bluuebunny/crossref_metadata_2025_split huggingface dataset:
ChemGLaM: Chemical-Genomics Language Models for Compound-Protein Interaction Prediction
Authors: Koyama Takuto , Tsumura Hayato , Matsumoto Shigeyuki , Okita Ryunosuke , Kojima Ryosuke , Okuno Yasushi 
Published: February 2024

AbstractAccurate prediction of compound-protein interaction (CPI) is of great importance for drug discovery. For creating generalizable CPI prediction deep learning (DL) models, the expansion of CPI data through experimental validation is crucial. However, the cost associated with these experimental validations is a bottleneck. Recently developed large language models (LLMs) such as chemical language models (CLMs) and protein language models (PLMs) have emerged as foundation models, demonstrating high generalization performance in various tasks involving compounds and proteins. Inspired by this, we propose a chemical-genomics language model, ChemGLaM, for predicting compound-protein interactions. ChemGLaM is based on the 2 independent language models, MoLFormer for compounds and ESM-2 for proteins, and fine-tuned for the CPI datasets using an interaction block with a cross-attention mechanism. ChemGLaM is capable of predicting interactions between unknown compounds and proteins with higher accuracy than existing CPI prediction models, demonstrating that combining the independently pre-trained foundation models is effective for obtaining sophisticated representation of compound-protein interactions. Furthermore, visualizing the learned cross-attention map can offer explainable insights into the mechanism of compound-protein interaction. This study emphasizes the potential of integrating the independent foundation models for the tasks of multi-modality such as CPI prediction.
MobileLAMP: A portable, low-cost, open-source device for isothermal nucleic acid amplification
Authors: Bhupathi Mohini , Hegde Smitha , Devarapu Ganga Chinna Rao , Molloy Jennifer C 
Published: February 2024

1AbstractIsothermal amplification-based methods for pathogen DNA or RNA detection offer high sensitivity, rapid detection, and the potential for deployment in remote fields and home testing. Consequently, they are emerging as alternatives to PCR and saw a surge in research activity and deployment for the rapid detection of SARS-CoV-2 during the Covid-19 pandemic. The most common isothermal DNA detection methods rely on minimal reagents for DNA amplification and simple hardware that can maintain isothermal conditions and read-out a fluorescent or colorimetric signal. Many researchers globally are working on improving these components based on diverse end-user needs. In this work, we have recognized the need for an open-source hardware device for isothermal amplification, composed of off-the-shelf components that are easily accessible in any part of the world, is easily manufacturable in a distributed and scalable way using 3D printing, and that can be powered using a wide diversity of batteries and power sources. We demonstrate the easy assembly of our device design and demonstrate its efficacy using colorimetric LAMP for both RNA and DNA targets.
Predicting the macrovascular contribution to resting-state fMRI functional connectivity at 3 Tesla: A model-informed approach
Authors: Zhong Xiaole Z. , Polimeni Jonathan R. , Chen J. Jean 
Published: February 2024

AbstractMacrovascular biases have been a long-standing challenge for fMRI, limiting its ability to detect spatially specific neural activity. Recent experimental studies, including our own (Huck et al., 2023; Zhong et al., 2023), found substantial resting-state macrovascular BOLD fMRI contributions from large veins and arteries, extending into the perivascular tissue at 3 T and 7 T. The objective of this study is to demonstrate the feasibility of predicting, using a biophysical model, the experimental resting-state BOLD fluctuation amplitude (RSFA) and associated functional connectivity (FC) values at 3 Tesla. We investigated the feasibility of both 2D and 3D infinite-cylinder models as well as macrovascular anatomical networks (mVANs) derived from angiograms. Our results demonstrate that: 1) with the availability of mVANs, it is feasible to model macrovascular BOLD FC using both the mVAN-based model and 3D infinite-cylinder models, though the former performed better; 2) biophysical modelling can accurately predict the BOLD pairwise correlation near to large veins (with R2ranging from 0.53 to 0.93 across different subjects), but not near to large arteries; 3) compared with FC, biophysical modelling provided less accurate predictions for RSFA; 4) modelling of perivascular BOLD connectivity was feasible at close distances from veins (with R2ranging from 0.08 to 0.57), but not arteries, with performance deteriorating with increasing distance. While our current study demonstrates the feasibility of simulating macrovascular BOLD in the resting state, our methodology may also apply to understanding task-based BOLD. Furthermore, these results suggest the possibility of correcting for macrovascular bias in resting-state fMRI and other types of fMRI using biophysical modelling based on vascular anatomy.
Gel-Assisted Proteome Position Integral Shift (GAPPIS) Assay Returns Molecular Weight to Shotgun Proteomics and Identifies Novel Caspase 3 Substrates
Authors: Meng Zhaowei , Saei Amir Ata , Zhang Xuepei , Lyu Hezheng , Gharibi Hassan , Lundström Susanna L , Végvári Ákos , Gaetani Massimiliano , Zubarev Roman A. 
Published: February 2024

