bluuebunny/crossref_metadata_2025_split huggingface dataset:
Emergence of rhythmic chunking in complex stepping of mice
Authors: Hirokane Kojiro , Nakamura Toru , Kubota Yasuo , Hu Dan , Yagi Takeshi , Graybiel Ann M. , Kitsukawa Takashi 
Published: March 2023

SummaryMotor chunking is important for motor execution, allowing atomization and efficiency of movement sequences. However, it remains unclear why and how chunks contribute to motor execution. To analyze the structure of naturally occurring chunks, we trained mice to run in a complex series of steps and identified the formation of chunks. We found that intervals (cycle) and the positional relationship between the left and right limbs (phase) of steps inside the chunks, unlike those outside the chunks, were consistent across occurrences. Further, licking by the mice was also more periodic and linked to the specific phases of limb movements within the chunk. Based on these findings, we propose therhythm chunking hypothesis, whereby within chunks, the repetitive movements of many body parts are linked by the rhythm parameters: cycle and phase. The computational complexity of movement may thereby be reduced by adjusting movements as the combination of rhythms.
A high sugar diet, but not obesity, reduces female fertility inDrosophila melanogaster
Authors: Nunes Rodrigo Dutra , Drummond-Barbosa Daniela 
Published: March 2023

ABSTRACTMany studies fromDrosophilato humans show a strong link between obesity and reduced fertility. However, obesity is often induced by changes in diet or eating behavior, such that it remains unclear whether reduced fertility is a consequence of obesity itself, diet, or both. Here, we report that a high sugar diet reducesDrosophilafemale fertility by increasing death of early germline cysts (prior to follicle formation) and degeneration of vitellogenic follicles; that obesity in and of itself does not impair fertility; and that high glucose levels closely correlate with reduced fertility on a high sugar diet. Females on a high sugar diet rapidly develop obesity (and display high glycogen, glucose, and trehalose levels, and insulin resistance) and decreased fertility. In stark contrast to high-sugar-obese females, females in which similar levels of obesity are induced by adipocyte-specific knockdown of anti-obesity genesbrummeroradiposehave normal fertility and sugar metabolic indicators. Remarkably, females on a high sugar diet supplemented with a separate source of water also have normal fertility and glucose levels, despite persistent obesity, high glycogen and trehalose levels, and insulin resistance markers. These results strengthen our conclusion that obesity itself does not impair fertility, show an inverse correlation between high glucose levels and fertility, and demonstrate that insulin signaling levels remain sufficiently high to maintain insulin-dependent processes during oogenesis irrespective of insulin resistance markers.
Enrichment and delivery of target proteins into the cell cytosolviaOuter Membrane Vesicles
Authors: Wan Huan , Tao Zhiqing , Zhao XiaoLing , Wang Guan , Chen Yihao , Zhang Juan , Zhang Xu , Liu Maili , Jiang Guosheng , He Lichun 
Published: March 2023

ABSTRACTAdvanced intracellular delivery of proteins has profound applications in both scientific investigations and therapies. However, existing strategies relying on various chemical and physical methods, have drawbacks such as the requirement of high concentrationin vitroprepared target proteins and difficulty in labeling target proteins. Developing new delivery systems integrating the enveloping and labeling of target proteins would bring great advantages for efficient protein transfections. Here, we enriched a high concentration (62 mg/ml) of several target proteins into outer membrane vesicles (OMVs) ofE. colito employ the native property of OMVs to deliver proteins into the cytosol of eukaryotic cells. The results revealed a high protein transfection efficiency arranging from 90-97% for different cell lines. Moreover, the free penetration of molecules less than 600 Dalton across the membrane of OMVs allows direct labeling of target proteins within OMVs, facilitating the visualization of target proteins. Importantly, the nanobody delivered intracellularly by OMVs retains the biological activity of binding with its target, highlighting the advantages of OMVs as an emerging tool for efficient intracellular delivery of proteins.
Polygenic outcomes of sexually antagonistic selection
Authors: Muralidhar Pavitra , Coop Graham 
Published: March 2023

AbstractSexual antagonism occurs when males and females have different fitness optima for a phenotype, but are constrained from evolving to these optima because of their shared genome. We study the response of a polygenic phenotype to the onset of sexually antagonistic selection, modeling a phenotype initially under stabilizing selection around an optimum, followed by a sudden divergence of the male and female optima. We observe rapid phenotypic evolution to these new optima via small changes in allele frequencies genome-wide. We study the role of sex chromosomes in this divergence and find that, in the absence of dosage compensation, the X chromosome favors evolution toward the female optimum, inducing co-evolutionary male-biased responses on the autosomes. However, dosage compensation obscures the female-biased interests of the X, causing it to contribute equally to male and female phenotypic change. In both scenarios, we see little effect of dominance in the genetic variation utilized by the X chromosome vs. the autosomes. We go on to examine the dynamics of stabilizing selection once the male and female optima have been reached, exploring a subtle mechanism through which the X chromosome, via the Bulmer effect, can cause higher equilibrium phenotypic variance in males than females. Finally, we consider how sexual antagonistic selection might persist across longer time scales, demonstrating that random fluctuations in an adaptive landscape can generate prolonged intragenomic conflict. Overall, our results provide insight into the response of complex phenotypes to sexually antagonistic selection and the evolution of sexual dimorphism.
Biliatresone treatment of pregnant mice causes changes in bile metabolism and liver inflammation in their offspring
Authors: Gupta Kapish , Xu Jimmy P. , Diamond Tamir , De Jong Iris , Glass Andrew , Llewellyn Jessica , Theise Neil D. , Winkler Jeffrey D. , Behrens Edward M. , Mesaros Clementina , Wells Rebecca G. 
Published: March 2023

