bluuebunny/crossref_metadata_2025_split huggingface dataset:
The kinetics of SARS-CoV-2 nsp7-11 polyprotein processing and impact on complexation with nsp16
Authors: Schamoni-Kast Kira , Krichel Boris , Damjanović Tomislav , Kierspel Thomas , Toker Sibel , Uetrecht Charlotte 
Published: January 2024

AbstractIn severe-acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, polyproteins (pp1a/pp1ab) are processed into non-structural proteins (nsps), which largely form the replication/transcription complex (RTC). The polyprotein processing and complex formation is critical and offers potential therapeutic targets. However, the interplay of polyprotein processing and RTC-assembly are poorly understood. Here, we studied two key aspects: The influence of the pp1a terminal nsp11 on the order of polyprotein processing by viral main protease Mproand the influence of polyprotein processing on core enzyme complex formation. We established a method based on native MS to determine rate constantskconsidering the structural environment. This enabled us to quantify the multi-reaction kinetics of coronavirus polyprotein processing for the first time. Our results serve as a blueprint for other multi-cleavage reactions. Further, it offers a detailed and quantifiable perspective to the dynamic reactions of SARS-CoV-2 polyprotein processing, which is required for development of novel antivirals.
Machine Learning-based Classification of transcriptome Signatures of non-ulcerative Bladder Pain Syndrome
Authors: Akshay Akshay , Besic Mustafa , Kuhn Annette , Burkhard Fiona C. , Bigger-Allen Alex , Adam Rosalyn M. , Monastyrskaya Katia , Gheinani Ali Hashemi 
Published: January 2024

ABSTRACTLower urinary tract dysfunction (LUTD) presents a global health challenge with symptoms impacting a substantial percentage of the population. The absence of reliable biomarkers complicates the accurate classification of LUTD subtypes with shared symptoms such as non- ulcerative Bladder Pain Syndrome (BPS) and overactive bladder caused by bladder outlet obstruction with Detrusor Overactivity (DO). This study introduces a machine learning (ML)- based approach for the identification of mRNA signatures specific to non-ulcerative BPS.Using next-generation sequencing (NGS) transcriptome data from bladder biopsies of patients with BPS, benign prostatic obstruction with DO and controls, our statistical approach successfully identified 13 candidate genes capable of discerning BPS from control and DO patients. This set was subsequently validated using Quantitative Polymerase Chain Reaction (QPCR) in a larger patient cohort. To confirm our findings, we applied both supervised and unsupervised ML approaches to the QPCR dataset. Notably, a three-mRNA signature TPPP3, FAT1, and NCALD, emerged as a robust classifier, effectively distinguishing patients with non- ulcerative BPS from controls and patients with DO. This signature was universally selected by both supervised and unsupervised approaches.The ML-based framework used to define BPS classifiers not only establishes a solid foundation for comprehending the specific gene expression changes in the bladder of the patients with BPS but also serves as a valuable resource and methodology for advancing signature identification in other fields. The proposed ML pipeline demonstrates its efficacy in handling challenges associated with limited sample sizes, offering a promising avenue for applications in similar domains.
A choroid plexus apocrine secretion mechanism shapes CSF proteome and embryonic brain development
Authors: Courtney Ya’el , Head Joshua P. , Yimer Elizabeth D. , Dani Neil , Shipley Frederick B. , Libermann Towia A. , Lehtinen Maria K. 
Published: January 2024

ABSTRACTWe discovered that apocrine secretion by embryonic choroid plexus (ChP) epithelial cells contributes to the cerebrospinal fluid (CSF) proteome and influences brain development in mice. The apocrine response relies on sustained intracellular calcium signaling and calpain-mediated cytoskeletal remodeling. It rapidly alters the embryonic CSF proteome, activating neural progenitors lining the brain’s ventricles. Supraphysiological apocrine secretion induced during mouse development by maternal administration of a serotonergic 5HT2C receptor agonist dysregulates offspring cerebral cortical development, alters the fate of CSF-contacting neural progenitors, and ultimately changes adult social behaviors. Critically, exposure to maternal illness or to the psychedelic drug LSD during pregnancy also overactivates the ChP, inducing excessive secretion. Collectively, our findings demonstrate a new mechanism by which maternal exposure to diverse stressors disruptsin uterobrain development.
Inositol polyphosphate multikinase regulates Th1 and Th17 cell differentiation by controlling Akt-mTOR signaling
Authors: Yuk Chae Min , Kim Dongeon , Hong Sehoon , Kim Mingyo , Jeong Hyun-Woo , Park Seung Ju , Min Hyungyu , Kim Wooseob , Kim Sang-Gyu , Seong Rho Hyun , Kim Seyun , Lee Seung-Hyo 
Published: January 2024

