bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of a Novel Chemotype as DYRK1A Inhibitors against Alzheimer’s disease: Computational Modeling and Biological Evaluation
Authors: Qiu Nianzhuang , Qian Chenliang , Guo Tingting , Wang Yaling , Jin Hongwei , Yao Mingli , Li Mei , Guo Tianyang , Lv Yuli , Si Xinxin , Wu Song , Wang Hao , Zhang Xuehui , Xia Jie 
Published: November 2023

AbstractDual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays an essential role in tau and Aβ pathology closely related to Alzheimer’s disease (AD). Accumulative evidence has demonstrated DYRK1A inhibition is able to reduce the pathological features of AD. Nevertheless, there is no approved DYRK1A inhibitors for clinical use as anti-AD drugs. This is somewhat the lack of effective and safe chemotypes of DYRK1A inhibitors. To address this issue, we carried outin silicoscreening,in vitroassays andin vivoefficacy evaluation with the aim to discover a new class of DYRK1A inhibitors for potential treatment of AD. Byin silicoscreening, we selected and purchased 16 potential DYRK1A inhibitors from the Specs chemical library. Among them, compoundQ17(Specs ID: AO-476/40829177) potently inhibited DYRK1A. The hydrogen bonds between compoundQ17and each of three amino acid residues named GLU239, LEU241 and LYS188, were uncovered by molecular docking and molecular dynamics simulation. The cell-based assays showed that compoundQ17could protect SH-SY5Y cells from okadaic acid (OA)-induced injury by targeting DYRK1A. More importantly, compoundQ17significantly improved cognitive dysfunction in 3×Tg-AD mice, ameliorated pathological changes, and reduced the expression of DYRK1A, GSK-3β and GSK-3β (pSer9), attenuated tau hyperphosphorylation and Aβ deposition as well. In summary, our computational modeling strategy is effective to identify novel chemotypes of DYRK1A inhibitors with great potential to treat AD, and the identified compoundQ17in this study is worthy of further study.Graphic Abstract
Systematic elucidation of independently modulated genes inLactobacillus plantarumreveals a trade-off between secondary and primary metabolism
Authors: Qiu Sizhe , Huang Yidi , Liang Shishun , Zeng Hong , Yang Aidong 
Published: November 2023

AbstractLactobacillus plantarumis a probiotic bacteria widely used in food and health industries, but its gene regulatory information is limited in existing databases, which impedes the research of its physiology and its applications. To obtain a better understanding of the transcriptional regulatory network ofL. plantarum, independent component analysis (ICA) of its transcriptomes was used to derive 45 sets of independently modulated genes (iModulons). Those iModulons were annotated for associated transcription factors (TFs) and functional pathways, and active iModulons in response to different growth conditions were identified and characterized in detail. Eventually, the analysis of iModulon activities reveals a trade-off between regulatory activities of secondary and primary metabolism inL. plantarum.
Preclinical lentiviral vector-mediated hematopoietic stem and progenitor cell gene therapy corrects Pompe disease-related muscle and neurological manifestations
Authors: Yoon John K. , Schindler Jeffrey W. , Loperfido Mariana , Baricordi Cristina , DeAndrade Mark P. , Jacobs Mary E. , Treleaven Christopher , Plasschaert Robert N. , Yan Aimin , Barese Cecilia N. , Dogan Yildirim , Chen Vicky Ping , Fiorini Claudia , Hull Fritz , Barbarossa Luigi , Unnisa Zeenath , Ivanov Daniel , Kutner Robert H. , Guda Swaroopa , Oborski Christine , Maiwald Tim , Michaud Véronique , Rothe Michael , Schambach Axel , Pfeifer Richard , Mason Chris , Biasco Luca , van Til Niek P. 
Published: November 2023

