bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuromuscular fatigue reduces responsiveness when controlling leg external forces
Authors: Kudzia Pawel , Wakeling James M. , Robinovitch Stephen N. , Donelan J. Maxwell 
Published: May 2023

AbstractIn legged movement, our legs push against the ground, generating external force vectors that enable agile movements. Neuromuscular fatigue can reduce agility by causing physiological changes, such as slowing muscle reaction time, altering proprioception, and delaying neuromuscular control. Fatigue may deteriorate the nervous system’s control of leg external forces, contributing to reductions in agility. In this study, we investigated the effect of fatigue on the performance of the nervous system in controlling the vertical component of leg external force ground reaction forces. We hypothesized that increased leg fatigue would lead to declines in both the responsiveness (speed) and accuracy of leg force control. To test this hypothesis, we used an apparatus that allowed participants to exert controlled vertical forces with one leg against a force plate while immobilizing the rest of their bodies. Participants adjusted their leg external force to match step targets displayed on a screen. We induced fatigue by having participants maintain submaximal leg forces, and we measured leg force control performance between fatigue trials. Results showed a significant 26% reduction in mean maximum force production, leading to a substantial decline in leg force control responsiveness, as evidenced by a 23% increase in rise time and a 25% narrowing of bandwidth. However, fatigue did not significantly reduce leg force control accuracy. Understanding the effects of fatigue on leg force control can inform the development of strategies and technologies to sustain agile performance, even in the presence of fatigue.New and NoteworthyWe developed a method to probe the influence of neuromuscular fatigue on the control of leg external forces. Our findings demonstrate that while fatigue significantly diminishes responsiveness (speed), it does not compromise the accuracy of control. These insights enhance our understanding of legged agility and could guide the development of strategies for optimizing leg force control performance. This study paves the way for future research aimed at identifying and employing effective strategies to maintain agility in the face of fatigue.
Genome wide characterization and expression analysis of CrRLK1L gene family in wheat unravels their roles in development and stress-specific responses
Authors: Gawande Nilesh D. , Sankaranarayanan Subramanian 
Published: May 2023

AbstractCatharanthus roseusreceptor-like kinase 1-like (CrRLK1L) genes encode a subfamily of receptor-like kinases (RLK) that regulate diverse processes during plant growth, development and stress responses. This study aims to provide a comprehensive genome-wide functional characterization of CrRLK1L family in bread wheat (Triticum aestivum). The genome ofT. aestivumencodes 15CrRLK1Lfamily genes that has 43 paralogous copies with three homeologs each, except for-2-Dand-7-A, which were found to be absent. In addition, a frame shift deletion was identified in the Paralog-2-B. Chromosomal localization analysis revealed a markedly uneven distribution ofTa-CrRLK1Lgenes across seven different chromosomes, with chromosome 4 housing the highest number of genes while chromosome 6 lacked any CrRLK1L genes. Tissue-specific gene expression analysis revealed distinct expression patterns among the members of the gene family, with certain members exhibiting heightened expression in reproductive tissues. Gene expression analysis under various abiotic and biotic stress conditions unveiled differential regulation of different gene family members. An examination of cis-acting elements in the promoter regions, identified specific elements crucial for plant growth and developmental processes. This comprehensive genome wide analysis and expression study provide valuable insights into the essential functions of CrRLK1L members in wheat.
THE STRIATAL HETERODIMERS A2AR-D2Rs ARE LINKED TO ERGOGENIC EFFECTS OF CAFFEINE
Authors: Alves Ana Cristina de Bem , Santos Naiara de Souza , Tavares Ana Paula , Panatta Gabriela , Aguiar Aderbal S 
Published: May 2023