AbstractActivated proinflammatory T helper (Th) cells, such as Th1 and Th17 cells, mediate immune responses against intra- and extra-cellular pathogens as well as cause the development of various autoimmune diseases. Inositol polyphosphate multikinase (IPMK) is a key enzyme essential for inositol phosphate and phosphoinositide metabolism, which is known to control major biological events such as growth; however, its role in the function of Th cells remains unclear. Here we show that the expression of IPMK is highly induced in distinct Th1 and Th17 subsets. Further, while conditional deletion of IPMK in CD4+T cells is dispensable for Th2-dependent immune responses, both Th1- and Th17-mediated immune responses are markedly diminished when this enzyme is absent resulting in reduced resistance toLeishmania majorinfection and attenuation of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. In addition, IPMK-deficient naive CD4+T cells display aberrant T cell activation and impaired differentiation into Th17 cells, which is associated with reduced activation of Akt, mechanistic target of rapamycin (mTOR), and STAT3. Mechanistically, IPMK as a phosphatidylinositol 3-kinase (PI3-kinase) controls the production of phosphatidylinositol (3,4,5)-trisphosphate, thereby promoting T cell activation, differentiation, and effector functions. Our findings suggest that IPMK acts as a critical regulator of Th1 and Th17 differentiation, highlighting the physiological importance of IPMK in Th1- and Th17-mediated immune homeostasis.
Arm movements increase acoustic markers of expiratory flow
Authors: Werner Raphael , Selen Luc , Pouw Wim 
Published: January 2024

AbstractThe gesture-speech physics theory suggests that there are biomechanical interactions of the voice with the whole body, driving speech to align fluctuations in loudness and F0 with upper-limb movement. This exploratory study offers a possible falsification of the gesture-speech physics theory, which would predict effects of upper-limb movement on voice as well as respiration. We therefore investigate co-movement expiration. Seventeen participants were asked to produce a continuous exhalation for several seconds. After 3s, they execute one of five within-subject movement conditions with their arm with and without a wrist weight (no movement, elbow flexion, elbow extension, internal arm rotation, external arm rotation). We analyzed the smoothed amplitude envelope of the acoustic signal in relation to arm movement. Compared to no movement, all four movements lead to higher positive peaks in the amplitude peaks, while weight did not influence the amplitude. We also found that across movement conditions, positive amplitude peaks are structurally timed relative to peaks in kine-matics (speed, acceleration). We conclude that the reason why upper-limb movements affect voice loudness is still best understood through gesture-speech physics theory, where upper-limb movements affect the voice directly by modulating sub-glottal pressures. Multimodal prosody is therefore partly literally embodied.
MAIT cells protect against sterile lung injury
Authors: Zhang Xiawei , Li Shuailin , Lason Wojciech , Greco Maria , Klenerman Paul , Hinks Timothy SC 
Published: January 2024

AbstractMucosal-associated invariant T (MAIT) cells, the most abundant unconventional T cells in the lung, have been recently linked to tissue protection and repair. Their role, especially in sterile lung injury, is unknown. Using single cell RNA sequencing (scRNA-seq), spectral analysis and adoptive transfer in a bleomycin-induced sterile lung injury, we found that bleomycin activates murine pulmonary MAIT cells and induces an accompanying tissue repair programme, associated with a protective role against bleomycin-induced lung injury. MAIT cells drive the accumulation of type 1 conventional dendritic cells (cDC1), limiting tissue damage in a DNGR-1 dependent manner. Human scRNA-seq data revealed that MAIT cells were activated, with increased cDC populations in idiopathic pulmonary fibrosis patients. Thus, MAIT cells enhance defence against sterile lung injury by fostering cDC1-driven anti-fibrotic pathways.
Target-aware Molecule Generation for Drug Design Using a Chemical Language Model*
Authors: Xia Yingce , Wu Kehan , Deng Pan , Liu Renhe , Zhang Yuan , Guo Han , Cui Yumeng , Pei Qizhi , Wu Lijun , Xie Shufang , Chen Si , Lu Xi , Hu Song , Wu Jinzhi , Chan Chi-Kin , Chen Shuo , Zhou Liangliang , Yu Nenghai , Liu Haiguang , Guo Jinjiang , Qin Tao , Liu Tie-Yan 
Published: January 2024