AbstractBackground & AimsBiliary atresia is a neonatal disease characterized by bile duct and liver damage, fibrosis, inflammation and abnormal bile metabolism. It appears to result from a prenatal exposure that spares the mother and affects the fetus. Our aim was to define the phenotype in neonatal mice after maternal exposure to low-dose biliatresone, a plant toxin implicated in biliary atresia in livestock.MethodsPregnant mice were treated orally with low-doses of biliatresone. Histological changes, bile acid profiles and immune profiles were analyzed in postnatal day 5 and 21 pups born to treated mothers.ResultsThe pups of mothers treated with this dose of biliatresone had no evidence of significant liver or ductular injury or fibrosis at postnatal day 5 or 21 and they grew normally. However, serum levels of glycocholic acid were elevated at postnatal day 5, suggesting altered bile metabolism, and bile metabolism became increasingly abnormal through postnatal day 21, with enhanced glycine conjugation of bile acids. There was also immune cell activation observed in the liver at postnatal day 21.ConclusionPrenatal exposure to low doses of an environmental toxin can cause liver inflammation and aberrant bile metabolism even in the absence of histological changes.Lay summaryPrenatal exposure to low doses of an environmental toxin can cause changes in bile metabolism in neonatal mice.
Epigenomic divergence underlies sequence polymorphism and the evolutionary fate of duplicate paralogs inA. thaliana
Authors: Kenchanmane Raju Sunil K. , Lensink Mariele , Kliebenstein Daniel J. , Niederhuth Chad , Monroe Grey 
Published: March 2023

AbstractProcesses affecting rates of sequence polymorphism are fundamental to molecular evolution and the evolutionary fate of gene duplicates. The relationship between gene activity and sequence polymorphism can influence the likelihood that functionally redundant gene copies are co-maintained in stable evolutionary equilibria versus other outcomes such as neo-functionalization. Here we investigate genic variation in epigenome-associated polymorphism rates inArabidopsis thalianaand consider whether these affect the evolution of gene duplicates. We compared the frequency of sequence polymorphism and patterns of genetic differentiation between genes classified by exon methylation patterns: unmethylated (unM), gene-body methylated (gbM), and transposon-like methylated (teM) states, which reflect divergence in gene expression. We found that the frequency of polymorphism was higher in teM (transcriptionally repressed, tissue-specific) genes and lower in gbM (active, constitutively expressed) genes. Comparisons of gene duplicates were largely consistent with genome-wide patterns - gene copies that exhibit teM tend to accumulate higher sequence polymorphism, evolve faster, and are in chromatin states associated with reduced DNA repair. This relationship between expression, the epigenome, and polymorphism may lead to the breakdown of equilibrium states that would otherwise maintain genetic redundancies. Epigenome-mediated polymorphism rate variation may therefore aid the pseudogenization of duplicate paralogs or increase the evolution of novel gene functions in duplicate paralogs maintained over evolutionary time.
Respiration is essential for aerobic growth ofZymomonas mobilisZM4
Authors: Felczak Magdalena M. , TerAvest Michaela A. 
Published: March 2023