AbstractPompe disease, a rare genetic neuromuscular disorder, is caused by a deficiency of acid alpha-glucosidase (GAA), leading to the accumulation of glycogen in lysosomes and the progressive development of muscle weakness. The current standard treatment, enzyme replacement therapy (ERT), is not curative and demonstrates poor penetration into skeletal muscle and the central and peripheral nervous systems, susceptibility to immune responses against the recombinant enzyme, and the need for high doses and frequent infusions. To overcome these limitations, lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy has been proposed as a next-generation approach for treating Pompe disease. This study demonstrates the potential of lentiviral HSPC gene therapy to reverse the pathological effects of Pompe disease in a preclinical mouse model. It includes a comprehensive safety assessment via integration site analysis, along with single-cell RNA sequencing analysis of CNS samples to gain insights into the underlying mechanisms of phenotype correction.One Sentence Summary:Preclinical hematopoietic stem cell gene therapy for the treatment of Pompe disease.
Aging in zebrafish is associated with reduced locomotor activity and strain-dependent changes in predator avoidance behaviors related to anxiety
Authors: Hudock Jacob , Kenney Justin W. 
Published: November 2023

AbstractAging is associated with a wide range of physiological and behavioral changes in many species. Like humans, zebrafish exhibit gradual senescence, and thus may be a useful model organism for identifying evolutionarily conserved mechanisms related to aging. Here, we compared behavior in the novel tank test of young (6-month-old) and middle aged (12-month-old) zebrafish from two strains (TL and TU) and both sexes. We find that this modest age difference results in a reduction in locomotor activity and strain dependent changes in predator avoidance behaviors related to anxiety. Older TL fish have an elevation in bottom dwelling whereas older TU fish have a decrease in thigmotaxis. We found no consistent effects of age on either short-term (within session) or long-term (1 day later) habituation to the novel tank. Our findings support the use of zebrafish for the study of how age affects locomotion and how genetics interacts with age to alter the regulation of emotional behaviors in response to novelty.
VAV2-Dependent Regulation of Ribosome Biogenesis in Keratinocytes and Oral Squamous Cell Carcinoma
Authors: Fernández-Parejo Natalia , Lorenzo-Martín L. Francisco , García-Pedrero Juana M. , Rodrigo Juan P. , Dosil Mercedes , Bustelo Xosé R. 
Published: November 2023

ABSTRACTVAV2 is an activator of RHO GTPases that promotes and maintains regenerative proliferation-like states in normal keratinocytes and oral squamous cell carcinoma (oSCC) cells, respectively. Here, we demonstrate that VAV2 also plays critical roles in the regulation of ribosome biogenesis in those cells, a program associated with poor prognosis of human papilloma virus negative oSCC patients. Mechanistic analyses indicate that VAV2 regulates this process in a catalysis-dependent manner using a conserved pathway composed of the GTPases RAC1 and RHOA, members of the PAK and ROCK family kinases, and the transcriptional factors c-MYC and YAP/TAZ. This pathway directly promotes RNA polymerase I activity and the ensuing synthesis of 47S pre-rRNA precursors. This process is further consolidated by the upregulation of ribosome biogenesis factors and the acquisition of the YAP/TAZ-dependent cell undifferentiation state. Finally, we show that RNA polymerase I is a therapeutic Achilles’ heel for both keratinocytes and hnSCC patient derived cells endowed with high VAV2 catalytic activity. Collectively, these findings highlight the therapeutic potential of the VAV2 and ribosome biogenesis pathways in both preneoplastic and late progression stages of oSCC.
Structure prediction of protein-ligand complexes from sequence information with Umol
Authors: Bryant Patrick , Kelkar Atharva , Guljas Andrea , Clementi Cecilia , Noé Frank 
Published: November 2023

AbstractProtein-ligand docking is an established tool in drug discovery and development to narrow down potential therapeutics for experimental testing. However, a high-quality protein structure is required and often the protein is treated as fully or partially rigid. Here we develop an AI system that can predict the fully flexible all-atom structure of protein-ligand complexes directly, given a multiple sequence alignment representation of the protein and a SMILES string representing the ligand. At a high accuracy threshold, unseen protein-ligand complexes can be predicted more accurately than for RoseTTAFold-AA, and at medium accuracy even classical docking methods that use known protein structures as input are surpassed. The high accuracy presented here suggests that the goal of AI-based drug discovery is one step closer, but there is still a way to go to fully grasp the complexity of protein-ligand interactions. Umol is available at:https://github.com/patrickbryant1/Umol
Highly resolved genomes as a tool for studying speciation history of two closely related louse lineages with different host specificities
Authors: Martinů Jana , Tarabai Hassan , Štefka Jan , Hypša Václav 
Published: November 2023