AbstractHere we present a high-throughput virtual top-down proteomics approach that restores the molecular weight (MW) information in shotgun proteomics, and demonstrate its utility in studying proteolytic events in programmed cell death. With Gel-Assisted Proteome Position Integral Shift (GAPPIS), we quantified over 7000 proteins in staurosporine-induced apoptotic HeLa cells and identified 89 proteins exhibiting in a statistically significant manner at least two of the following features: 1) a negative MW shift; 2) an elevated ratio in a pair of a semi-tryptic and tryptic peptide, 3) a negative shift in the standard deviation of MW estimated for different peptides, and 4) a negative shift in skewness of the same data. Of these proteins, 60 molecules were novel caspase 3 substrates. Further analysis identified the preferred cleavage sites consistent with the known caspase cleavages after the DXXD motif. As a powerful tool for high-throughput MW analysis simultaneously with the conventional expression analysis, GAPPIS assay can prove useful in studying a broad range of biological processes involving proteolytic events.
Transient Impairment in Microglial Function Causes Sex-Specific Deficits in Synaptic and Hippocampal Function in Mice Exposed to Early Adversity
Authors: Ahmed Sahabuddin , Polis Baruh , Jamwal Sumit , Sanganahalli Basavaraju G. , MacDowell Kaswan Zoe , Islam Rafiad , Kim Dana , Bowers Christian , Giuliano Lauryn , Biederer Thomas , Hyder Fahmeed , Kaffman Arie 
Published: February 2024

AbstractAbnormal development and function of the hippocampus are two of the most consistent findings in humans and rodents exposed to early life adversity, with males often being more affected than females. Using the limited bedding (LB) paradigm as a rodent model of early life adversity, we found that male adolescent mice that had been exposed to LB exhibit significant deficits in contextual fear conditioning and synaptic connectivity in the hippocampus, which are not observed in females. This is linked to altered developmental refinement of connectivity, with LB severely impairing microglial-mediated synaptic pruning in the hippocampus of male and female pups on postnatal day 17 (P17), but not in adolescent P33 mice when levels of synaptic engulfment by microglia are substantially lower. Since the hippocampus undergoes intense synaptic pruning during the second and third weeks of life, we investigated whether microglia are required for the synaptic and behavioral aberrations observed in adolescent LB mice. Indeed, transient ablation of microglia from P13-21, in normally developing mice caused sex-specific behavioral and synaptic abnormalities similar to those observed in adolescent LB mice. Furthermore, chemogenetic activation of microglia during the same period reversed the microglial-mediated phagocytic deficits at P17 and restored normal contextual fear conditioning and synaptic connectivity in adolescent LB male mice. Our data support an additional contribution of astrocytes in the sex-specific effects of LB, with increased expression of the membrane receptor MEGF10 and enhanced synaptic engulfment in hippocampal astrocytes of 17-day-old LB females, but not in LB male littermates. This finding suggests a potential compensatory mechanism that may explain the relative resilience of LB females. Collectively, these studies highlight a novel role for glial cells in mediating sex-specific hippocampal deficits in a mouse model of early-life adversity.
Investigating T cell Recruitment in Atherosclerosis using a novel Human 3D Tissue-Culture Model reveals the role of CXCL12 in intraplaque neovessels
Authors: Parma Laura , Sachs Nadja , Li Zhaolong , Merchant Kevin , Sobczak Nikola , Slütter Bram , Maegdefessel Lars , Weber Christian , Duchene Johan , Megens Remco T.A. 
Published: February 2024