AbstractAdenosine 2A receptors (A2ARs) are abundant in the striatum, and they are found co-localized with dopamine D2 receptors (D2R) and in the heterodimer form A2AR-D2R. Previous we demonstrated that caffeine delays central fatigue through adenosine 2A receptors (A2ARs) antagonism, striatal neuroplasticity and mitochondrial metabolism enhancement. In this study we demonstrate the participation of striatal A2AR-D2R in the ergogenic outcomes. Two-hundred swiss adult mice were treated systemically (i.p.) and centrally (striatum-st.) with caffeine, SCH58261 (A2AR antagonist), DPCPX (A1R antagonist) and haloperidol (D2R antagonist), and performed the open field test, treadmill incremental exercise and grip strength meter test We observed that A2AR-D2R antagonic effects are linked to motor control (p< 0.05) and enhancement of power (p< 0.05). However, the role of A2AR-D2R in the mechanism of strength generation seems to differ from motor control.
Mutation Patterns Predict Drug Sensitivity in Acute Myeloid Leukemia
Authors: Qin Guangrong , Dai Jin , Chien Sylvia , Martins Timothy J. , Loera Brenda , Nguyen Quy , Oakes Melanie L. , Tercan Bahar , Aguilar Boris , Hagen Lauren , McCune Jeannine , Gelinas Richard , Monnat Raymond J. , Shmulevich Ilya , Becker Pamela S. 
Published: May 2023

AbstractAcute myeloid leukemia (AML) is an aggressive malignancy of myeloid progenitor cells characterized by successive acquisition of genetic alterations. This inherent heterogeneity poses challenges in the development of precise and effective therapies. To gain insights into the genetic influence on drug response and optimize treatment selection, we performed targeted sequencing,ex vivodrug screening, and single-cell genomic profiling on leukemia cell samples derived from AML patients. We detected genetic signatures associated with sensitivity or resistance to specific agents. By integrating large public datasets, we discovered statistical patterns of co-occurring and mutually exclusive mutations in AML. The application of single-cell genomic sequencing unveiled the co-occurrence of variants at the individual cell level, highlighting the presence of distinct sub- clones within AML patients. Machine learning models were built to predictex vivodrug sensitivity using the genetic variants. Notably, these models demonstrated high accuracy in predicting sensitivity to some drugs, such as MEK inhibitors. Our study provides valuable resources for characterizing AML patients and predicting drug sensitivity, emphasizing the significance of considering subclonal distribution in drug response prediction. These findings provide a foundation for advancing precision medicine in AML. By tailoring treatment based on individual genetic profiles and functional testing, as well as accounting for the presence of subclones, we envision a future of improved therapeutic strategies for AML patients.One Sentence Summary:Integrative computational and experimental analysis of mutation patterns and drug responses provide biologic insight and therapeutic guidance for patients with adult AML.
PKCδ regulates chromatin remodeling and DNA repair through SIRT6
Authors: Affandi Trisiani , Haas Ami , Ohm Angela M. , Wright Gregory M. , Black Joshua C. , Reyland Mary E. 
Published: May 2023

AbstractProtein kinase C delta (PKCδ) is a ubiquitous kinase whose function is defined in part by localization to specific cellular compartments. Nuclear PKCδ is both necessary and sufficient for IR-induced apoptosis, while inhibition of PKCδ activity provides radioprotectionin vivo.How nuclear PKCδ regulates DNA-damage induced cell death is poorly understood. Here we show that PKCδ regulates histone modification, chromatin accessibility, and double stranded break (DSB) repair through a mechanism that requires SIRT6. Overexpression of PKCδ promotes genomic instability and increases DNA damage and apoptosis. Conversely, depletion of PKCδ increases DNA repair via non-homologous end joining (NHEJ) and homologous recombination (HR) as evidenced by more rapid formation of NHEJ (DNA-PK) and HR (Rad51) DNA damage foci, increased expression of repair proteins, and increased repair of NHEJ and HR fluorescent reporter constructs. Nuclease sensitivity indicates that PKCδ depletion is associated with more open chromatin, while overexpression of PKCδ reduces chromatin accessibility. Epiproteome analysis revealed that PKCδ depletion increases chromatin associated H3K36me2, and reduces ribosylation of KDM2A and chromatin bound KDM2A. We identify SIRT6 as a downstream mediator of PKCδ. PKCδ-depleted cells have increased expression of SIRT6, and depletion of SIRT6 reverses the changes in chromatin accessibility, histone modification and NHEJ and HR DNA repair seen with PKCδ-depletion. Furthermore, depletion of SIRT6 reverses radioprotection in PKCδ-depleted cells. Our studies describe a novel pathway whereby PKCδ orchestrates SIRT6- dependent changes in chromatin accessibility to increase DNA repair, and define a mechanism for regulation of radiation-induced apoptosis by PKCδ.One Sentence SummaryProtein kinase C delta modifies chromatin structure via SIRT6 to regulate DNA repair.
THE PALISADE LAYER OF THE POXVIRUS CORE IS COMPOSED OF FLEXIBLE A10-TRIMERS
Authors: Liu Jiasui , Corroyer-Dulmont Simon , Pražák Vojtěch , Khusainov Iskander , Bahrami Karola , Welsch Sonja , Vasishtan Daven , Obarska-Kosińska Agnieszka , Thorkelsson Sigurdur R. , Grunewald Kay , Quemin Emmanuelle R. J. , Turoňová Beata , Locker Jacomina Krijnse 
Published: May 2023