AbstractSucking lice of the suborder Anoplura are permanent ectoparasites with specific lifestyle and highly derived features. Currently, genomic data are only available for a single species, the human lousePediculus humanus. In this study we present genomes of two distinct lineages, with different host spectra, of a rodent lousePolyplax serrata. Genomes of these ecologically different lineages are closely similar in gene content, display a high level of synteny, but they also differ by a few duplications/translocations and single inversion. Compared toP. humanus, the twoP. serratagenomes are noticeably larger (139 Mbp vs. 111 Mbp) and encode a higher number of genes. Similar toP. humanus, they are significantly reduced in sensory-related categories such as vision and olfaction. Utilizing a genome-wide set of genes, we perform phylogenetic reconstruction and evolutionary dating of theP. serratalineages. Obtained estimates reveal their relatively deep origin (approx. 6.5 Mya), comparable to the time of split between the human and chimpanzee licePediculus humanusandP. schaeffi. This dating supports the view that theP. serratalineages are likely to represent two cryptic species with different host spectra. Historical demographies of the two lineages show glaciation-related population size (Ne) reduction, but recent restoration of Ne was seen only in the less host specific lineage. Together with the louse genomes, we analyze genomes of their bacterial symbiontLegionella polyplacis, and evaluate their potential complementarity in synthesis of amino acids and B vitamins. We show that both systems,Polyplax/LegionellaandPediculus/Riesia, display almost identical patterns, with symbionts involved in synthesis of B vitamins but not amino acids.
Generation of human induced pluripotent stem cell (hiPSC) lines from patients with extreme high and low polygenic scores for QT interval
Authors: Mitchell Devyn , Ullah Rizwan , Vanags Loren , Shen Alex , Jones Luke , O’Neill Matthew , Davogustto Giovanni , Shaffer Christian , Roden Dan , Shoemaker Ben , Williams Hollie , Strickland Teresa , Agee Taylor , Johnson Christopher , Kroncke Brett 
Published: November 2023

AbstractLong QT syndrome (LQTS) is an inherited cardiac arrhythmia syndrome with congenital and drug-induced presentations and known monogenic and polygenic contributions. LQTS represents a significant clinical challenge due to its complex genetic underpinning and propensity for fatal arrhythmias. In this study, we generated induced pluripotent stem cells (iPSCs) reprogrammed from peripheral blood mononuclear cells (PBMCs) of six patients with extreme polygenic scores for short and long corrected QT intervals. iPSC lines were rigorously validated for genomic integrity through karyotyping and targeted mutation analysis specific to a lengthened or shortened QT interval. Pluripotency was confirmed by expression of key markers TRA 1-60, TRA 1-81, SOX2, OCT4, NANOG, and REX1 via quantitative PCR and immunofluorescence. Subsequent cardiac induction successfully generated cardiomyocytes that were further characterized. This patient-specific approach will enable us to better understand variable expressivity and penetrance of LQTS. Rigorously validated iPSC lines serve as a vital resource for elucidating the molecular mechanisms underlying LQTS. Our study provides a robust and clinically relevant resource to facilitate our understanding the genetic and cellular complexity of LQTS.
HiCMC: High-Efficiency Contact Matrix Compressor
Authors: Adhisantoso Yeremia Gunawan , Körner Tim , Müntefering Fabian , Ostermann Jörn , Voges Jan 
Published: November 2023

