bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular organization of autonomic, respiratory, and spinally-projecting neurons in the mouse ventrolateral medulla
Authors: Schwalbe Dana C. , Stornetta Daniel S. , Abraham-Fan Ruei-Jen , Souza George M. P. R. , Jalil Maira , Crook Maisie E. , Campbell John N. , Abbott Stephen B. G. 
Published: November 2023

AbstractThe ventrolateral medulla (VLM) is a crucial region in the brain for visceral and somatic control. It also serves as a significant source of synaptic input to the spinal cord. Experimental studies have shown that gene expression in individual VLM neurons is predictive of their function. However, the organizing principles of the VLM have remained uncertain. This study aimed to create a comprehensive dataset of VLM cells using single-cell RNA sequencing. The dataset was enriched with targeted sequencing of spinally-projecting and adrenergic/noradrenergic VLM neurons. Based on differentially expressed genes, the resulting dataset of 114,805 VLM cells identifies 23 subtypes of neurons, excluding those in the inferior olive, and 5 subtypes of astrocytes. Spinally-projecting neurons were found to be abundant in 7 subtypes of neurons, which were validated through in-situ hybridization. These subtypes included adrenergic/noradrenergic neurons, serotonergic neurons, and neurons expressing gene markers associated with pre-motor neurons in the ventromedial medulla. Further analysis of adrenergic/noradrenergic neurons and serotonergic neurons identified 9 and 6 subtypes, respectively, within each class of monoaminergic neurons. Marker genes that identify the neural network responsible for breathing were concentrated in 2 subtypes of neurons, delineated from each other by markers for excitatory and inhibitory neurons. These datasets are available for public download and for analysis with a user-friendly interface. Collectively, this study provides a fine-scale molecular identification of cells in the VLM, forming the foundation for a better understanding of the VLM’s role in vital functions and motor control.
DataSAIL: Data Splitting Against Information Leakage
Authors: Joeres Roman , Blumenthal David B. , Kalinina Olga V. 
Published: November 2023

AbstractInformation Leakage is an increasing problem in machine learning research. It is a common practice to report models with benchmarks, comparing them to the state-of-the-art performance on the test splits of datasets. If two or more dataset splits contain identical or highly similar samples, a model risks simply memorizing them, and hence, the true performance is overestimated, which is one form of Information Leakage. Depending on the application of the model, the challenge is to find splits that minimize the similarity between data points in any two splits. Frequently, after reducing the similarity between training and test sets, one sees a considerable drop in performance, which is a signal of removed Information Leakage. Recent work has shown that Information Leakage is an emerging problem in model performance assessment.This work presents DataSAIL, a tool for splitting biological datasets while minimizing Information Leakage in different settings. This is done by splitting the dataset such that the total similarity of any two samples in different splits is minimized. To this end, we formulate data splitting as a Binary Linear Program (BLP) following the rules of Disciplined Quasi-Convex Programming (DQCP) and optimize a solution. DataSAIL can split one-dimensional data, e.g., for property prediction, and two-dimensional data, e.g., data organized as a matrix of binding affinities between two sets of molecules, accounting for similarities along each dimension and missing values. We compute splits of the MoleculeNet benchmarks using DeepChem, the LoHi splitter, GraphPart, and DataSAIL to compare their computational speed and quality. We show that DataSAIL can impose more complex learning tasks on machine learning models and allows for a better assessment of how well the model generalizes beyond the data presented during training.
Computational Modeling of Stapled Coiled-Coil Inhibitors Against Bcr-Abl: Toward a Treatment Strategy for CML
Authors: Lima Maria Carolina P. , Hornsby Braxten D. , Lim Carol S. , Cheatham Thomas E. 
Published: November 2023

