bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased force and elastic energy storage are not the mechanisms that improve jump performance with accentuated eccentric loading during a constrained vertical jump
Authors: Su Eric Yung-Sheng , Carroll Timothy J. , Farris Dominic J. , Lichtwark Glen 
Published: November 2023

AbstractObjectiveAccentuated eccentric loading (AEL) involves higher load applied during the eccentric phase of a stretch-shortening cycle movement, followed by a sudden removal of load before the concentric phase. Previous studies suggest that AEL enhances human countermovement jump performance, however the mechanism is not fully understood. Here we explore whether isolating additional load during the countermovement is sufficient to increase ground reaction force, and hence elastic energy stored, at the start of the upward movement and whether this leads to increased jump height or power generation.MethodsWe conducted a trunk-constrained vertical jump test on a custom-built device to isolate the effect of additional load while controlling for effects of squat depth, arm swing, and coordination. Twelve healthy, recreationally active adults (7 males, 5 females) performed maximal jumps without AEL, followed by randomised AEL conditions prescribed as a percentage of body mass (10%, 20%, and 30%), before repeating jumps without AEL.Results.No significant changes in vertical ground reaction force at the turning point were observed. High load AEL conditions (20% and 30% body weight) led to slight reductions in jump height, primarily due to decreased hip joint and centre of mass work. AEL conditions did not alter peak or integrated activation levels of the knee extensor muscles.ConclusionThese findings suggest that increased elastic energy return may not be the primary mechanism behind the potentiating effects of AEL on jump performance, and other factors such as rate of descent, squat depth, or body configuration may contribute to effective AEL.
Principles of Computation by Competitive Protein Dimerization Networks
Authors: Parres-Gold Jacob , Levine Matthew , Emert Benjamin , Stuart Andrew , Elowitz Michael B. 
Published: November 2023

SummaryMany biological signaling pathways employ proteins that competitively dimerize in diverse combinations. These dimerization networks can perform biochemical computations, in which the concentrations of monomers (inputs) determine the concentrations of dimers (outputs). Despite their prevalence, little is known about the range of input-output computations that dimerization networks can perform (their “expressivity”) and how it depends on network size and connectivity. Using a systematic computational approach, we demonstrate that even small dimerization networks (3-6 monomers) areexpressive, performing diverse multi-input computations. Further, dimerization networks areversatile, performing different computations when their protein components are expressed at different levels, such as in different cell types. Remarkably, individual networks with random interaction affinities, when large enough (≥8 proteins), can perform nearly all (∼90%) potential one-input network computations merely by tuning their monomer expression levels. Thus, even the simple process of competitive dimerization provides a powerful architecture for multi-input, cell-type-specific signal processing.Graphical Abstract
Berberine impairs spermatogenesis in mice by modulating ornithine metabolism via gut microbiota regulation
Authors: Qu Wei , Xu Yumin , Lei Junhao , Yang Jing , Shi Hanqing , Wang Junli , Yu Xinnai , Chen Jiemin , Wang Binyi , Han Yan , Luo Mengcheng , Liu Rong 
Published: November 2023