AbstractChromosome organization plays an important role in biological processes such as replication, regulation, and transcription. One way to study the relationship between chromosome structure and its biological functions is through Hi-C studies, a genome-wide method for capturing chromosome conformations. Such studies generate vast amounts of data. The problem is exacerbated by the fact that chromosome organization is dynamic, requiring snapshots at different points in time, further increasing the amount of data to be stored. We present a novel approach called the High-Efficiency Contact Matrix Compressor (HiCMC) for efficient compression of Hi-C data. By modeling the underlying structures found in the contact matrix, such as compartments and domains, HiCMC outperforms CMC by approximately 8% and more than 50% against cooler, LZMA, and bzip2 over the state of the art across multiple cell lines and resolutions. In addition, the domain information that is embedded in the data can be used to speed up downstream analysis. HiCMC is available athttps://github.com/sXperfect/hicmc.
Proteomics of Patient-derived Breast Tumours Identifies a Pro-migratory Osteomodulin-Cyclin Dependent Kinase 1 Axis which Drives Bone Metastasis
Authors: Parsons Joseph , Harrison Hannah , Kedward Thomas , Fullwood Paul , Cabral Sara , Spence Katherine , Barden Danielle , Ferguson Jennifer , Watson Joanne , Behan Caron , Ali Nisha , Smith Michael P. , O’Brien Ciara , Clarke Robert B. , Francavilla Chiara 
Published: November 2023

AbstractBreast cancer remains a leading cause of mortality, predominantly due to the development of metastases to vital organs. At present, predictive biomarkers of organ specific metastasis and therapies targeted to the metastatic niche are limited. Here, to identify the molecular determinants of breast cancer metastasis we analysed patient-derived breast tumours by combining quantitative proteomics, bioinformatics, and functional assaysin vitroandin vivo.We identified elevated levels of the protein Osteomodulin (OMD) associated with breast cancer bone metastases in patient-derived samples. OMD overexpression in the breast cancer MDA-MB-231 cell model significantly increases cell migrationin vitroand promotes the formation of bone metastasesin vivo. Phosphoproteomics analysis of MDA-MB-231 cells expressing OMD identifies active Cyclin-dependent kinase 1 (CDK1) downstream of OMD. The importance of the OMD-CDK1 axis was validated using two independent phosphoproteomics datasets analysing patient-derived breast cancer samples. We also show that the OMD-CDK1 axis drives cell migration and cell viabilityin vitroand the formation of bone metastasesin vivo. Finally, CDK1 inhibition reducesin vitrocell viability of an independent cohort of metastatic patient samples showing high CDK1 activity. Therefore, the OMD-CDK1 axis will determine which breast cancer patients develop bone metastases and is a therapeutic target to treat or prevent breast cancer bone metastases.
Morphine-context associative memory and locomotor sensitization in mice are modulated by sex and context in a dose-dependent manner
Authors: Hámor Peter U. , Hartmann Matthew C. , Garcia Aaron , Liu Dezhi , Pleil Kristen E. 
Published: November 2023

AbstractSex differences in opioid use, development of opioid used disorder, and relapse behaviors indicate potential variations in opioid effects between men and women. The locomotor and interoceptive effects of opioids play essential roles in opioid addiction, and uncovering the neural mechanisms underlying these effects remain crucial for developing effective treatments. In this study, we examined the dose-dependent effects of morphine on locomotor sensitization and the strength and stability of morphine-context associations in the conditioned place preference (CPP) paradigm in male and female mice, as well as the relationships between these measures. We observed that while CPP is similar between sexes, the locomotor effects of repeated morphine administration and withdrawal differentially contributed to the strength and stability of morphine-context associations. Specifically, females exhibited higher morphine-induced hyperlocomotion than males regardless of the context in which morphine was experienced. Greater locomotor sensitization to morphine in females than males emerged in a dose-dependent manner only when there was sufficient context information for CPP to be established. Additionally, the relationships between the locomotor effects of morphine and the strength and stability of CPP were different in males and females. In females, positive acute and sensitizing locomotor effects of morphine were correlated with a higher CPP score, while the opposite direction of this relationship was found in males. These results suggest that different aspects of the subjective experience of morphine intoxication and withdrawal are important for morphine abuse-related behaviors and highlight the importance of sex-specific responses in the context of opioid addiction.
The development of hepatic steatosis depends on the presence of liver-innervating parasympathetic cholinergic neurons in mice fed a high-fat diet
Authors: Hwang Jiyeon , Okada Junichi , Liu Li , Pessin Jeffrey E. , Schwartz Gary J. , Jo Young-Hwan 
Published: November 2023