AbstractThe chimeric oncoprotein Bcr-Abl is the causative agent of virtually all chronic myeloid leukemias (CML) and a subset of acute lymphoblastic leukemias (ALL). As a result of the so-called Philadelphia Chromosome translocation t(9;22), Bcr-Abl manifests as a constitutively active tyrosine kinase which promotes leukemogenesis by activation of cell cycle signaling pathways. Constitutive and oncogenic activation is mediated by an N-terminal coiled-coil oligomerization domain in Bcr (Bcr-CC), presenting a therapeutic target for inhibition of Bcr-Abl activity toward the treatment of Bcr-Abl+ leukemias. Previously, we demonstrated that a rationally designed Bcr-CC mutant, CCmut3, exerts a dominant negative effect upon Bcr-Abl activity by preferential oligomerization with Bcr-CC. Moreover, we have shown conjugation to a leukemia-specific cell-penetrating peptide (CPP-CCmut3) improves intracellular delivery and activity. However, our full-length CPP-CCmut3 construct (81 aa) is encumbered by an intrinsically high degree of conformational variability and susceptibility to proteolytic degradation, relative to traditional small molecule therapeutics. Here, we iterate a new generation of our inhibitor against Bcr-CC mediated Bcr-Abl assembly that is designed to address these constraints through incorporation of all-hydrocarbon staples spanning i, i + 7 positions in helix α2 (CPP-CCmut3-st). We utilize computational modeling and biomolecular simulation to design and characterize single and double staple candidates in silico, evaluating binding energetics and building upon our seminal work modeling single hydrocarbon staples when applied to a truncated Bcr-CC sequence. This strategy enables us to efficiently build, characterize, and screen lead single/double stapled CPP-CCmut3-st candidates for experimental studies and validation in vitro and in vivo. In addition to full-length CPP-CCmut, we model a truncated system characterized by deletion of helix α1 and the flexible-loop linker, which are known to impart high conformational variability. To study the impact of the N-terminal cyclic CPP toward model stability and inhibitor activity, we also model the full-length and truncated systems without CPP, with cyclized CPP, and with linear CPP, for a total of six systems which comprise our library. From this library, we present lead stapled peptide candidates to be synthesized and evaluated experimentally as our next-generation inhibitors against Bcr-Abl.
The histone modifier KAT2A presents a selective target in a subset of well-differentiated microsatellite-stable colorectal cancers
Authors: Kufrin Vida , Seiler Annika , Brilloff Silke , Rothfuß Helen , Schuster Sandra , Schäfer Silvia , Rahimian Elahe , Baumgarten Jonas , Ball Claudia R. , Bornhäuser Martin , Glimm Hanno , Bill Marius , Wurm Alexander A. 
Published: November 2023

AbstractBackgroundLysine acetyltransferase 2A (KAT2A) plays a pivotal role in epigenetic gene regulation across various types of cancer. In colorectal cancer (CRC), upregulation of KAT2A is associated with a more aggressive phenotype. Our study aims to elucidate the molecular underpinnings ofKAT2Adependency in CRC and assess the consequences ofKAT2Adepletion.MethodsWe conducted a comprehensive analysis by integrating CRISPR-Cas9 screening data with genomics, transcriptomics, and global acetylation patterns in CRC cell lines to pinpoint molecular markers indicative ofKAT2Adependency. Additionally, we characterized the phenotypic effect of a CRISPR-Cas9-mediatedKAT2Aknockout and chemical inhibition of KAT2A in CRC cell lines and patient- derived 3D spheroid cultures.ResultsOur findings reveal thatKAT2Adependency is closely associated with a lower mutational burden and increased differentiation grade in CRC cell lines, independent of theKAT2Aexpression levels.KAT2Adependent CRC cell lines display enriched H3K27ac marks at gene loci linked to enterocytic differentiation. Loss ofKAT2Aleads to decreased cell growth and viability, downregulation of proliferation- and stem cell-associated genes, and induction of differentiation markers.ConclusionA specific subset of CRCs with a more differentiated phenotype relies on KAT2A. For these CRC cases, KAT2A might represent a promising novel therapeutic target.
From CFTR to a CF signalling network: a systems biology approach to study Cystic Fibrosis
Authors: Najm Matthieu , Martignetti Loredana , Cornet Matthieu , Kelly-Aubert Mairead , Sermet Isabelle , Calzone Laurence , Stoven Véronique 
Published: November 2023

