bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Small Molecule Ligand Binding Sites On and In the ARNT PAS-B Domain
Authors: Xu Xingjian , Closson Joseph , Marcelino Leandro Pimentel , Favaro Denize C. , Silvestrini Marion L. , Solazzo Riccardo , Chong Lillian T. , Gardner Kevin H. 
Published: November 2023

AbstractTranscription factors are generally challenging to target with small molecule inhibitors due to their structural plasticity and lack of catalytic sites. Notable exceptions include several naturally ligand-regulated transcription factors, including our prior work with the heterodimeric HIF-2 transcription factor which showed that small molecule binding within an internal pocket of the HIF-2α PAS-B domain can disrupt its interactions with its dimerization partner, ARNT. Here, we explore the feasibility of similarly targeting small molecules to the analogous ARNT PAS-B domain itself, potentially opening a promising route to simultaneously modulate several ARNT-mediated signaling pathways. Using solution NMR screening of an in-house fragment library, we previously identified several compounds that bind ARNT PAS-B and, in certain cases, antagonize ARNT association with the TACC3 transcriptional coactivator. However, these ligands have only modest binding affinities, complicating characterization of their binding sites. We address this challenge by combining NMR, MD simulations, and ensemble docking to identify ligand-binding ‘hotspots’ on and within the ARNT PAS-B domain. Our data indicate that the two ARNT/TACC3 inhibitors, KG-548 and KG-655, bind to a β-sheet surface implicated in both HIF-2 dimerization and coactivator recruitment. Furthermore, while KG-548 binds exclusively to the β-sheet surface, KG-655 can additionally bind within a water-accessible internal cavity in ARNT PAS-B. Finally, KG-279, while not a coactivator inhibitor, exemplifies ligands that preferentially bind only to the internal cavity. All three ligands promoted ARNT PAS-B homodimerization, albeit to varying degrees. Taken together, our findings provide a comprehensive overview of ARNT PAS-B ligand-binding sites and may guide the development of more potent coactivator inhibitors for cellular and functional studies.
Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the Study of Muscle, Mobility and Aging (SOMMA)
Authors: Coen Paul M , Huo Zhiguang , Tranah Gregory J , Barnes Haley N , Cawthon Peggy M , Hepple Russell T , Toledo Frederico G S , Evans Daniel S , Fernández Olaya Santiago , Cuervo Ana Maria , Kritchevsky Steven B , Newman Anne B , Cummings Steven R , Esser Karyn A 
Published: November 2023

AbstractAutophagy is an essential component of proteostasis and a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy and mTOR/upstream pathways were determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2peak, 400m walking speed, and leg power), and thigh muscle volume were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB-related genes (RELA, RELB, NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy and pexophagy (PPARGC1A, PPARA, EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion and fission related genes (NIPSNAP2, DNM1L, OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1) and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence.
Knockout of cyclin dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice
Authors: Bruter Alexandra V. , Varlamova Ekaterina A. , Stavskaya Nina I. , Antysheva Zoia G. , Manskikh Vasily N. , Tvorogova Anna V. , Korshunova Diana. S. , Khamidullina Alvina I. , Utkina Marina V. , Bogdanov Viktor P. , Baikova Iuliia P. , Nikiforova Alyona I. , Albert Eugene A. , Maksimov Denis O. , Li Jing , Chen Mengqian , Schools Gary. P , Feoktistov Alexey V. , Shtil Alexander A. , Roninson Igor B. , Mogila Vladislav A. , Silaeva Yulia Y. , Tatarskiy Victor V. 
Published: November 2023