AbstractGenerative drug design facilitates the creation of compounds effective against pathogenic target proteins. This opens up the potential to discover novel compounds within the vast chemical space and fosters the development of innovative therapeutic strategies. However, the practicality of generated molecules is often limited, as many designs focus on a narrow set of drug-related properties, failing to improve the success rate of subsequent drug discovery process. To overcome these challenges, we develop TamGen, a method that employs a GPT-like chemical language model and enables target-aware molecule generation and compound refinement. We demonstrate that the compounds generated by TamGen have improved molecular quality and viability. Additionally, we have integrated TamGen into a drug discovery pipeline and identified 7 compounds showing compelling inhibitory activity against the Tuberculosis ClpP protease, with the most effective compound exhibiting a half maximal inhibitory concentration (IC50) of1.9μM. Our findings underscore the practical potential and real-world applicability of generative drug design approaches, paving the way for future advancements in the field.
Glioblastoma cells imitate neuronal excitability in humans
Authors: Tong T , Ozsvar A , Eschen JT , Elbæk KJ , Cortnum SOS , Sindby AKR , Kristensen BW , Meier K , Mikic N , Sørensen JCH , Ting JT , Capogna M , Hou WH , Korshøj AR 
Published: January 2024

SummaryGlioblastomas (GBM) are renowned for their pronounced intratumoral heterogeneity, characterized by a diverse array of plastic cell types, which poses a significant challenge to effective targeting and treatment [1]. Recent research has documented the presence of neuronal-progenitor-like transcriptomic cell states of GBM [2, 3], notably in the leading edge of the tumor, where synaptic input from adjacent neurons drives disease proliferation [4]. However, conflicting observations regarding GBM cell excitability, ranging from non-excitable [5] to neuron-like excitability [6], add complexity to our comprehension of the pathophysiological diversity of GBM cells. Here we established a novel experimental workflow enabling comprehensive and selective investigation of the electrophysiological characteristics of cancer cells and neurons within cancer-infiltrated organotypic tissue specimens from GBM patients, using viral genetic labelling to target cellular subtypes. We observed that GBM cells exhibit distinct electrophysiological features in humans, characterized by hyperexcitability and neuron-like action potential generation. Our research provides direct evidence of excitability and a comprehensive description of the electrophysiological characteristics of GBM cells in the cancer-infiltrated cortex of humans, contributing to a deeper understanding of the cellular biology of GBM. These insights have broader implications for understanding cell-cell interactions in malignant tumors and could inform targeted therapies across diverse cancer types, offering a new lens for tackling tumor heterogeneity.
Unraveling wheat endosperm development: epigenetic regulation and novel regulators for enhanced yield and quality
Authors: Zhao Long , Chen Jinchao , Zhang Zhaoheng , Wu Wenying , Lin Xuelei , Gao Mingxiang , Yang Yiman , Zhao Peng , Yao Yingyin , Zhang Aiming , Liu Dongcheng , Wang Dongzhi , Xiao Jun 
Published: January 2024

AbstractStarch content and seed storage protein (SSP) composition are critical factors influencing wheat grain yield and quality. To uncover the molecular mechanisms governing their biosynthesis, we conducted transcriptome and epigenome profiling across key endosperm developmental stages, revealing that chromatin accessibility, H3K27ac, and H3K27me3 collectively regulate SSP and starch genes with varying impact. Population transcriptome and phenotype analyses highlighted the crucial role of accessible promoter regions as a genetic variation resource, influencing grain yield and quality in a core collection of wheat accessions. By integrating time-serial RNA-seq and ATAC-seq data, we constructed a hierarchical transcriptional regulatory network (TRN) governing starch and SSP biosynthesis, identifying 42 high-confidence novel candidates. These candidates exhibited overlap with genetic regions associated with grain size and quality traits, and their functional significance was validated through expression-phenotype association analysis among wheat accessions and TILLING mutants. In-depth functional analysis ofwheat abscisic acid insensitive 3-A1(TaABI3-A1) with genome editing knock-out lines demonstrated its role in promoting SSP accumulation while repressing starch biosynthesis through transcriptional regulation. An elite haplotype ofTaABI3-A1with higher grain weight was identified during the breeding process in China, and its superior trait was associated with alteredTaABI3-A1expression levels. Additionally, we identified the potential upstream regulator, wheat GAGA-binding transcription factor 1 (TaGBP1), influencingTaABI3-A1expression. Our study provides novel and high-confidence regulators, presenting an effective strategy for understanding the regulation of SSP and starch biosynthesis and contributing to breeding enhancement.
Dynamic evolution of the heterochromatin sensing histone demethylase IBM1
Authors: Zhang Yinwen , Jang Hosung , Luo Ziliang , Dong Yinxin , Xu Yangyang , Kantamneni Yamini , Schmitz Robert J. 
Published: January 2024