AbstractAlthough vaccinia virus (VACV) is the best studied poxvirus, the structure of the mature virus (MV) remains poorly understood. Its asymmetric shape, size and compactness poses a major challenge for electron microscopy (EM) analysis, including cryoEM. Sub-viral particles, in particular membrane-free viral cores, may overcome these limitations. We compare cores obtained by detergent-stripping MVs with cores in the cellular cytoplasm, early in infection. By combining cryo-electron tomography (cryoET), subtomogram averaging (STA) and AlphaFold2 (AF2), abundant core-structures are analyzed, focusing on the prominent palisade layer on the core surface. On detergent-stripped cores, the palisade is composed of densely packed trimers of the major core protein A10. On the core surface they display a random order and their classification indicate structural flexibility. On cytoplasmic cores A10 is organized in a similar manner, indicating that the structures obtainedin vitroare physiologically relevant. CryoET and STA also uncover unexpected details of the layers beneath the palisade both onin vitroandin situcores, that are compared to AF2 structure predictions of known VACV core-associated proteins. Altogether, our data identify for the first time the structure and molecular composition of the palisade units. The results are discussed in the context of the VACV replicative cycle, the assembly and disassembly of the infectious MV.
scGHOST: Identifying single-cell 3D genome subcompartments
Authors: Xiong Kyle , Zhang Ruochi , Ma Jian 
Published: May 2023

AbstractNew single-cell Hi-C (scHi-C) technologies enable probing of the genome-wide cell-to-cell variability in 3D genome organization from individual cells. Several computational methods have been developed to reveal single-cell 3D genome features based on scHi-C data, including A/B compartments, topologically-associating domains, and chromatin loops. However, no scHi-C analysis method currently exists for annotating single-cell subcompartments, which are crucial for providing a more refined view of large-scale chromosome spatial localization in single cells. Here, we present SCGHOST, a single-cell subcompartment annotation method based on graph embedding with constrained random walk sampling. Applications of SCGHOST to scHi-C data and single-cell 3D genome imaging data demonstrate the reliable identification of single-cell subcompartments and offer new insights into cell-to-cell variability of nuclear subcompartments. Using scHi-C data from the human prefrontal cortex, SCGHOST identifies cell type-specific subcompartments that are strongly connected to cell type-specific gene expression, suggesting the functional implications of single-cell subcompartments. Overall, SCGHOST is an effective new method for single-cell 3D genome subcompartment annotation based on scHi-C data for a broad range of biological contexts.
Influence of visual information on sniffing behavior in a routinely trichromatic primate
Authors: Weiß Brigitte M. , Widdig Anja 
Published: May 2023

ABSTRACTMost catarrhine primates are considered to be strongly visually oriented, obtaining information about conspecifics and their environment from a diversity of visual cues. Other sensory modalities may provide information that is redundant and/or complimentary to visual cues. When cues from multiple sensory modalities are available, these may reinforce or suppress each other, as shown in several taxa ranging from insects to humans. Here, we tested how the presence and ambiguity of visual information affects the use of olfactory cues when exploring food and non-food items in semi-free ranging Barbary macaques at Affenberg Salem, Germany. We presented monkeys with pipes containing food (peanuts, popcorn), non-food (stones, feces) or no items in transparent or opaque containers, and assessed whether animals looked, sniffed and/or grabbed into the pipes depending on visibility of the contents (experiment 1). Visual information had no robust effect on sniffing probability, but it did affect sniffing behavior with respect to the timing of olfactory inspections (i.e. whether sniffing occurred first). Both visual and olfactory information affected, whether or not monkeys attempted to retrieve the items from the pipes. Furthermore, we manipulated the visual appearance of familiar food items (popcorn) with food colorant (experiment 2), which resulted in substantially increased olfactory inspections compared to unmanipulated popcorn. Taken together, reliance on the olfactory sense was modulated by the available visual information, emphasizing the interplay between different sensory modalities for obtaining information about the environment.
PEP444c encoded within theMIR444cgene regulates microRNA444c accumulation in barley
Authors: Chojnacka A , Smoczynska A , Bielewicz D , Pacak A , Hensel G , Kumlehn J , Karlowski WM , Grabsztunowicz M , Sobieszczuk-Nowicka E , Jarmolowski A , Szweykowska-Kulinska Z 
Published: May 2023