AbstractParalogs CDK8 and CDK19 are regulatory kinases associated with the transcriptional Mediator complex. We have e generated mice with the systemic inducibleCdk8knockout on the background ofCdk19constitutive knockout.Cdk8/19double knockout (iDKO) males, but not singleCdk8andCdk19KO, had an atrophic reproductive system and were infertile. The iDKO males lacked postmeiotic spermatids and spermatocytes after meiosis I pachytene. Testosterone levels were decreased whereas the amounts of the luteinizing hormone were unchanged. Single cell RNA sequencing showed marked differences in the expression of steroidogenic genes (such asCyp17a1, StarandFads) in Leydig cells concomitant with alterations in Sertoli cells and spermatocytes likely associated with impaired synthesis of steroids.StarandFadswere also downregulated in cultivated Leydig cells after iDKO. The treatment of primary Leydig cells culture with a CDK8/19 inhibitor did not induce the same changes in gene expression as iDKO, and prolonged treatment of mice with a CDK8/19 inhibitor did not affect the size of testes. iDKO, in contrast to single knockouts or treatment with a CDK8/19 kinase inhibitor, led to depletion of cyclin C (CcnC), the binding partner of CDK8/19 that has been implicated in CDK8/19-independent functions. This suggests that the observed phenotype was likely mediated through kinase-independent activities of CDK8/19, such as CcnC stabilization.
A High-Throughput Data-Independent Acquisition Workflow for Deep Characterisation of thesn-Isomer Lipidome
Authors: Michael Jesse A. , Young Reuben S. E. , Balez Rachelle , Jekimovs Lachlan J. , Marshall David. L. , Poad Berwyck L. J. , Mitchell Todd W. , Blanksby Stephen J. , Ejsing Christer S. , Ellis Shane R. 
Published: November 2023

AbstractWe report a workflow based on ozone-induced dissociation for untargeted characterization of hundreds ofsn-resolved glycerophospholipid isomers from biological extracts in under 20 minutes, coupled with an automated data analysis pipeline. It provides an order of magnitude increase in the number ofsn-isomer pairs identified compared to previous reports, reveals thatsn-isomer populations are tightly regulated and significantly different between cell lines, and enables identification of rare lipids containing ultra-long chain monounsaturated acyl chains.
Tgif1-deficiency impairs cytoskeletal architecture in osteoblasts by activating PAK3 signaling
Authors: Bolamperti Simona , Saito Hiroaki , Heerdmann Sarah , Hesse Eric , Taipaleenmäki Hanna 
Published: November 2023

SummaryOsteoblast adherence to bone surfaces is important for remodeling of the bone tissue. This study demonstrates that deficiency of TG-interacting factor 1 (Tgif1) in osteoblasts results in altered cell morphology, reduced adherence to collagen type I-coated surfaces, and impaired migration capacity. Tgif1 is essential for osteoblasts to adapt a regular cell morphology and to efficiently adhere and migrate on collagen type I-rich matricesin vitro. Furthermore, Tgif1 acts as transcriptional repressor of p21-activated kinase 3 (PAK3), an important regulator of focal adhesion formation and osteoblast spreading. Absence of Tgif1 leads to increased PAK3 expression, which impairs osteoblast spreading. Additionally, Tgif1 is implicated in osteoblast recruitment and activation of bone surfaces in the context of bone regeneration and in response to parathyroid hormone 1-34 (PTH 1-34) treatmentin vivo. These findings provide important novel insights in the regulation of the cytoskeletal architecture of osteoblasts.
Vina-GPU 2.1: towards further optimizing docking speed and precision of AutoDock Vina and its derivatives
Authors: Tang Shidi , Ding Ji , Zhu Xiangyu , Wang Zheng , Zhao Haitao , Wu Jiansheng 
Published: November 2023