AbstractHeterochromatin constitutes a fundamental aspect of genomes that is crucial for maintaining genome stability. In flowering plants, maintenance of heterochromatin relies on a positive feedback loop involving the histone 3 lysine nine methyltransferase (H3K9), KRYPTONITE (KYP), and the DNA methyltransferase, CHROMOMETHYLASE3 (CMT3). An H3K9 demethylase, INCREASED IN BONSAI METHYLATION 1 (IBM1), has evolved to modulate the activity of KYP-CMT3 within transcribed genes. The absence of IBM1 activity results in aberrant methylation of gene bodies, which is deleterious. This study demonstrates extensive genetic and gene expression variations inKYP,CMT3, andIBM1within and between flowering plant species. IBM1 activity inArabidopsis thalianais uniquely regulated by the abundance of H3K9me2 in a repetitive sequence within an intron preceding the histone demethylase domain. This mechanism enables IBM1 to monitor global levels of H3K9me2. We discovered that the methylated intron is prevalent across flowering plants, however, its underlying sequence exhibits dynamic evolution. Its absence in species lacking gene body DNA methylation suggests its primary role in sensing H3K9me2 and preventing its integration into these constitutively expressed genes. Furthermore, our investigation uncoveredArabidopsis thalianaaccessions resembling weakibm1mutants, several Brassicaceae species with reducedIBM1expression, and a potentialIBM1deletion. Evolution towards reduced IBM1 activity in some flowering plants could explain the frequent natural occurrence of diminished or lost CMT3 activity, ascmt3mutants inA. thalianamitigate the deleterious effects of IBM1.
Epsins oversee smooth muscle cell reprograming by influencing master regulators KLF4 and OCT4
Authors: Wang Beibei , Cui Kui , Zhu Bo , Dong Yunzhou , Wang Donghai , Singh Bandana , Wu Hao , Li Kathryn , Eisa-Beygi Shahram , Sun Yong , Wong Scott , Cowan Douglas B. , Chen Yabing , Du Mulong , Chen Hong 
Published: January 2024

AbstractSmooth muscle cells in major arteries play a crucial role in regulating coronary artery disease. Conversion of smooth muscle cells into other adverse cell types in the artery propels the pathogenesis of the disease. Curtailing artery plaque buildup by modulating smooth muscle cell reprograming presents us a new opportunity to thwart coronary artery disease. Here, our report how Epsins, a family of endocytic adaptor proteins oversee the smooth muscle cell reprograming by influencing master regulators OCT4 and KLF4. Using single-cell RNA sequencing, we characterized the phenotype of modulated smooth muscle cells in mouse atherosclerotic plaque and found that smooth muscle cells lacking epsins undergo profound reprogramming into not only beneficial myofibroblasts but also endothelial cells for injury repair of diseased endothelium. Our work lays concrete groundwork to explore an uncharted territory as we show that depleting Epsins bolsters smooth muscle cells reprograming to endothelial cells by augmenting OCT4 activity but restrain them from reprograming to harmful foam cells by destabilizing KLF4, a master regulator of adverse reprograming of smooth muscle cells. Moreover, the expression of Epsins in smooth muscle cells positively correlates with the severity of both human and mouse coronary artery disease. Integrating our scRNA- seq data with human Genome-Wide Association Studies (GWAS) identifies pivotal roles Epsins play in smooth muscle cells in the pathological process leading to coronary artery disease. Our findings reveal a previously unexplored direction for smooth muscle cell phenotypic modulation in the development and progression of coronary artery disease and unveil Epsins and their downstream new targets as promising novel therapeutic targets for mitigating metabolic disorders.
Systemic Dosing of Virus-derived Serpin Improves Survival and Immunothrombotic Damage in Murine Colitis
Authors: Zhang Liqiang , Turk Julie , Monder Henna , Woodrow Cheyanne , Spaccarelli Laurel , Garg Aman , Schlievert Jessika , Elmadbouly Nora , Dupati Aashika , Aliskevich Emily , Saju Rohan , Kilbourne Jacqueline , Lowe Kenneth , Hamada Mostafa , Pinteric Aubrey , Zanetti Isabela R. , Satyanarayanan Ritvik Srivant , Enow Junior , Florsheim Esther , Rahman Masmudur , Irving James , McFadden Grant , Kong Wei , Lucas Alexandra R. 
Published: January 2024