AbstractBackgroundDevelopment of effective treatments for atherosclerosis requires new models that better predict the human immune response. Although T cells are abundant in human atherosclerotic lesions and play a key role in the pathogenesis, the mechanism involved in plaque infiltration remains ill defined.MethodsWe developed a three-dimensional tissue-culture model to study leukocyte recruitment to human atherosclerotic plaques. In this study, human atherosclerotic plaques obtained during carotid endarterectomy surgery were co-cultured with patient-matching T cells. Exogenous T cells were stained using a multi-factor staining strategy, which involved intracellular fluorescent cell tracker dyes combined with nuclear labels. Flow cytometry was used to assess the presence of the labeled cells within the plaques, and microscopic analysis was performed to examine their localization.ResultsFlow cytometry and microscopy cell-tracking analysis demonstrated that exogenous T cells successfully migrated into atherosclerotic plaques. Furthermore, infiltrated CD8+T cells displayed a significant increase of CD69 expression, indicating their activation within the tissue. Blocking chemokine receptors, particularly CXCR4, significantly impaired T cell infiltration, demonstrating that exogenous CD8+T cells invade plaques through chemotactic migration. Surprisingly, 3D microscopy combined with optical tissue clearing strategy revealed that CXCL12, the sole ligand of CXCR4, mainly accumulated in intraplaque neovessels. Single-cell RNA sequencing (scRNAseq) analysis further confirmed that endothelial cells from intraplaque neovessels were the primary source for CXCL12. Additionally, exogenous T cells were found within and in proximity to these neovessels, suggesting that the CXCL12/CXCR4 axis regulates T cell recruitment through intraplaque neovessels.ConclusionsOverall, these findings shed new light on the mechanism of action of CXCL12 in atherosclerosis and demonstrated the potential of the model to advance our understanding of leukocyte accumulation in human atherosclerosis and assist in testing novel pharmacological therapies.
Optical Control of Cell-Surface and Endomembrane-Exclusive β-Adrenergic Receptor Signaling
Authors: Thotamune Waruna , Ubeysinghe Sithurandi , Shrestha Kendra K. , Mostafa Mahmoud Elhusseiny , Young Michael C. , Karunarathne Ajith 
Published: February 2024

ABSTRACTBeta-adrenergic receptors (βARs) are G protein-coupled receptors (GPCRs) that mediate catecholamine-induced stress responses, such as heart rate increase and bronchodilation. In addition to signals from the cell surface, βARs also broadcast non-canonical signaling activities from the cell interior membranes (endomembranes). Dysregulation of these receptor pathways underlies severe pathological conditions. Excessive βAR stimulation is linked to cardiac hypertrophy, leading to heart failure, while impaired stimulation causes compromised fight or flight stress responses and homeostasis. In addition to plasma membrane βAR, emerging evidence indicates potential pathological implications of deeper endomembrane βARs, such as inducing cardiomyocyte hypertrophy and apoptosis, underlying heart failure. However, the lack of approaches to control their signaling in subcellular compartments exclusively has impeded linking endomembrane βAR signaling with pathology. Informed by the β1AR-catecholamine interactions, we engineered an efficiently photo-labile, protected hydroxy β1AR pro-ligand (OptoIso) to trigger βAR signaling at the cell surface, as well as exclusive endomembrane regions upon blue light stimulation. Not only does OptoIso undergo blue light deprotection in seconds, but it also efficiently enters cells and allows examination of G protein heterotrimer activation exclusively at endomembranes. In addition to its application in the optical interrogation of βARs in unmodified cells, given its ability to control deep organelle βAR signaling, OptoIso will be a valuable experimental tool.
Importin-β specific nuclear transport defects recapitulate phenotypic and transcriptional alterations seen in neurodegeneration
Authors: Plessis-Belair Jonathan , Ravano Kathryn , Han Ellen , Janniello Aubrey , Molina Catalina , Sher Roger 
Published: February 2024