AbstractBackgroundCystic Fibrosis (CF) is a monogenic disease caused by mutations in the gene coding the Cystic Fibrosis Transmembrane Regulator (CFTR) protein, but its overall physio-pathology cannot be solely explained by the loss of the CFTR chloride channel function. Indeed, CFTR belongs to a yet not fully deciphered network of proteins participating in various signalling pathways.MethodsWe propose a systems biology approach to study how the absence of the CFTR protein at the membrane leads to perturbation of these pathways, resulting in a panel of deleterious CF cellular phenotypes.ResultsBased on publicly available transcriptomic datasets, we built and analyzed a CF network that recapitulates signalling dysregulations. The CF network topology and its resulting phenotype was found to be consistent with CF pathology.ConclusionAnalysis of the network topology highlighted a few proteins that may initiate the propagation of dysregulations, those that trigger CF cellular phenotypes, and suggested several candidate therapeutic targets. Although our research is focused on CF, the global approach proposed in the present paper could also be followed to study other rare monogenic diseases.
Abnormal white matter development during early childhood in autism and developmental disability
Authors: Liu Yuqi , Zhang Jiaying , Rolls Edmund T. , Dai Yuan , Geng Shujie , Deng Lin , Chen Zilin , Zhang Yue , Tao Minyi , Zhang Lingli , Ren Tai , Feng Jianfeng , Cao Miao , Li Fei 
Published: November 2023

AbstractThe abnormal maturation of white matter microstructure in autism spectrum disorder (ASD) compared with typical developing (TD) and developmental delay/intellectual disorder (DD/ID) during early childhood and their associations with clinical implications remain unclear. Here, we characterized spatial and temporal patterns of white matter development in 364 children (including ASD, DD/ID and TD) under 8 years old using neurite orientation dispersion and density imaging. Using neurite density index (NDI), we consistently detected three white matter clusters across all the groups through clustering analysis, indicating the conserved spatial layout in atypical development. Further, three developmental stages with successively lower growth rates were identified in ASD, similar to those in TD but delayed overall. Meanwhile, DD/ID children showed the slowest growth rates and lacked staging features. Finally, for ASD children, the NDI was correlated with cognitive impairments at the fast developmental stage but associated with social deficits during the moderate-to-slow stage.
LPS-Induced Inflammation Reduces GABAergic Interneuron markers and Brain-derived Neurotrophic Factor in Mouse Prefrontal Cortex and Hippocampus
Authors: Rezaei Sara , Prévot Thomas D. , Vieira Erica , Sibille Etienne 
Published: November 2023

AbstractInflammation, reduced gamma-aminobutyric acidergic (GABAergic) function and altered neuroplasticity are co-occurring pathophysiologies in major depressive disorder (MDD). However, the link between these biological changes remains unclear. We hypothesized that inflammation induces deficits in GABAergic interneuron markers and that this effect is mediated by brain-derived neurotrophic factor (BDNF). We report here that systemic inflammation induced by intraperitoneal injection of lipopolysaccharide (LPS) (0.125, 0.25, 0.5, 1, 2mg/kg) in the first cohort of C57BL/6 mice (n=72; 9-12 weeks; 50% female) resulted in increased interleukin 1-beta and interleukin-6 in prefrontal cortex (PFC) and hippocampus (HPC), as measured using enzyme-linked immunosorbent assay (ELISA). Quantitative real-time polymerase reaction (qPCR) was used to explore the effect of LPS on the expression of GABAergic interneuron markers. In the PFC of the second cohort (n=39; 9-12 weeks; 50% female), 2mg/kg of LPS decreased the expression of somatostatin (Sst) (p=0.0014), parvalbumin (Pv) (p=0.0257), cortistatin (Cort) (p=0.0003), neuropeptide Y (Npy) (p=0.0033) and cholecystokinin (Cck) (p=0.0041), and did not affect corticotropin-releasing hormone (Crh) and vasoactive intestinal peptide (Vip) expression. In the HPC, 2mg/kg of LPS decreased the expression ofSst(P=0.0543),Cort (p=0.0011),Npy(p=0.0001), andCck(p<0.0001), and did not affectCrh, Pv,andVipexpression. LPS decreased the expression ofBdnfin the PFC (P<0.0001) and HPC (P=0.0003), which significantly correlated with affected markers (Sst, Pv, Cort, Cck,andNpy). Collectively, these results suggest that inflammation may causally contribute to cortical cell microcircuit GABAergic deficits observed in MDD.
A Myelin Map of Trunk Folds in the Elephant Trigeminal Nucleus
Authors: Reveyaz Noémie , Schneeweiß Undine , Heise Olivia , Gerhardt Ben , Gui Andreea M. , Kaufmann Lena V. , Alfken Jette , Reichmann Jakob , Salditt Tim , Hildebrandt Thomas , Brecht Michael 
Published: November 2023