AbstractBerberine (BBR) is used to treat diarrhea clinically, its reproductive toxicity, however, is poorly documented. This study aims to investigate the impact of BBR on the male reproductive system. Gradient doses of BBR were administered orally to experimental mice for consecutive 14 days. The gut microbiota, sperm concentration of cauda epididymis, and serum testosterone levels were measured after the last dose for assessing the effects of BBR. Moreover, the metabolome and transcriptome of the mice and microbiota were also investigated. Intragastric BBR administration resulted in a significant decrease in serum testosterone levels and epididymal sperm concentration in mice, which was attributed to a dramatic decrease of Muribaculaceae abundance in the gut microbiota of mice. Both fecal microbiota transplantation (FMT) and polyethylene glycol (PEG) treatment experiments also demonstrated that Muribaculaceae is necessary for spermatogenesis. Metabolomic analysis revealed that BBR affected the arginine and proline metabolism pathways, of which ornithine levels were downregulated after BBR administration. Intragastric administration ofM.intestinaleand its metabolite ornithine to BBR-treated mice achieved a recovery of sperm concentration and testosterone levels. RNA sequencing of testes showed the genes related to the LDLR-mediated cholesterol-synthesis testosterone pathway were downregulated after BBR administration. The levels of testosterone increased andLdlrgene became more transcriptionally active in TM3 cells cultured in media supplemented with ornithine. This study for the first time revealed an association between BBR-induced gut Muribaculaceae dysbiosis and defects in spermatogenesis via ornithine metabolism, which provided a candidate and strategy for the treatment of infertility caused by a decreased serum testosterone level-induced by gut microbiota dysbiosis.
Post-fertilization transcription initiation in an ancestral LTR retrotransposon drives lineage-specific genomic imprinting ofZDBF2
Authors: Kobayashi Hisato , Igaki Tatsushi , Kumamoto Soichiro , Tanaka Keisuke , Takashima Tomoya , Nagaoka So I. , Suzuki Shunsuke , Hayashi Masaaki , Renfree Marilyn B. , Kawahara Manabu , Saito Shun , Kobayashi Toshihiro , Nagashima Hiroshi , Matsunari Hitomi , Nakano Kazuaki , Uchikura Ayuko , Kiyonari Hiroshi , Kaneko Mari , Imai Hiroo , Nakabayashi Kazuhiko , Lorincz Matthew C. , Kurimoto Kazuki 
Published: November 2023

ABSTRACTThe imprintedZDBF2gene is controlled by oocyte-derived DNA methylation, but its epigenetic regulation is quite different from that of other canonically imprinted genes that are dependent on DNA methylation deposited in the gametes. At theZDBF2locus, maternal DNA methylation in the imprinted differentially methylated region (DMR) does not persist after implantation. Instead, a transient transcript expressed in the early embryo exclusively from the unmethylated paternal allele of the DMR, known asGPR1-ASin humans andLizin mice, contributes to establishing secondary DMRs that maintain paternal expression ofZDBF2in the somatic lineage. While the imprinting ofZDBF2is evident in humans and mice, whether this process is conserved in other mammals has not been addressed. Here, we show that the first exon of humanGPR1-ASoverlaps with that of a long terminal repeat (LTR) belonging to the MER21C subfamily of retrotransposons. Although this LTR family appears and is amplified in Boroeutherians, the magnorder of placental mammals that includes the Euarchontoglires and Laurasiatheria superorders, the MER21C insertion into theGPR1-ASorthologous region occurred specifically in the common ancestor of Euarchontoglires, a clade that includes extant primates, rodents, and rabbits. The first exon of mouseLizdoes not overlap with an annotated LTR in standard repeat annotation; however, promoter activity assay and multiple sequence alignment suggests that it retains a functionally conserved relationship with the MER21C-overlapping first exon ofGPR1-AS. Furthermore, directional RNA sequencing of placental tissues from rabbits and nonhuman primates also revealedGPR1-ASorthologs, with their first exon embedded within the same ancestral LTR. In contrast, allele-specific expression profiling of cow and tammar wallaby, mammals outside the Euarchontoglires group, revealed expression from both alleles in all tissues analyzed. Taken together, these observations suggest that imprinting ofZDBF2in Euarchontoglires had its genesis in the insertion of a MER21C element in their common ancestor. Our previous studies showed that LTRs reactivated in oocytes contribute to lineage-specific imprinting during mammalian evolution. The data presented here suggest that post-fertilization activation of an ancestral LTR-derived sequence can also contribute to the lineage-specific establishment of imprinted genes.
Identification of two novel DnaJ chaperone family proteins as modifiers of Huntingtin aggregates
Authors: Deo Ankita , Ghosh Rishita , Ahire Snehal , Majumdar Amitabha , Bose Tania 
Published: November 2023