ABSTRACTMicroRNAs are small, non-coding RNA molecules that regulate expression of their target genes. TheMIR444gene family is present exclusively in monocotyledons, and microRNAs444 from this family have been shown to target certain MADS-box transcription factors in rice and barley. We identified three barleyMIR444(MIR444a/b/c) genes and comprehensively characterized their structure and the processing pattern of the primary transcripts (pri-miRNAs444). Pri-microRNAs444 undergo extensive alternative splicing, by which functional and non-functional pri-miRNA444 isoforms are generated. We show that barley pri-miRNAs444 contain numerous open reading frames (ORFs) whose transcripts associate with ribosomes. Using specific antibodies, we provide evidence that selected ORFs encoding PEP444a withinMIR444aand PEP444c withinMIR444care expressed in barley plants. Moreover, we demonstrate that CRISPR-associated endonuclease 9 (Cas9)-mediated mutagenesis of the PEP444c encoding sequence results in a decreased level ofPEP444transcript in barley shoots and roots, and a 5-fold reduced level of mature microRNA444c in roots. Taken together, our observations suggest that PEP444c encoded by theMIR444cgene is involved in microRNA444c biogenesis in barley.
Understanding the molecular basis for enhanced glutenase activity of actinidin
Authors: Puja Shivangi , Seth Shreya , Hora Rachna , Kaur Satinder , Mishra Prakash Chandra 
Published: May 2023

ABSTRACTManagement of gluten intolerance is currently possible only by consumption of gluten free diet(GFD) for a lifetime. The scientific community has been searching for alternatives to GFD, like inclusion of natural proteases with meals or pre-treatment of gluten containing foods with glutenases. Actinidin from kiwifruit has shown considerable promise in digesting immunogenic gliadin peptides as compared to other plant derived cysteine proteases. Through this article, we have attempted to understand the structural basis for elevated protease action of actinidin against gliadin peptides by using anin silicoapproach. Docking experiments reveal key differences between the binding of gliadin peptide to actinidin and papain, which may be responsible for their differential digestive action. Sequence comparison of different plant cysteine proteases highlights amino acid residues surrounding the active site pocket of actinidin that are unique to this molecule and hence likely to contribute to its digestive properties.Graphical summary
Computational insights on the destabilizing mutations in the binding site of 3CL-protease SARS-CoV-2 Omicron (VOC)
Authors: Ullah Samee , Amir Afreenish , Ikram Aamer , Vicidomini Caterina , Palumbo Rosanna , Roviello Giovanni N. 
Published: May 2023

AbstractThe COVID-19 (Corona Virus Disease 19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is causing enormous difficulties in the world’s economies and there is uncertainty as to whether the current prophylactic measures will offer adequate protection globally after the appearance of virus variants that like that indicated as Omicron emerged in the presence of global vaccine-based immunization. While several studies are available describing the main differences in the spike protein of Omicron compared to the other variants previously emerged, there was no structural insights into the 3CL-protease (3CLpro) associated to the new variant. Herein, we performed a computational study based on genomic data and amino acid sequences available in the most updated COVID-19-related databases that allowed us to build upin silicothe 3D structure of Omicron 3CLpro. Moreover, by molecular dynamics simulation we demonstrated that currently available drugs acting as inhibitors of the SARS-CoV-2 main protease could be less effective in the case of Omicron variant due to the different chemical interactions in the binding site occurred after the recent amino acid mutations. Ultimately, our study highlights the need of exploitingin silicoand in vitro methods to discover novel 3CLproinhibitors starting from the computationally based structure we presented herein, and more in general to direct the major efforts to targeting the most conserved 3CLproregions that appeared unchanged in the context of the Omicron variant.
Water will find its way: transport through narrow tunnels in hydrolases
Authors: Sequeiros-Borja Carlos , Thirunavukarasu Aravind Selvaram , Dongmo Foumthuim Cedrix J. , Brezovsky Jan 
Published: May 2023