AbstractHepatic lipid metabolism is regulated by the autonomic nervous system of the liver, with the sympathetic innervation being extensively studied, while the parasympathetic efferent innervation is less understood despite its potential importance. In this study, we investigate the consequences of disrupted brain-liver communication on hepatic lipid metabolism in mice exposed to obesogenic conditions. We found that a subset of hepatocytes and cholangiocytes are innervated by parasympathetic nerve terminals originating from the dorsal motor nucleus of the vagus. The elimination of the brain-liver axis by deleting parasympathetic cholinergic neurons innervating the liver prevents hepatic steatosis and promotes browning of inguinal white adipose tissue (ingWAT). The loss of liver-innervating cholinergic neurons increases hepaticCyp7b1expression and fasting serum bile acid levels. Furthermore, knockdown of the G protein-coupled bile acid receptor 1 gene in ingWAT reverses the beneficial effects of the loss of liver-innervating cholinergic neurons, leading to the reappearance of hepatic steatosis. Deleting liver-innervating cholinergic neurons has a small but significant effect on body weight, which is accompanied by an increase in energy expenditure. Taken together, these data suggest that targeting the parasympathetic cholinergic innervation of the liver is a potential therapeutic approach for enhancing hepatic lipid metabolism in obesity and diabetes.
Competition and Cooperation of Assembly Sequences in Recurrent Neural Networks
Authors: Stöber Tristan M. , Lehr Andrew B. , Fyhn Marianne , Kumar Arvind 
Published: November 2023

AbstractNeural activity sequences are ubiquitous in the brain and play pivotal roles in functions such as long-term memory formation and motor control. While conditions for storing and reactivating individual sequences have been thoroughly characterized, it remains unclear how multiple sequences may interact when activated simultaneously in recurrent neural networks. This question is especially relevant for weak sequences, comprised of fewer neurons, competing against strong sequences. Using a non-linear rate model with discrete, pre-configured assemblies, we demonstrate that weak sequences can compensate for their competitive disadvantage either by increasing excitatory connections between subsequent assemblies or by cooperating with other co-active sequences. Further, our model suggests that such cooperation can negatively affect sequence speed unless subsequently active assemblies are paired. Our analysis, validated by an analytically tractable linear approximation, characterizes the conditions for successful sequence progression in isolated, competing, and cooperating sequences, and identifies the distinct contributions of recurrent and feed-forward projections. This proof-of-principle study shows how even disadvantaged sequences can be prioritized for reactivation, a process which has recently been implicated in hippocampal memory processing.
Vectorized instructive signals in cortical dendrites during a brain-computer interface task
Authors: Francioni Valerio , Tang Vincent D. , Toloza Enrique H.S. , Brown Norma J. , Harnett Mark T. 
Published: November 2023

AbstractVectorization of teaching signals is a key element of virtually all modern machine learning algorithms, including backpropagation, target propagation and reinforcement learning. Vectorization allows a scalable and computationally efficient solution to the credit assignment problem by tailoring instructive signals to individual neurons. Recent theoretical models have suggested that neural circuits could implement single-phase vectorized learning at the cellular level by processing feedforward and feedback information streams in separate dendritic compartments1–5. This presents a compelling, but untested, hypothesis for how cortical circuits could solve credit assignment in the brain. We leveraged a neurofeedback brain-computer interface (BCI) task with an experimenter-defined reward function to test for vectorized instructive signals in dendrites. We trained mice to modulate the activity of two spatially intermingled populations (4 or 5 neurons each) of layer 5 pyramidal neurons in the retrosplenial cortex to rotate a visual grating towards a target orientation while we recorded GCaMP activity from somas and corresponding distal apical dendrites. We observed that the relative magnitudes of somatic versus dendritic signals could be predicted using the activity of the surrounding network and contained information about task-related variables that could serve as instructive signals, including reward and error. The signs of these putative teaching signals both depended on the causal role of individual neurons in the task and predicted changes in overall activity over the course of learning. Furthermore, targeted optogenetic perturbation of these signals disrupted learning. These results provide the first biological evidence of a vectorized instructive signal in the brain, implemented via semi-independent computation in cortical dendrites, unveiling a potential mechanism for solving credit assignment in the brain.