AbstractAutoDock Vina and its derivatives have established themselves as a prevailing pipeline for virtual screening in contemporary drug discovery. Our Vina-GPU method leverages the parallel computing power of GPUs to accelerate AutoDock Vina, and Vina-GPU 2.0 further enhances the speed of AutoDock Vina and its derivatives. Given the prevalence of large virtual screens in modern drug discovery, the improvement of speed and accuracy in virtual screening has become a longstanding challenge. In this study, we propose Vina-GPU 2.1, aimed at enhancing the docking speed and precision of AutoDock Vina and its derivatives through the integration of novel algorithms to facil-itate improved docking and virtual screening outcomes. Building upon the foundations laid by Vina-GPU 2.0, we introduce a novel algorithm, namely Reduced Iteration and Low Complexity BFGS (RILC-BFGS), designed to expedite the most time-consuming operation. Additionally, we implement grid cache optimization to further enhance the docking speed. Furthermore, we employ optimal strategies to individually optimize the structures of ligands, receptors, and binding pockets, thereby enhancing the docking precision. To assess the performance of Vina-GPU 2.1, we conduct extensive virtual screening experiments on three prominent targets, utilizing two fundamental compound libraries and seven docking tools. Our results demonstrate that Vina-GPU 2.1 achieves an average 4.97-fold acceleration in docking speed and an average 342% improvement in EF1% compared to Vina-GPU 2.0. The source code and tools for Vina-GPU 2.1 are freely available athttps://github.com/DeltaGroupNJUPT/Vina-GPU-2.1, accompanied by comprehensive instructions and illustrative examples.
lociPARSE: a locality-aware invariant point attention model for scoring RNA 3D structures
Authors: Tarafder Sumit , Bhattacharya Debswapna 
Published: November 2023

AbstractA scoring function that can reliably assess the accuracy of a 3D RNA structural model in the absence of experimental structure is not only important for model evaluation and selection but also useful for scoring-guided conformational sampling. However, high-fidelity RNA scoring has proven to be difficult using conventional knowledge-based statistical potentials and currently-available machine learning-based approaches. Here we present lociPARSE, a locality-aware invariant point attention architecture for scoring RNA 3D structures. Unlike existing machine learning methods that estimate superposition-based root mean square deviation (RMSD), lociPARSE estimates Local Distance Difference Test (lDDT) scores capturing the accuracy of each nucleotide and its surrounding local atomic environment in a superposition-free manner, before aggregating information to predict global structural accuracy. Tested on multiple datasets including CASP15, lociPARSE significantly outperforms existing statistical potentials (rsRNASP, cgRNASP, DFIRE-RNA, and RASP) and machine learning methods (ARES and RNA3DCNN) across complementary assessment metrics. lociPARSE is freely available athttps://github.com/Bhattacharya-Lab/lociPARSE.
Vegetation ofChamaecyparismontane cloud forest in Lalashan Forest Dynamics Plot
Authors: Chen Ting , Lee Yi-Nuo , Lin Po-Yu , Wu Kun-Sung , Zelený David 
Published: November 2023

AbstractTo understand the vegetation-environment relationships within theChamaecyparismontane mixed cloud forest in Taiwan, we established a 1-ha Lalashan Forest Dynamics Plot (LFDP) in northern Taiwan (24°42D N, 121°26D E). We established the plot in July 2019 and finished the first census of all woody species in August 2020. We collected environmental factors related to the topography and soil properties, measured microclimate and soil moisture within the plot, and collected further microclimatic data with a nearby weather station. In total, we recorded 5220 individuals belonging to 65 species, 42 genera and 29 families, with a basal area of 69.1 m2ha−1, dominated byChamaecyparis obtusavar.formosana,Rhododendron formosanumandQuercus sessilifolia. Modified TWINSPAN classified vegetation into three types (ridge, east-facing slope and valley). Unconstrained ordination showed that the main gradients behind compositional changes are related to windwardness and convexity. The prevailing wind direction in the area is from the northeast, linked to the winter monsoon. Both east-facing slope type and valley type have relatively lower temperatures than ridge type, especially during summer. Convexity is related to soil moisture gradient (from dryer convex to wet concave sites). Fog frequency is seasonal, with the highest values during autumn and winter months. From soil properties, pH is negatively and phosphorus is positively related to topographical convexity. Litter decomposition is linked to both topographical, soil and biotic variables. Collected data will serve as a baseline for future resurveys and monitoring changes within this montane cloud forest.
Investigating DNA methylation changes associated with food production using paleogenomes
Authors: Çokoğlu Sevim Seda , Koptekin Dilek , Fidan Fatma Rabia , Somel Mehmet 
Published: November 2023