ABSTRACTAn aqueous environment is vital for life as we know it, and water is essential for nearly all biochemical processes at a molecular level. Proteins utilize water molecules in various ways. Consequently, proteins must transport water molecules across their internal network of tunnels to reach the desired action sites, either within them or functioning as molecular pipes to control cellular osmotic pressure. Despite water playing a crucial role in enzymatic activity and stability, its transport has been largely overlooked, with studies primarily focusing on water transport across membrane proteins. The transport of molecules through a protein’s tunnel network is challenging to study experimentally, making molecular dynamics simulations the most popular approach for investigating such events. In this study, we focused on the transport of water molecules across three different α/β-hydrolases: haloalkane dehalogenase, epoxide hydrolase, and lipase. Using a 5 μs adaptive simulation per system, we observed that only a few tunnels were responsible for the majority of water transport in dehalogenase, in contrast to a higher diversity of tunnels in other enzymes. Interestingly, water molecules could traverse narrow tunnels with sub-angstrom bottlenecks, which is surprising given the commonly accepted water molecule radius of 1.4 Å. Our analysis of the transport events in such narrow tunnels revealed a markedly increased number of hydrogen bonds formed between the water molecules and the protein, likely compensating for the steric penalty of the process. Overall, these commonly disregarded narrow tunnels accounted for ∼20% of the total water transport observed, emphasizing the need to surpass the standard geometrical limits on the functional tunnels to properly account for relevant transport processes. Finally, we demonstrated how the obtained insights could be applied to explain the differences in a mutant of the human soluble epoxide hydrolase associated with a higher incidence of ischemic stroke.
Sex-biased regulatory changes in the placenta of native highlanders contribute to adaptive fetal development
Authors: Yue Tian , Guo Yongbo , Qi Xuebin , Zheng Wangshan , Zhang Hui , Wang Bin , Liu Kai , Zhou Bin , Zeng Xuerui , Ouzhuluobu  , He Yaoxi , Su Bing 
Published: May 2023

SummaryCompared with lowlander migrants, native Tibetans have a higher reproductive success at high altitude though the underlying mechanism remains unclear. Here, we compared the transcriptome and histology of full-term placentas between native Tibetans and Han migrants. We found that the placental trophoblast shows the largest expression divergence between Tibetans and Han, and Tibetans show decreased immune response and endoplasmic reticulum stress. Remarkably, we detected a sex-biased expression divergence, where the male-infant placentas show a greater between-population difference than the female-infant placentas. The umbilical cord plays a key role in the sex-biased expression divergence, which is associated with the higher birth weight of the male newborns of Tibetans. We also identified adaptive histological changes in the male-infant placentas of Tibetans, including larger umbilical artery wall and umbilical artery intima and media, and fewer syncytial knots. These findings provide valuable insights into the sex-biased adaptation of human populations, with significant implications for medical and genetic studies of human reproduction.
Harmonization of CSF and imaging biomarkers for Alzheimer’s disease biomarkers: need and practical applications for genetics studies and preclinical classification
Authors: Timsina Jigyasha , Ali Muhammad , Do Anh , Wang Lihua , Sung Yun Ju , Cruchaga Carlos 
Published: May 2023

AbstractINTRODUCTIONIn Alzheimer’s disease (AD) research, cerebrospinal fluid (CSF) Amyloid beta (Aβ), Tau and pTau are the most accepted and well validated biomarkers. Several methods and platforms exist to measure those biomarkers which leads to challenges in combining data across studies. Thus, there is a need to identify methods that harmonize and standardize these values.METHODSWe used a Z-score based approach to harmonize CSF and amyloid imaging data from multiple cohorts and compared GWAS result using this method with currently accepted methods. We also used a generalized mixture modelling to calculate the threshold for biomarker-positivity.RESULTSZ-scores method performed as well as meta-analysis and did not lead to any spurious results. Cutoffs calculated with this approach were found to be very similar to those reported previously.DISCUSSIONThis approach can be applied to heterogeneous platforms and provides biomarker cut-offs consistent with the classical approaches without requiring any additional data.