bluuebunny/crossref_metadata_2025_split huggingface dataset:
A clinically defined and xeno-free hydrogel system for regenerative medicine
Authors: Ong John , Gibbons George , Siang Lim Yee , Lei Zhou , Zhao Junzhe , Justin Alexander W. , Cammarata Federico , Rajarethinam Ravisankar , Limegrover Colleen , Sinha Sanjay , Lakatos Andras , Rouhani Foad J. , Young Dan Yock , Markaki Athina E. 
Published: June 2024

ABSTRACTBiofabricated scaffolds facilitate bona fide cellular interactions, cell type specification, and the formation of three-dimensional tissue architecture from human pluripotent stem cells (hPSCs). However, poorly defined and non-clinically approved synthetic biomaterials greatly hinder the translation of lab-grown therapies into clinical practice. Here, we describe a protein screen-based hydrogel system biofabricated from widely available clinical-grade human components. We show that “Alphagel”, a base hydrogel comprising human embryonic matrices, supports the trilineage differentiation of hPSCs into neural, cardiac, and liver tissue. Alphagel is also biocompatible and biodegradablein vivo. Further, by adding select proteins found in the maturing human foetal liver, the resulting hydrogel (termed “Hepatogel”) enhances the differentiation of hPSC-derived hepatocytes (H-iHeps) compared to Matrigel, a xenogenic and commonly used hydrogel that is prohibited in clinical use. Importantly, when injected into mice livers, Hepatogel significantly improves the engraftment rates of H-iHeps compared to standard cell injections. Altogether, our results provide proof of concept that this customisable hydrogel system is a useful tool for developing organ-specific and clinically translatable therapies for regenerative medicine and tissue engineering.
AlphaDIA enables End-to-End Transfer Learning for Feature-Free Proteomics
Authors: Wallmann Georg , Skowronek Patricia , Brennsteiner Vincenth , Lebedev Mikhail , Thielert Marvin , Steigerwald Sophia , Kotb Mohamed , Heymann Tim , Zhou Xie-Xuan , Schwörer Magnus , Strauss Maximilian T. , Ammar Constantin , Willems Sander , Zeng Wen-Feng , Mann Matthias 
Published: June 2024

AbstractMass spectrometry (MS)-based proteomics continues to evolve rapidly, opening more and more application areas. The scale of data generated on novel instrumentation and acquisition strategies pose a challenge to bioinformatic analysis. Search engines need to make optimal use of the data for biological discoveries while remaining statistically rigorous, transparent and performant. Here we present alphaDIA, a modular open-source search framework for data independent acquisition (DIA) proteomics. We developed a feature-free identification algorithm particularly suited for detecting patterns in data produced by sensitive time-of-flight instruments. It naturally adapts to novel, more eTicient scan modes that are not yet accessible to previous algorithms. Rigorous benchmarking demonstrates competitive identification and quantification performance. While supporting empirical spectral libraries, we propose a new search strategy named end-to-end transfer learning using fully predicted libraries. This entails continuously optimizing a deep neural network for predicting machine and experiment specific properties, enabling the generic DIA analysis of any post-translational modification (PTM). AlphaDIA provides a high performance and accessible framework running locally or in the cloud, opening DIA analysis to the community.
PhyloFunc: Phylogeny-informed Functional Distance as a New Ecological Metric for Metaproteomic Data Analysis
Authors: Wang Luman , Simopoulos Caitlin M. A. , Serrana Joeselle M. , Ning Zhibin , Li Yutong , Sun Boyan , Yuan Jinhui , Figeys Daniel , Li Leyuan 
Published: June 2024