AbstractInflammatory bowel disease (IBD) is potentially life-threatening, with risk of bleeding, clotting, infection, sepsis, cancer and toxic megacolon. Systemic and local immune and coagulation dysfunction increase IBD severity. Current treatments are partially effective, but there is no definitive cure.Serineprotease cascades activate thrombotic, thrombolytic and complement pathways and are regulated byinhibitors,serpins. Viruses encode proteins evolved from endogenous central regulatory pathways. A purified secreted Myxomavirus-derived serpin, Serp-1, dosed as a systemic anti-inflammatory drug, has proven efficacy in vascular and inflammatory disorders. PEGylated Serp-1 protein (PEGSerp-1) has improved efficacy in lupus and SARS-CoV-2 models. We examined PEGSerp-1 treatment in a mouse Dextran Sodium Sulfate (DSS) colitis model. Prophylactic PEGSerp-1 significantly improved survival in acute severe 4-5% DSS colitis, reducing inflammation and crypt damage in acute 4-5% DSS induced colitis and when dosed as a chronic delayed treatment for recurrent 2% DSS colitis. PEGSerp-1 reduced iNOS+M1 macrophage invasion, damage to crypt architecture and vascular inflammation with decreased uPAR, fXa, fibrinogen and complement activation. This work supports PEGSerp-1 as a tissue targeting serpin therapeutic.
Experimental nuclear quadrupole resonance and computational study of the structurally refined topological semimetal
TaSb2
Authors: Fujii T. , Janson O. , Yasuoka H. , Rosner H. , Prots Yu. , Burkhardt U. , Schmidt M. , Baenitz M. 
Published: January 2024

The local electric field gradients and magnetic dynamics of TaSb2 have been studied using Sb121, Sb123, and Ta181 nuclear quadrupole resonance (NQR) with density functional theory (DFT) calculations using XRD-determined crystal structures. By measuring all structurally expected 13 NQR lines, the nuclear quadrupole coupling constant (νQ) and asymmetric parameter (η) for Ta, Sb(1), and Sb(2) sites were obtained. These values are all in good agreement with the presented DFT calculations. Principal axes of the electric field gradients was determined for a single-crystal sample by measuring the angular dependencies of NMR frequency under a weak magnetic field. The unusual temperature dependence of η(T) of Sb(2) hints at the suppressed thermal expansion along the a axis. Spin-lattice relaxation rate (1/T1T) measurements reveal an activated-type behavior and an upturn below 30 K. Neither the low-temperature upturn nor the high-temperature activation-type behaviors are reproduced by the calculated 1/T1T based on the calculated density of states (DOS). On the other hand, the agreement between the calculated DOS and specific heat measurements indicates that the band renormalization is small. This fact indicates that TaSb2 deviates from the simple semimetal scenario, and magnetic excitations are not captured by Fermi liquid theory.

Published by the American Physical Society
2024
Eigenstate thermalization in (
2+1
)-dimensional SU(2) lattice gauge theory
Authors: Ebner Lukas , Schäfer Andreas , Seidl Clemens , Müller Berndt , Yao Xiaojun 
Published: January 2024

We present preliminary numerical evidence for the hypothesis that the Hamiltonian SU(2) gauge theory discretized on a lattice obeys the eigenstate thermalization hypothesis (ETH). To do so we study three approximations: (a) a linear plaquette chain in a reduced Hilbert space limiting the electric field basis to j=0,12, (b) a two-dimensional honeycomb lattice with periodic or closed boundary condition and the same Hilbert space constraint, and (c) a chain of only three plaquettes but such a sufficiently large electric field Hilbert space (j≤72) that convergence of all energy eigenvalues in the analyzed energy window is observed. While an unconstrained Hilbert space is required to reach the continuum limit of SU(2) gauge theory, numerical resource constraints do not permit us to realize this requirement for all values of the coupling constant and large lattices. In each of the three studied cases we check first for random matrix theory (RMT) behavior in the eigenenergy spectrum and then analyze the diagonal as well as the off-diagonal matrix elements between energy eigenstates for a few operators. Within current uncertainties all results for (a), (b) and (c) agree with ETH predictions. Furthermore, we find the off-diagonal matrix elements of the electric energy operator exhibit RMT behavior in frequency windows that are small enough in (b) and (c). To unambiguously establish ETH behavior and determine for which class of operators it applies, an extension of our investigations is necessary.

Published by the American Physical Society
2024