AbstractHuntington’s disease (HD) is a rare neurodegenerative disease. It is caused due to aggregation of Huntingtin (HTT) protein containing Q repeats more than 40. Similar protein aggregation is also a hallmark of several other neurodegenerative diseases related to loss of cognitive function. In search of modifiers of HTT aggregation, we have screened putative chaperone proteins fromDrosophilain both fly and yeast model of HD. DnaJ chaperones were screened by evaluating HTT protein aggregation related phenotypes using growth assays for studying the growth rate of the cells, imaging studies, and gel-based approaches like semi-denaturing detergent agarose gel electrophoresis (SDD-AGE). Our screening led us to categorize several proteins as suppressors and enhancers of the HTT associated phenotypes. Out of the 40 chaperones and co-chaperones, two chaperones that came up strikingly were CG5001 and P58IPK. Protein aggregation was found to be reduced in both S2 cells andDrosophilatransgenic lines with HTT103Q in presence of these class of chaperones. As these DnaJ chaperones have protein sequence similarity across species, these might be used as possible tools to combat the effects of neurodegenerative diseases, as evidenced specifically in Huntington’s disease and Amyotrophic Lateral Sclerosis (ALS).
Prion diseases disrupt the glutamate/glutamine metabolism in skeletal muscle
Authors: Caredio Davide , Koderman Maruša , Frontzek Karl , Sorce Silvia , Nuvolone Mario , Bremer Juliane , Schwarz Petra , Sellitto Stefano , Streichenberger Nathalie , Scheckel Claudia , Aguzzi Adriano 
Published: November 2023

AbstractIn prion diseases, aggregates of misfolded prion protein (PrPSc) accumulate not only in the brain but also in extraneural organs. This raises the question whether prion-specific pathologies arise also extraneurally. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes in all three organs, with skeletal muscle showing the most consistent alterations. The glutamate-ammonia ligase (GLUL) gene exhibited uniform upregulation in skeletal muscles of mice infected with three distinct scrapie prion strains (RML, ME7, and 22L) and in victims of human sporadic Creutzfeldt-Jakob disease.GLULdysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimer’s disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. These findings reveal an unexpected metabolic dimension of prion infections and point to a potential role for GLUL dysregulation in the glutamate/glutamine metabolism in prion-affected skeletal muscle.
Reduced dosage of multiple dynein arm preassembly factors limits cilia regeneration inChlamydomonas reinhardtii
Authors: Penny Gervette M. , Dutcher Susan K. 
Published: November 2023

AbstractMotile cilia are complex organelles comprised of >800 structural proteins. Variants in 58 of these genes cause primary ciliary dyskinesia (PCD) in humans. We used a second-site non-complementation approach in diploidChlamydomonas reinhardtiistrains to investigate whether reduced dosage of different combinations of motile cilia proteins affects cilia growth / regeneration. Temperature-sensitive mutants in intraflagellar transport genes fail to complement in heterozygous diploids at the restrictive temperature, which may be due to poisonous interactions or a reduction in protein levels. Diploid strains heterozygous for 211 double mutant combinations in 21 genes are phenotypically recessive when unperturbed and do not show SSNC. Consequently, we developed a sensitized screen. When protein synthesis is inhibited, cells utilize the existing cytoplasmic pool of proteins, which is insufficient to build full-length cilia. Six double heterozygous strains in dynein arm preassembly factors (DNAAFs)pf13, pf23, wdr92,andoda8regrow cilia that are shorter than wild-type diploids, which suggests that double heterozygosity limits the pool of assembled dynein arms further. We isolated a new null allele (pf23-4)that shows a more severe loss of ODAs and IDAs in cilia than the previously studiedpf23-1hypomorphic allele. We also identified a new role for PF23 in cytoplasmic modification of IC138, protein of the I1/finner dynein arm. In our SSNC assay, thepf23-4allele also exhibits a more severe phenotype thanpf23-1. Whole cell extract immunoblots show a reduction of PF23 protein to one-half of wild-type levels in both single and double heterozygous genotypes. Thepf13mutant shows SSNC with mutants in two outer dynein arm structural proteins, ODA6, andODA9. We suggest that reduction of multiple dynein preassembly factors limits the pool of assembled dynein arms needed for cilia assembly and regeneration. Our data support PF23 as a scaffolding hub protein involved in dynein arm assembly.Author SummaryMotile cilia are essential for movement of cells and fluids. In humans, motile cilia defects cause primary ciliary dyskinesia (PCD), a rare disease characterized by recurring respiratory infections, left-right asymmetry defects, ear infections, and infertility. Many genes are involved in motile cilia function and assembly. We useChlamydomonas reinhardtiito study the effects of changes in protein levels in different combinations of proteins needed for motile cilia. Our results show that the proteins that help fold and assemble the dynein motors in the cytoplasm are sensitive to changes in the dosage of these preassembly factors. Reductions in proteins involved in multiple steps of the pathway prevents efficient dynein preassembly and cilia regeneration under stressful cellular conditions.
The scramblases VMP1 and TMEM41b are required for primitive endoderm specification by targeting WNT signaling
Authors: Holzner Markus , Sonicki Tea , Hunn Hugo , Uliana Federico , Jiang Weijun , Gade Vamshidhar R. , Weis Karsten , Wutz Anton , Di Minin Giulio 
Published: November 2023