AbstractThe Neolithic transition introduced major diet and lifestyle changes to human populations across continents. Beyond well-documented bioarchaeological and genetic effects, whether these changes also had molecular-level epigenetic repercussions in past human populations has been an open question. In fact, methylation signatures can be inferred from UDG-treated ancient DNA through postmortem damage patterns, but with low signal-to-noise ratios; it is thus unclear whether published paleogenomes would provide the necessary resolution to discover systematic effects of lifestyle and diet shifts. To address this we compiled UDG-treated shotgun genomes of 13 pre-Neolithic hunter-gatherer (HGs) and 21 Neolithic farmer (NFs) individuals from West and North Eurasia, published by six different laboratories and with coverage c.1x-58x (median=9x). We used epiPALEOMIX and a Monte Carlo normalization scheme to estimate methylation levels per genome. Our paleomethylome dataset showed expected genome-wide methylation patterns such as CpG island hypomethylation. However, analysing the data using various approaches did not yield any systematic signals for subsistence type, genetic sex, or tissue effects. Comparing the HG-NF methylation differences in our dataset with methylation differences between hunter-gatherers vs. farmers in modern-day Central Africa also did not yield consistent results. Meanwhile, paleomethylome profiles did cluster strongly by their laboratories of origin. Our results mark the importance of minimizing technical noise for capturing subtle biological signals from paleomethylomes.
Sources of gene expression variation in a globally diverse human cohort
Authors: Taylor Dylan J. , Chhetri Surya B. , Tassia Michael G. , Biddanda Arjun , Battle Alexis , McCoy Rajiv C. 
Published: November 2023

Abstract/SummaryGenetic variation influencing gene expression and splicing is a key source of phenotypic diversity. Though invaluable, studies investigating these links in humans have been strongly biased toward participants of European ancestries, diminishing generalizability and hindering evolutionary research. To address these limitations, we developed MAGE, an open-access RNA-seq data set of lymphoblastoid cell lines from 731 individuals from the 1000 Genomes Project spread across 5 continental groups and 26 populations. Most variation in gene expression (92%) and splicing (95%) was distributed within versus between populations, mirroring variation in DNA sequence. We mapped associations between genetic variants and expression and splicing of nearby genes (cis-eQTLs andcis-sQTLs, respective), identifying >15,000 putatively causal eQTLs and >16,000 putatively causal sQTLs that are enriched for relevant epigenomic signatures. These include 1310 eQTLs and 1657 sQTLs that are largely private to previously underrepresented populations. Our data further indicate that the magnitude and direction of causal eQTL effects are highly consistent across populations and that apparent “population-specific” effects observed in previous studies were largely driven by low resolution or additional independent eQTLs of the same genes that were not detected. Together, our study expands understanding of gene expression diversity across human populations and provides an inclusive resource for studying the evolution and function of human genomes.
Cerebral thickness reveals sex differences in verbal and visuospatial memory
Authors: Sang Feng , Zhao Shaokun , Li Zilin , Yang Yiru , Chen Yaojing , Zhang Zhanjun 
Published: November 2023

AbstractAlthough sex differences in behavior/cognition and brain have previously been reported and reviewed, a sex difference of verbal and visuospatial memory and the underlying neural basis still need to be explored further. In this study, we used a machine learning model to explore a sex difference of the association between brain structure and verbal/visuospatial memory based on a community older cohort (n = 1153, age ranged from 50.42 to 86.67 years). We found females outperformed males in verbal memory (t= -5.431,p< 0.001), while males outperformed females in visuospatial memory (t= 3.201,p= 0.001). The key regions related to verbal memory in females include medial temporal cortex, orbitofrontal cortex, and some regions around insula. According to the overlapping with Yeo’s 7 networks, those regions are more located in limbic, dorsal attention and default model networks, and they are also associated with face recognition and perception processes. The key regions related to visuospatial memory, which is outstanding in males, include lateral prefrontal cortex, anterior cingulate gyrus, and some occipital regions. They overlapped more with dorsal attention, frontoparietal and visual networks, and associated with object recognition processes. These findings imply the memory performance advantage of females and males is related to the different memory preprocessing tendencies and its associated network.
Mapping Chromatin Occupancy ofPpp1r1b-lncRNAGenome-Wide Using Chromatin Isolation by RNA Purification (ChIRP)-seq
Authors: Hwang John , Kang Xuedong , Wolf Charlotte , Touma Marlin 
Published: November 2023

