However, these results change with the size and timing of the control load, as well as the target sex. Interestingly, we also find that population invasion by certain genetic biocontrol strategies is affected by the strength of density dependence. While the model is parameterized using the life history traits of the yellow fever mosquito,Aedes aegypti, the principles developed here apply to many pest species. We conclude by discussing what this means for pest population suppression moving forward.
Preprints vs. Journal Articles: Citation Impact in COVID-19 Research
Authors: Tsunoda Hiroyuki , Sun Yuan , Nishizawa Masaki , Liu Xiaomin , Amano Kou , Kominami Rie 
Published: November 2024

ABSTRACTFocusing on article and citation count, this study examined 110 academic journals whose papers on COVID-19 were indexed in PubMed from 2020 to 2023. To analyze these journals’ characteristics, this study introduced the concepts of paper ratio, citation ratio, and citation impact. Journals with similar trends in paper and citation count were positioned near the diagonal on a two-dimensional graph (y=x) with paper ratio on the x-axis and citation ratio on the y-axis, indicating a slope close to 1. Conversely, the greater the disparity between paper ratio and citation ratio, the wider the angle between the journal’s position and the diagonal. Of the 110 journals in 2020, 83 were above the diagonal with a citation impact greater than 1, while 27 were below the diagonal with a citation impact of 1 or lower. Notably, nine journals—BMC Health Services Research, Genome Medicine, Nature, Annals of Epidemiology, BMC Bioinformatics, Nature Microbiology, PLoS Computational Biology, Medicine (Baltimore), andJournal of Clinical Investigation—showed high citation impact, with preprint-distributed papers being cited nearly five times more than directly submitted papers. This study demonstrates that articles initially distributed as preprints in these journals tend to receive substantially more citations than directly submitted ones.