AbstractDefects in Nucleocytoplasmic transport have been implicated as an important neurodegenerative pathway in ALS/FTD. Here, we show that aNemfR86Smutation results in the disruption of NCT bothin vitroandin vivo. These disruptions are specific to Importin-β nuclear import, and result in the nuclear loss and cytoplasmic gain of NEMF, Importin-β, and TDP-43. We show that a transient nuclear import block is capable of inducing the mis-localization of TDP-43 and is associated with altered transcriptional expression of ALS, FTD, and AD/ARD genes. Taken together, these findings show that disrupted Importin-β nuclear import, whether through genetic forms such asNemfmutations, or through pharmacological inhibition, is the primary driver of TDP-43 pathology, disease-related transcriptional alterations, and neurodegeneration.
Feed-forward stimulation of CAMK2 by the oncogenic pseudokinase PEAK1 generates a therapeutically ‘actionable’ signalling axis in triple negative breast cancer
Authors: Yang Xue , Ma Xiuquan , Zhao Tianyue , Croucher David R , Nguyen Elizabeth V. , Clark Kimberley C. , Hu Changyuan , Latham Sharissa L , Bayly-Jones Charles , Nguyen Viet Chi Bao , Budnar Srikanth , Shin Sung-Young , Nguyen Lan K. , Cotton Thomas R. , Chüeh Anderly C. , Sian Terry C C Lim Kam , Stratton Margaret M. , Ellisdon Andrew M. , Daly Roger J 
Published: February 2024

SummaryThe PEAK family of pseudokinases, comprising PEAK1-3, are signalling scaffolds that play oncogenic roles in several poor prognosis human cancers, including triple negative breast cancer (TNBC). However, therapeutic targeting of pseudokinases is challenging due to their lack of catalytic activity. To address this, we screened for PEAK1 effectors by affinity purification and mass spectrometry, identifying calcium/calmodulin-dependent protein kinase 2 (CAMK2)D and CAMK2G. PEAK1 promoted CAMK2D/G activation in TNBC cells via a novel feed-forward mechanism involving PEAK1/PLCγ1/Ca2+signalling and direct binding via a consensus CAMK2 interaction motif in the PEAK1 N-terminus. In turn, CAMK2 phosphorylated PEAK1 to enhance association with PEAK2, which is critical for PEAK1 oncogenic signalling. To achieve pharmacologic targeting of PEAK1/CAMK2, we repurposed RA306, a second generation CAMK2 inhibitor under pre-clinical development for treatment of cardiovascular disease. RA306 demonstrated on-target activity against CAMK2 in TNBC cells and inhibited PEAK1-enhanced migration and invasionin vitro. Moreover, RA306 significantly attenuated TNBC xenograft growth and blocked metastasis in a manner mirrored by CRISPR-mediated PEAK1 ablation. Overall, these studies establish PEAK1 as a critical cell signalling nexus, identify a novel mechanism for regulation of Ca2+signalling and its integration with tyrosine kinase signals, and identify CAMK2 as a therapeutically ‘actionable’ target downstream of PEAK1.
Pangenomic landscapes shape the genetic circuit performance in aStutzerimonasbiodesign toolkit
Authors: Chan Dennis Tin Chat , Bernstein Hans C. 
Published: February 2024