AbstractElephants have elaborate trunk skills and large, but poorly understood brains. Here we study trunk representations in elephant trigeminal nuclei, which form large protrusions on the ventral brainstem. These ventral brainstem protrusions have previously been referred to as inferior olive, but a delineation of the olivo-cerebellar tract reveals these (trigeminal) nuclei are not connected to the cerebellum via climbing fibers. In contrast, the olivo-cerebellar tract connects to a large dorsolateral nucleus with a serrated cellular architecture, the putative elephant inferior olive. Dense vascularization and intense cytochrome-oxidase reactivity distinguish several elongated trigeminal putative trunk modules, which repeat in the anterior-posterior direction. We focus on the most anterior and largest of these units, the putative nucleus principalis trunk module. Module neuron density is low and non-neural cells outnumber neurons by ∼108:1. Dendritic trees are elongated along the axis of axon bundles (myelin stripes) transversing the trunk module. Synchrotron X-ray-phase-contrast tomography suggests myelin-stripe-axons transverse the trunk module. We show a remarkable correspondence of trunk module myelin stripes and trunk folds. Myelin stripes show little relation to trigeminal neurons and stripe-axons appear to often go nowhere; we suggest that myelin stripes might serve to separate trunk-fold domains rather than to connect neurons. Myelin-stripes-to-folds mapping allowed to determine neural magnification factors, which changed from 1000:1 proximally to 5:1 in the trunk finger. Asian elephants have fewer (∼640,000) trunk-module neurons than Africans (∼740,000) and show enlarged representations of trunk parts involved in object wrapping. The elephant trigeminal trunk module is exquisitely organized into trunk-fold-related units.
Multiplexed live-cell imaging for drug responses in patient-derived organoid models of cancer
Authors: Colling Kaitriana E. , Symons Emily L. , Buroni Lorenzo , Sumanisiri Hiruni K. , Andrew-Udoh Jessica , Witt Emily , Losh Haley A. , Morrison Abigail M. , Leslie Kimberly K. , Dunnill Christopher J. , De Bono Johann S. , Thiel Kristina W. 
Published: November 2023

ABSTRACTPatient-derived organoid (PDO) models of cancer are a multifunctional research system that better recapitulates human disease as compared to cancer cell lines. PDO models can be generated by culturing patient tumor cells in extracellular basement membrane extracts (BME) and plating as three-dimensional domes. However, commercially available reagents that have been optimized for phenotypic assays in monolayer cultures often are not compatible with BME. Herein we describe a method to plate PDO models and assess drug effects using an automated live-cell imaging system. In addition, we apply fluorescent dyes that are compatible with kinetic measurements to simultaneously quantitate cell health and apoptosis. Image capture can be customized to occur at regular time intervals over several days. Users can analyze drug effects in individual Z-plane images or a Z Projection of serial images from multiple focal planes. Using masking, specific parameters of interest are calculated, such as PDO number, area, and fluorescence intensity. We provide proof-of-concept data demonstrating the effect of cytotoxic agents on cell health, apoptosis and viability. This automated kinetic imaging platform can be expanded to other phenotypic readouts to understand diverse therapeutic effects in PDO models of cancer.SUMMARYPatient-derived tumor organoids are a sophisticated model system for basic and translational research. This methods article details the use of multiplexed fluorescent live-cell imaging for simultaneous kinetic assessment of different organoid phenotypes.
Promoting Transparent, Fair, and Inclusive Practices in Grantmaking: Lessons from the Open and Equitable Model Funding Program
Authors: Mercado-Lara Eunice , Tananbaum Greg , McKiernan Erin C. 
Published: November 2023