ABSTRACTThe ER resident proteins VMP1 and TMEM41b share a conserved DedA domain, which confers lipid scramblase activity. Loss of either gene results in embryonic lethality in mice and defects in autophagy and lipid droplet metabolism. We set out to investigate their role in pluripotency and specification. For this purpose, we generated Vmp1 and Tmem41b mutations in mouse embryonic stem cells (ESCs). We observed that ESCs carrying mutations in Vmp1 and Tmem41b show robust self-renewal and an unperturbed pluripotent expression profile but accumulate LC3-positive autophagosomes and lipid droplets consistent with defects in autophagy and lipid metabolism. ESCs carrying combined mutations in Vmp1 and Tmem41b can differentiate into a wide range of embryonic cell types. However, differentiation into primitive endoderm-like cells in culture is impaired, and the establishment of extra- embryonic endoderm stem (XEN) cells is delayed. Mechanistically, we show the deregulation of genes that are associated with WNT signaling. This is further confirmed by cell surface proteome profiling, which identified a significant reduction of the WNT receptor FZD2 at the plasma membrane in Vmp1 and Tmem41b double mutant ESCs. Importantly, we show that transgenic expression of Fzd2 rescues XEN differentiation. Our findings identify the role of the lipid scramblases VMP1 and TMEM41b in WNT signaling during extra-embryonic endoderm development and characterize their distinct and overlapping functions.
Social avoidance of mice in pain in naturalistic conditions
Authors: Moëne Olivia Le , Larsson Max 
Published: November 2023

AbstractPain and social behavior are subject to reciprocal modulation. Both humans and rodents experience emotional contagion from afflicted conspecifics, and may act to relieve the afflicted state of these. Little has been done to investigate the motivation of such prosocial behavior in rodents in naturalistic conditions. Here, we analyzed social interactions in mice group-housed in a seminatural environment (SNE). Social buffering reduced nocifensive behavior in formalin-injected mice. These mice were also both socially withdrawn and avoided by other mice. These findings appear counter to those showing empathy in mouse pain models. It is possible that in naturalistic conditions, healthy mice simply avoid individuals in pain and the cost associated with emotional contagion. Interestingly, behaviors involving direct body contact were not different between saline– and formalin-treated mice, and thus may carry a prosocial, altruistic component. These findings unveil new patterns of social modulation by pain in a naturalistic laboratory setting holding high translational value.TeaserIn a new, ethological assay, mice in pain are socially withdrawn and avoided by others, challenging findings of empathy in rodent models.
Functional characterization of the disease-associatedCCL2rs1024611G-rs13900T haplotype: The role of the RNA-binding protein HuR
Authors: Akhtar Feroz , Ruiz Joselin Hernandez , Liu Ya-Guang , Resendez Roy G. , Feliers Denis , Morales Liza D. , Diaz-Badillo Alvaro , Lehman Donna M. , Arya Rector , Lopez-Alvarenga Juan Carlos , Blangero John , Duggirala Ravindranath , Mummidi Srinivas 
Published: November 2023