AbstractBackgroundBeta-diversity is a fundamental ecological metric for exploring dissimilarities between microbial communities. On the functional dimension, metaproteomics data can be used to quantify beta-diversity to understand how microbial community functional profiles vary under different environmental conditions. Conventional approaches to metaproteomic functional beta-diversity often treat protein functions as independent features, ignoring the evolutionary relationships among microbial taxa from which different proteins originate. A more informative functional distance metric that incorporates evolutionary relatedness is needed to better understand microbiome functional dissimilarities.ResultsHere, we introduce PhyloFunc, a novel functional beta-diversity metric that incorporates microbiome phylogeny to inform on metaproteomic functional distance. Leveraging the phylogenetic framework of weighted UniFrac distance, PhyloFunc innovatively utilizes branch lengths to weigh between-sample functional distances for each taxon, rather than differences in taxonomic abundance as in weighted UniFrac. Proof-of-concept using a simulated toy dataset and a real dataset from mouse inoculated with a synthetic gut microbiome and fed different diets show that PhyloFunc successfully captured functional compensatory effects between phylogenetically related taxa. We further tested a third dataset of complex human gut microbiomes treated with five different drugs to compare PhyloFunc’s performance with other traditional distance methods. PCoA and machine learning-based classification algorithms revealed higher sensitivity of PhyloFunc in microbiome responses to paracetamol. We providePhyloFuncas an open-source Python package (available athttps://pydigger.com/pypi/PhyloFunc), enabling efficient calculation of functional beta-diversity distances between a pair of samples or the generation of a distance matrix for all samples within a dataset.ConclusionsUnlike traditional approaches that consider metaproteomics features as independent and unrelated, PhyloFunc acknowledges the role of phylogenetic context in shaping the functional landscape in metaproteomes. In particular, we report that PhyloFunc accounts for the functional compensatory effect of taxonomically related species. Its effectiveness, ecological relevance, and enhanced sensitivity in distinguishing group variations are demonstrated through the specific applications presented in this study.
AFsample2: Predicting multiple conformations and ensembles with AlphaFold2
Authors: Kalakoti Yogesh , Wallner Björn 
Published: June 2024

AbstractUnderstanding protein dynamics and conformational states carries profound scientific and practical implications for several areas of research, ranging from a general understanding of biological processes at the molecular level to a detailed understanding of disease mechanisms, which in turn can open up new avenues in drug development. Multiple solutions have been recently developed to widen the conformational landscape of predictions made by Alphafold2 (AF2). Here, we introduce AFsample2, a method employing random MSA column masking to reduce the influence of co-evolutionary signals to enhance the structural diversity of models generated by the AF2 neural network. AFsample2 improves the prediction of alternative states for a broad range of proteins, yielding high-quality end states and diverse conformational ensembles. In the data set of open-closed conformations (OC23), alternate state models improved in 17 out of 23 cases without compromising the generation of the preferred state. Consistent results were observed in 16 membrane protein transporters, with improvements in 12 out of 16 targets. TM-score improvements to experimental end states were substantial, sometimes exceeding 50%, elevating mediocre scores from 0.58 to nearly perfect 0.98. Furthermore, AFsample2 increased the diversity of intermediate conformations by 70% compared to the standard AF2 system, producing highly confident models, that could potentially be on-path between the two states. In addition, we also propose a way of selecting the end-states in generated model ensembles. These solutions could potentially enhance the generation and identification of alternative protein conformations, thereby providing a more comprehensive understanding of protein function and dynamics. Future work will focus on validating the accuracy of these intermediate conformations and exploring their relevance to functional transitions in proteins.
Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats
Authors: Floris Gabriele , Dabrowski Konrad R. , Zanda Mary Tresa , Daws Stephanie E. 
Published: June 2024

AbstractPreclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in more >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT2AR), a well-documented target for modulation of drug seeking, and evidence suggests 5-HT2AR agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HT2AR antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075 mg/kg/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg/kg psilocybin 4-24 hours prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HT2AR antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naïve rats received psilocybin and/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24 hours later for RNA-sequencing. 3.0 mg/kg psilocybin regulated ∼2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked >90% of psilocybin-regulated genes, including the IL-17a cytokine receptor,Il17ra. Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, includingIl17a, and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking.
A hemoperfusion column selectively adsorbs LAP+lymphocytes to improve anti-tumor immunity and survival of tumor-bearing rats
Authors: Teramoto Kazuo , Ueda Yuji , Murai Ryosuke , Ogasawara Kazumasa , Nakayama Misako , Ishigaki Hirohito , Itoh Yasushi 
Published: June 2024

AbstractA decrease of immune suppressive cells in blood is thought to be one of the means to activate anti-tumor immunity that works as a treatment for cancers. We have developed an adsorbent that selectively adsorbs lymphocytes expressing latency-associated peptide (LAP), which include regulatory T cells (Tregs). The adsorbent, diethylenetriamine-conjugated polysulfone coated on polyethylene terephthalate fibers, was packed in a column for direct hemoperfusion (DHP). The therapeutic efficacy of DHP with the column was examined in rats carrying KDH-V liver cancer cells, in which LAP+cells were increased in blood. After DHP, LAP+T cells were decreased in peripheral blood, and a cytotoxic T-lymphocyte response against KDH-V cells was increased in tumor-bearing rats that had been immunized with X ray-irradiated KDH-V cells. Furthermore, the survival time of the rats was longer than that of rats without DHP. Thus, the removal of LAP+T cells can potentially be applied to the treatment of cancer regardless of the origin since an increase in the number of LAP+cells has been observed in the peripheral blood of various cancer patients.
Inference of heterogeneous effects in single-cell genetic perturbation screens
Authors: Fu Zichu , Hou Lin 
Published: June 2024

AbstractRecent single-cell CRISPR screening experiments have combined the advances of genetic editing and single-cell technologies, leading to transcriptome-scale readouts of responses to perturbations at single-cell resolution. An outstanding question is how to efficiently identify heterogeneous causal effects of perturbations using these technologies. Here we present scCAPE, a tool designed to facilitate causal analysis of heterogeneous perturbation effects at the single-cell level. scCAPE disentangles perturbation effects from the inherent cell-state variations and provides nonparametric inferences of perturbation effects at single-cell resolution, permitting a range of downstream tasks including perturbation effect analysis, genetic interaction analysis, perturbation clustering and prioritizing. We benchmarked scCAPE through simulation studies and real datasets to evaluate its performance in characterizing latent confounding factors and accuracy in estimating heterogeneous perturbation effects. The application of scCAPE identified novel heterogeneous genetic interactions among erythroid differentiation drivers. For example, our analysis pinpointed the role of the synergistic interaction between CBL and CNN1 in the S phase.
Decoding the hidden variabilities in mPFC descending pathways across emotional states
Authors: Lai Chien-Hsien , Park Gyeongah , Xu Pan , Sun Xiaoqian , Ge Qian , Jin Zhen , Betts Sarah , Liu Xiaojie , Liu Qingsong , Simha Rahul , Zeng Chen , Lu Hui , Du Jianyang 
Published: June 2024

ABSTRACTEffective emotional regulation, crucial for adaptive behavior, is mediated by the medial prefrontal cortex (mPFC) via connections to the basolateral amygdala (BLA) and nucleus accumbens (NAc), traditionally considered functionally similar in modulating reward and aversion responses. However, how the mPFC balances these descending pathways to control behavioral outcomes remains unclear. We found that while overall firing patterns appeared consistent across emotional states, deeper analysis revealed distinct variabilities. Specifically, mPFC→BLA neurons, especially “center-ON” neurons, exhibited heightened activity during anxiety-related behaviors, highlighting their role in anxiety encoding. Conversely, mPFC→NAc neurons were more active during exploratory behaviors, implicating them in processing positive emotional states. Notably, mPFC→NAc neurons showed significant pattern decorrelation during social interactions, suggesting a pivotal role in encoding social preference. Additionally, chronic emotional states affected these pathways differently: positive states enhanced mPFC→NAc activity, while negative states boosted mPFC→BLA activity. These findings challenge the assumed functional similarity and highlight distinct contributions to emotional regulation, suggesting new avenues for therapeutic interventions.
Exposure to the pesticide tefluthrin causes developmental neurotoxicity in zebrafish
Authors: Mesmar Fahmi , Muhsen Maram , Farooq Ibraheem , Maxey Grant , Tourigny Jason P. , Tennessen Jason , Bondesson Maria 
Published: June 2024