ABSTRACTImplementation of identical biodesign strategies into different species often results in different performance, a process called the “chassis effect”. Our current understanding of how cellular host context underpins its ability to be engineered is lacking and closing this knowledge gap will greatly improve the rational design of microorganisms. Here, we combined global differential gene expression analysis and pangenomics to uncover how genome structure and function relates to the observed chassis effect of an engineered genetic inverter device operating in six closely relatedStutzerimonashosts. The differential expression of the core genome, gene clusters shared between all hosts, was found to be the main source of significant concordance to the observed device performance, whereas specialty genes from respective accessory genomes were not significant. A data-driven investigation revealed that genes related to denitrification and efflux pumps were among the most differentially expressed gene clusters in response to the engineered device. This study establishes that the effectiveness of synthetic gene circuits can be traced along differences in closely related microbial hosts that each represent unique hardware options for biodesign.
Adaptation of human cell populations to different levels of centriole amplification involves a two-step response
Authors: Dias Louro Marco António , Peneda Catarina , Bank Claudia , Bettencourt-Dias Mónica 
Published: February 2024

SummaryCentrioles are the main components of cilia and centrosomes, which play a central role in cell proliferation and signalling. Their number is strictly regulated. Centriole amplification, or the presence of extra centrioles, often occurs in tumours and leads to aneuploidy and altered signalling and has been associated with cancer development and malignancy. Negative selection of cells with extra centrioles prevents numerical errors from expanding in the population, resulting in an overproduction-selection balance. However, how chronic perturbation of key centriolar regulators affect centriole number dynamics is poorly described.PLK4, a key regulator of centriole biogenesis, is often overexpressed in cancer and is associated with worse prognosis in breast cancer. Here we show that centriole amplification cannot be sustained in cultured MCF10A breast cells exposed to low and high levels of chronic PLK4 overexpression. We observed a short-term response in which negative selection and reduction in PLK4 mRNA limit centriole amplification. This was followed by long-term adaptation in which a rise in PLK4 mRNA levels was decoupled from accumulation of the protein at the centrosome. Furthermore, adaptation was dose-dependent. Populations evolved in low-overexpression conditions retained the ability to generate extra centrioles when PLK4 was further overexpressed, whereas centriole overproduction was irreversibly inhibited in populations evolved under high PLK4 overexpression. Taken together, our data reveal a two step mode of centriole number regulation and suggest that differences in the level of PLK4 overexpression may condition cancer evolution.
Metagenome-assembled genomes provide insight into the microbial taxonomy and ecology of the Buhera Soda Pans, Zimbabwe
Authors: Mangoma Ngonidzashe , Zhou Nerve , Ncube Thembekile 
Published: February 2024

AbstractThe use of metagenomics has substantially improved our understanding of the taxonomy, phylogeny and ecology of extreme environment microbiomes. Advances in bioinformatics now permit the reconstruction of almost intact microbial genomes, called metagenome-assembled genomes (MAGs), from metagenomic sequence data, allowing for more precise cell-level taxonomic, phylogenetic and functional profiling of uncultured extremophiles. Here, we report on the recovery and characterisation of metagenome-assembled genomes from the Buhera soda pans located in eastern Zimbabwe. This ecosystem has not been studied despite its unique geochemistry and potential as a habitat for unique microorganisms. Metagenomic DNA from the soda pan was sequenced using the DNA Nanoball Sequencing (DNBSEQR) technique. Sequence analysis, done on the Knowledgebase (KBase) platform, involved quality assessment, read assembly, contig binning, and MAG extraction. The MAGs were subjected to taxonomic placement, phylogenetic profiling and functional annotation in order to establish their possible ecological roles in the soda pan ecosystem. A total of 16 bacterial MAGs of medium to high quality were recovered, all distributed among five phyla dominated byProteobacteriaandFirmicutes. Of the ten MAGs that were taxonomically classified up to genus level, five of them belonged to the halophilic/ haloalkaliphilic generaAlkalibacterium, Vibrio, Thioalkalivibrio, CecembiaandNitrincola. Functional profiling revealed the use of diverse carbohydrate-metabolising pathways among the MAGs, with glycolysis and the pentose phosphate pathways appearing to be key pathways in this ecosystem. Several MAGs harboured both sulphur/ sulphate reduction and respiratory pathways, suggesting a possible mechanism of energy generation through sulphur/ suphate respiration. In conclusion, this study revealed a highly taxonomically and functionally diverse microbial community in the soda pans, dominated by halophilic and haloalkaliphilic bacteria.