AbstractCC-chemokine ligand 2 (CCL2) is involved in the pathogenesis of several diseases associated with monocyte/macrophage recruitment, such as HIV-associated neurocognitive disorder (HAND), tuberculosis, and atherosclerosis. The rs1024611 (alleles:A>G; G is the risk allele) polymorphism in theCCL2 cis-regulatory region is associated with increased CCL2 expression in vitro and ex vivo, leukocyte mobilization in vivo, and deleterious disease outcomes. However, the molecular basis for the rs1024611-associated differential CCL2 expression remains poorly characterized. It is conceivable that genetic variant(s) in linkage disequilibrium (LD) with rs1024611 could mediate such effects. Previously, we used rs13900 (alleles: C>T) in theCCL23’ untranslated region (3’ UTR) that is in perfect LD with rs1024611 to demonstrate allelic expression imbalance (AEI) ofCCL2in heterozygous individuals. Here we tested the hypothesis that the rs13900 could modulateCCL2expression by altering mRNA turnover and/or translatability. The rs13900 T allele conferred greater stability to theCCL2transcript when compared to the rs13900 C allele. The rs13900 T allele also had increased binding to Human Antigen R (HuR), an RNA-binding protein, in vitro and ex vivo. The rs13900 alleles imparted differential activity to reporter vectors and influenced the translatability of the reporter transcript. We further demonstrated a role for HuR in mediating allele-specific effects on CCL2 expression in overexpression and silencing studies. The presence of the rs1024611G-rs13900T conferred a distinct transcriptomic signature related to inflammation and immunity. Our studies suggest that the differential interactions of HuR with rs13900 could modulate CCL2 expression and explain the interindividual differences in CCL2-mediated disease susceptibility.
Cell type-specific representation of spatial context in the rat prefrontal cortex
Authors: Brünner H , Kim H , Ährlund-Richter S , van Lunteren J , Crestani AP , Meletis K , Carlén M 
Published: November 2023

SummaryThe ability to represent one’s own position in relation to cues, goals, or threats is crucial to successful goal-directed behavior. Using transgenic rats expressing Cre recombinase in parvalbumin (PV) neurons (PV-Cre rats) we demonstrate cell type-specific encoding of spatial and movement variables in the medial prefrontal cortex (mPFC) during reward foraging. Single neurons encoded the conjunction of the animal’s spatial position and the location of the reward, referred to as the spatial context. The spatial context was most prominently represented by the inhibitory PV interneurons. Movement towards the reward was signified by increased local field potential (LFP) oscillations in the gamma band but this LFP signature was not related to the spatial information in the neuronal firing. The results highlight how spatial information is incorporated into cognitive operations in the mPFC. The presented PV-Cre line opens for expanded research approaches in rats.
High-quality long-read genome assemblies reveal evolutionary patterns of transposable elements and DNA methylation in termites
Authors: Qiu Bitao , Elsner Daniel , Korb Judith 
Published: November 2023

SummaryTermites are social cockroaches that evolved eusociality independently from social Hymenoptera (ants, bees, wasps). Termites’ large genome sizes, generally composed of around 50% of transposable elements, make it challenging to obtain high quality genome assemblies with short-read sequencing technology. Correspondingly, there are only six published termite genome assemblies. Using PacBio HiFi sequencing, we generated high quality genome assemblies using single individuals for three additional termite species (Trinervitermessp.1,Odontotermessp.2,Macrotermes bellicosus) and a highly improved assembly for a fourth species (Cryptotermes secundus). We simultaneously profiled TE abundance and CpG DNA methylation from the same individuals. We show that TE abundance and DNA methylation levels across species reflect their phylogenetic relationships. We identified lineage- and species-specific TE- and DNA-methylation patterns, and revealed a negative correlation between TE abundance and methylation level. These results imply evolutionary arms-races between TE and DNA methylation during termite evolution.