BACKGROUNDThe insecticide tefluthrin is widely used in agriculture, resulting in widespread pollution. Tefluthrin is a type I pyrethroid characterized by its high persistence in the environment. Understanding the mechanisms of toxicity of tefluthrin will improve its risk assessment.OBJECTIVESWe aimed to decipher the molecular modes of action of tefluthrin.METHODSPhenotypic developmental toxicity was assessed by exposing zebrafish embryos and larvae to increasing concentrations of tefluthrin.Tg(mnx:mGFP)line was used to assess neurotoxicity. Multi-omics approaches including transcriptomics and lipidomics were applied to analyze RNA and lipid contents, respectively. Finally, anin-silicoligand–protein docking computational method was used to study a possible interaction between tefluthrin and a protein target.RESULTSTefluthrin exposure caused severe morphological malformations in zebrafish larvae, including motor neuron abnormalities. The differentially expressed genes were associated with neurotoxicity and metabolic disruption. Lipidomics analysis revealed a disruption in fatty acid, phospholipid, and lysophospholipid recycling. Protein docking modeling suggested that the LPCAT3 enzyme, which recycles lysophospholipids in the Land’s cycle, directly interacts with tefluthrin.CONCLUSIONSTefluthrin exposure causes morphological and neuronal malformations in zebrafish larvae at nanomolar concentrations. Multi-omics results revealed a potential molecular initiating event i.e., inhibition of LPCAT3, and key events i.e., an altered lysophospholipid to phospholipid ratio, leading to the adverse outcomes of neurotoxicity and metabolic disruption.
Capillary interactions drive the self-organization of bacterial colonies
Authors: Black Matthew E. , Fei Chenyi , Alert Ricard , Wingreen Ned S. , Shaevitz Joshua W. 
Published: June 2024

AbstractMany bacteria inhabit thin layers of water on solid surfaces both naturally in soils or on hosts or textiles and in the lab on agar hydrogels. In these environments, cells experience capillary forces, yet an understanding of how these forces shape bacterial collective behaviors remains elusive. Here, we show that the water menisci formed around bacteria lead to capillary attraction between cells while still allowing them to slide past one another. We develop an experimental apparatus that allows us to control bacterial collective behaviors by varying the strength and range of capillary forces. Combining 3D imaging and cell tracking with agent-based modeling, we demonstrate that capillary attraction organizes rod-shaped bacteria into densely packed, nematic groups, and profoundly influences their collective dynamics and morphologies. Our results suggest that capillary forces may be a ubiquitous physical ingredient in shaping microbial communities in partially hydrated environments.
The intestinal microbiota contributes to the development of immune-mediated cardiovascular inflammation and vasculitis in mice
Authors: Jena Prasant K. , Wakita Daiko , Gomez Angela C. , Carvalho Thacyana T. , Atici Asli E. , Narayanan Meena , Lee Youngho , Fishbein Michael C. , Cani Patrice D. , de Vos Willem M. , Underhill David M. , Devkota Suzanne , Chen Shuang , Shimada Kenichi , Crother Timothy R. , Arditi Moshe , Rivas Magali Noval 
Published: June 2024