ABSTRACTLong non-coding RNA (lncRNA) mediated transcriptional regulation is increasingly recognized as an important gene regulatory mechanism during development and disease. LncRNAs are emerging as critical regulators of chromatin state; yet the nature and the extent of their interactions with chromatin remain to be fully revealed. We have previously identifiedPpp1r1b-lncRNAas an essential epigenetic regulator of myogenic differentiation in cardiac and skeletal myocytes in mice and humans. We further demonstrated thatPpp1r1b-lncRNAfunction is mediated by the interaction with the chromatin-modifying complex polycomb repressive complex 2 (PRC2) at the promoter of myogenic differentiation transcription factors,TBX5andMyoD1. Herein, we employed an unbiased chromatin isolation by RNA purification (ChIRP) and high throughput sequencing to map the repertoire ofPpp1r1b-lncRNAchromatin occupancy genome-wide in the mouse muscle myoblast cell line. We uncovered a total of 99732 true peaks corresponding toPpp1r1b-lncRNAbinding sites at high confidence (P-value < 1e-5 and enrichment score ≥ 10). ThePpp1r1b-lncRNA-binding sites averaged 558 bp in length and were distributed widely within the coding and non-coding regions of the genome. Approximately 46% of these true peaks were mapped to gene elements, of which 1180 were mapped to experimentally validated promoter sequences. Importantly, the promoter-mapped binding sites were enriched in myogenic transcription factors and heart development while exhibiting focal interactions with known motifs of proximal promoters and transcription initiation by RNA polII, including TATA, transcription initiator, CCAAT-box, and GC-box, supportingPpp1r1b-lncRNArole in transcription initiation of myogenic regulators. Remarkably, nearly 40% ofPpp1r1b-lncRNA-binding sites mapped to gene introns, were enriched with the Homeobox family of transcription factors, and exhibited TA-rich motif sequences, suggesting potential motif specificPpp1r1b-lncRNA-bound introns. Lastly, more than 136521enhancer sequences were detected inPpp1r1b-lncRNA-occupancy sites at high confidence. Among these enhancers,12% exhibited cell type/tissue-specific enrichment in fetal heart and muscles. Together, our findings provide further insights into the genome-widePpp1r1b-lncRNA:Chromatin interactome that may potentially dictate its function in myogenic differentiation and potentially other cellular and biological processes.
Egg MVBs elicit an antimicrobial pathway to degrade paternal mitochondria after fertilization
Authors: Ben-Hur Sharon , Afar Sara , Politi Yoav , Gal Liron , Golani Ofra , Sivan Ehud , Haffner-Krausz Rebecca , Maizenberg Elina , Peretz Sima , Roth Zvi , Kalo Dorit , Dezorella Nili , Morgenstern David , Pietrokovski Shmuel , Yacobi-Sharon Keren , Arama Eli 
Published: November 2023

AbstractMitochondria are maternally inherited, but the mechanisms underlying paternal mitochondrial elimination (PME) after fertilization are far less clear. UsingDrosophila, we show that special egg-derived multivesicular bodies (MVBs) promote PME by activating LC3-associated phagocytosis (LAP), a cellular defense pathway commonly employed against invading microbes. Upon fertilization, the egg MVBs engage and densely coat the sperm flagellum, forming extended flagellum vesicular sheaths (FVSs), within which the paternal mitochondria degrade. Inactivation of multiple LAP pathway components, such as Rubicon, a LAP-specific class III PI(3)K complex protein, significantly attenuates PME. Furthermore, recruitment of Atg8/LC3 to the FVS requires both Rubicon and the Atg8/LC3 conjugation machinery. Other LAP pathway events, such as production of the phospholipid PtdIns(3)P and reactive oxygen species (ROS), also unfold during PME. Finally, we provide evidence that a similar pathway might also mediate PME in mammals, highlighting the notion that eggs may regard paternal mitochondria as potentially dangerous trespassers.