AbstractThe Open Research Funders Group (ORFG) has been instrumental in promoting open and equitable scholarship to enhance academic research’s transparency and accessibility. In 2020, the ORFG formed the Equity & Open Science Working Group, leading to the launch of the Open & Equitable Model Funding Program in 2021. This program aimed to refine grantmaking processes for broader inclusivity and equitable open scholarship practices.The program gathered a cohort of 11 funding organizations and focused on applying various proposed interventions within existing funding programs to improve grantmaking practices. The initiative highlighted the importance of targeted intervention selection and the need for delimited goal-setting, revealing challenges in implementation due to limited resources and the complexity of the processes involved.Participants valued the pilot for its structured approach and opportunities for shared learning despite some facing complexities in fully implementing the interventions. The ORFG’s future approach involves flexible intervention selection, effective resource management, and fostering a collaborative community, aiming for a more inclusive and practical application of open scholarship principles.
Single phage proteins sequester TIR- and cGAS-generated signaling molecules
Authors: Li Dong , Xiao Yu , Xiong Weijia , Fedorova Iana , Wang Yu , Liu Xi , Huiting Erin , Ren Jie , Gao Zirui , Zhao Xingyu , Cao Xueli , Zhang Yi , Bondy-Denomy Joseph , Feng Yue 
Published: November 2023

AbstractProkaryotic anti-phage immune systems use TIR (toll/interleukin-1 receptor) and cGAS (cyclic GMP-AMP synthase) enzymes to produce 1’’-3’/1’’-2’ glycocyclic ADPR (gcADPR) and cyclid di-/tri-nucleotides (CDNs and CTNs) signaling molecules that limit phage replication, respectively1–3. However, how phages neutralize these common systems is largely unknown. Here, we show thatThoerisanti-defense proteins Tad14and Tad25both have anti-CBASS activity by simultaneously sequestering CBASS cyclic oligonucleotides. Strikingly, apart from binding Thoeris signals 1’’-3’ and 1’’-2’ gcADPR, Tad1 also binds numerous CBASS CDNs/CTNs with high affinity, inhibiting CBASS systems using these moleculesin vivoandin vitro.The hexameric Tad1 has six binding sites for CDNs or gcADPR, which are independent from two high affinity binding sites for CTNs. Tad2 also sequesters various CDNs in addition to gcADPR molecules, inhibiting CBASS systems using these CDNs. However, the binding pockets for CDNs and gcADPR are different in Tad2, whereby a tetramer can bind two CDNs and two gcADPR molecules simultaneously. Taken together, Tad1 and Tad2 are both two-pronged inhibitors that, alongside anti-CBASS protein 2, establish a paradigm of phage proteins that flexibly sequester a remarkable breadth of cyclic nucleotides involved in TIR- and cGAS-based anti-phage immunity.
Influence of mixed and single infection of grapevine leafroll-associated virus and viral load on berry quality
Authors: Salo Wisam , Considine John A. , Considine Michael J. 
Published: November 2023

1AbstractGrapevine leafroll disease (GLD) is a viral disease that affects grapevines (Vitis viniferaL.) and has a severe economic impact on viticulture. In this study, the effect of grapevine leafroll-associated viruses (GLRaV) on berry quality was investigated in clones of cultivar cv. Crimson Seedless table grapes infected with GLRaV. RT-PCR confirmed the identity of the clones: clone 3236, infected only with GLRaV-3 (termed Single); clone 3215, infected with GLRaV-3, GLRaV-4 strain 9 and grapevine virus A (termed Mixed), and a viral free clone of the same genetic background of the infected clones (termed Control). The berry quality indices of size, sugar, acidity, and anthocyanin content were measured at harvest maturity. RT-qPCR was used to determine viral load. The study was repeated over two years. A two-way, multivariate analysis of variance (MANOVA) was applied with clone and season as independent variables and the measured berry quality parameters as a dependent variable. All dependent variables were significantly affected by viral infection (Wilks, λ, [2,33] = 0.033895, p-value < 0.001), while only titratable acidity (TA) was affected by season. Average berry dry mass decreased (p-value < 0.001). The water content of both infected clones was greater than that of the control (p-value < 0.001). Both infected clones displayed reduced sugar content as a fraction of the berry dry mass (p-value < 0.001). The anthocyanin and the phenol content of the infected clones were significantly reduced compared to the control clone (p< 0.001,p< 0.05, clone 3236 and clone 3215, respectively). Finally, the viral load was highly variable, and no quantitative relationship between viral load and berry composition was found.