SUMMARYAlterations in the intestinal microbiota contribute to the pathogenesis of various cardiovascular disorders, but how they affect the development of Kawasaki disease (KD), an acute pediatric vasculitis, remains unclear. We report that depleting the gut microbiota reduces the development of cardiovascular inflammation in a murine model mimicking KD vasculitis. The development of cardiovascular lesions was associated with alterations in the intestinal microbiota composition and, notably, a decreased abundance ofAkkermansia muciniphilaandFaecalibacterium prausnitzii.Oral supplementation with either of these live or pasteurized individual bacteria, or with short-chain fatty acids (SCFAs) produced by them, attenuated cardiovascular inflammation. Treatment with Amuc_1100, the TLR-2 signaling outer membrane protein fromA. muciniphila, also decreased the severity of vascular inflammation. This study reveals an underappreciated gut microbiota-cardiovascular inflammation axis in KD vasculitis pathogenesis and identifies specific intestinal commensals that regulate vasculitis in mice by producing metabolites or via extracellular proteins acting on gut barrier function.IN BRIEFIt remains unclear whether changes in the intestinal microbiota composition are involved in the development of cardiovascular lesions associated with Kawasaki disease (KD), an immune-mediated vasculitis. Jenaet al.observe alterations in the intestinal microbiota composition of mice developing vasculitis, characterized by reducedA. muciniphilaandF. prausnitzii. Oral supplementation with either of these bacteria, live or pasteurized, or with bacteria-produced short-chain fatty acids (SCFAs) or Amuc_1100, the TLR-2 signaling outer membrane protein ofA. muciniphila, was sufficient to alleviate the development of cardiovascular lesions in mice by promoting intestinal barrier function.HIGHLIGHTSAbsence or depletion of the microbiota decreases the severity of vasculitis in a murine model mimicking KD vasculitis.Supplementation ofB. wadsworthiaandB. fragilispromotes murine KD vasculitis.Decreased abundances ofF. prausnitziiandA. muciniphilaare associated with the development of cardiovascular lesions in mice.Supplementation with either live or pasteurizedA. muciniphilaandF. prausnitzii,or the TLR-2 signaling Amuc_1100, reduces the severity of vasculitis by promoting gut barrier function.
ApoE ε4-dependent alteration of CXCR3+CD127+CD4+T cells is associated with elevated plasma neurofilament light chain in Alzheimer’s disease
Authors: Hu Dan , Chen Mei , Li Xuyang , Morin Peter , Daley Sarah , Han Yuyang , Hemberg Martin , Weiner Howard L. , Xia Weiming 
Published: June 2024

ABSTRACTRecent findings indicate a correlation between the peripheral adaptive immune system and neuroinflammation in Alzheimer’s disease (AD). To characterize the composition of adaptive immune cells in the peripheral blood of AD patients, we utilized single-cell mass cytometry (CyTOF) to profile peripheral blood mononuclear cells (PBMCs). Concurrently, we assessed the concentration of proteins associated with AD and neuroinflammation in the plasma of the same subjects. We found that the abundance of proinflammatory CXCR3+CD127+Type 1 T helper (Th1) cells in AD patients was negatively correlated with the abundance of neurofilament light chain (NfL) protein. This correlation is apolipoprotein E (ApoE) ε4-dependent. Analyzing public single-cell RNA-sequencing (scRNA-seq) data, we found that, contrary to the scenario in the peripheral blood, the cell frequency of CXCR3+CD127+Th1 cells in the cerebrospinal fluid (CSF) of AD patients was increased compared to healthy controls (HCs). Moreover, the proinflammatory capacity of CXCR3+CD127+Th1 cells in the CSF of AD patients was further increased compared to HCs. These results reveal an association of a peripheral T-cell change with neuroinflammation in AD and suggest that dysregulation of peripheral adaptive immune responses, particularly involving CXCR3+CD127+Th1 cells, may potentially be mediated by factors such as ApoE ε4 genotype.One sentence summaryAn apolipoprotein E (ApoE) ε4-dependent alteration of CD4 T cell subpopulation in peripheral blood is associated with neuroinflammation in patients with Alzheimer’s disease.