AbstractZymomonas mobilisis an alpha-proteobacterium that is a promising platform for industrial scale production of biofuels or valuable products due to its efficient ethanol fermentation and low biomass generation.Z. mobilishas also intriguing physiology, sometimes difficult to explain by the rules and strategies commonly observed in other bacteria. One of the most mysterious features ofZ. mobilisis its growth in oxic conditions.Z. mobilisis an aerotolerant bacterium that encodes a complete respiratory electron transport chain but the benefit of respiration for growth in oxic conditions has never been confirmed, despite decades of research. Quite the opposite, growth and ethanol production of WTZ. mobilisis poor in oxic conditions indicating that it does not benefit from oxidative phosphorylation. Additionally, in previous studies, aerobic growth improved significantly when respiratory genes were disrupted (ndh) or acquired point mutations (cydA, cydB)even if respiration was significantly reduced by these changes. Here, we obtained clean deletions of respiratory genesndhandcydAB, individually and in combination, and showed, for the first time, that deletion ofcydABcompletely inhibited O2respiration and dramatically reduced growth in oxic conditions. Both respiration and aerobic growth were restored by expressing a heterologous, water-forming NADH oxidase,noxE. This result shows that the main role of the electron transport chain inZ. mobilisis reducing the toxicity of molecular oxygen, helping to explain why it is beneficial forZ. mobilisto use electron transport chain complexes that contribute little to oxidative phosphorylation.ImportanceA key to producing next generation biofuels is to engineer microbes that efficiently convert non-food materials into drop-in fuels and to engineer microbes effectively we must understand their metabolism thoroughly.Zymomonas mobilisis a bacterium that is a promising candidate biofuel producer but its metabolism remains poorly understood, especially its metabolism when exposed to oxygen. AlthoughZ. mobilisrespires with oxygen, its aerobic growth is poor and disruption of genes related to respiration counterintuitively improves aerobic growth. This unusual result has sparked decades of research and debate regarding the function of respiration inZ. mobilis. Here, we used a new set of mutants to determine that respiration is essential for aerobic growth and likely protects the cells from oxidative damage caused by molecular oxygen. These results indicate that respiration has a non-canonical function inZ. mobilisand expand our understanding of the role of respiration in metabolism and oxidative stress.
Inhibition of hostN-myristoylation compromises the infectivity of SARS-CoV-2 due to Golgi-bypassing egress from lysosomes and endoplasmic reticulum
Authors: Saber Saber H. , Shaker Mohammed R. , Sng Julian , Yak Nyakuoy , Morrison Sean D. , Pars Selin , Zheng Huiwen , Pietrogrande Giovanni , Binder Tobias , Lu Siyuan , Floetenmeyer Matthias , Ojha Ravi , Quirin Tania , Ruuska Janika , Smura Teemu , Strandin Tomas , Kant Ravi , Kareinen Lauri , Sironen Tarja , Talbo Gert Hoy , Zhu Yanshan , Short Kirsty R. , Mar Jessica , Kallemeijn Wouter W. , Tate Edward W. , Solari Roberto , van Waardenberg Ashley J. , Vapalahti Olli , Wolvetang Ernst , Balistreri Giuseppe , Joensuu Merja 
Published: March 2023

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic, remains a global health concern despite vaccines, neutralizing antibodies, and antiviral drugs. Emerging mutations can reduce the effectiveness of these treatments, suggesting that targeting host cell factors may be a valuable alternative.N-myristoyltransferases (NMT) are essential enzymes for proteinN-myristoylation, affecting stability, interaction, localization, and function of numerous proteins. We demonstrate that selective inhibition of host cell NMT decreases SARS-CoV-2 infection by 90% in human lung and primary nasal epithelial cells, and choroid plexus-cortical neuron organoids. NMT inhibition does not affect viral entry, replication or release, but impairs the maturation and incorporation of viral envelope proteins into newly assembled virions, leading to compromised infectivity of released virions. The inhibition of host NMT triggers a Golgi-bypassing pathway for SARS-CoV-2 progeny virion egress, which occurs through endoplasmic reticulum and lysosomal intermediates.
Underlying causes for prevalent false positives and false negatives in STARR-seq data
Authors: Ni Pengyu , Wu Siwen , Su Zhengchang 
Published: March 2023

AbstractSTARR-seq and its variants have been widely used to characterize enhancers. However, it has been reported that up to 87% of STARR peaks are located in repressive chromatins and are not functional in the tested cells. While some of the STARR peaks in repressive chromatins might be active in other cell/tissue types, some others might be false positives. Meanwhile, many active enhancers may not be identified by the current STARR-seq methods. However, the prevalence of and underlying causes for the artifacts are not fully understood. Based on predictedcis-regulatory modules (CRMs) and non-CRMs in the human genome as well as predicted active CRMs and non-active CRMs in a few human cell lines with STARR-seq data available, we reveal prevalent false positives and false negatives in STARR peaks and possible underlying causes. Our results will help design strategies to improve STARR-seq methods and interpret the results.
Chromatin Accessibility and Pioneer Factor FOXA1 Shape Glucocorticoid Receptor Action in Prostate Cancer
Authors: Helminen Laura , Huttunen Jasmin , Aaltonen Niina , Niskanen Einari A. , Palvimo Jorma J. , Paakinaho Ville 
Published: March 2023

ABSTRACTTreatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the antiandrogen therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR function. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs have remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in enzalutamide-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of theNR3C1(gene encoding GR) expressionviathe corepressor TLE3. Moreover, the small-molecule inhibition of coactivator p300’s enzymatic activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated antiandrogen resistance.
Differential expression and function of SVIP in breast cancer cell lines andin silicoanalysis of its expression and prognostic potential in human breast cancer
Authors: Atalay Şahar Esra , Ballar Kirmizibayrak Petek 
Published: March 2023

AbstractThe heterogeneity of cancer strongly suggests the need to explore additional pathways to target. As cancer cells have increased proteotoxic stress, targeting proteotoxic stress-related pathways such as endoplasmic reticulum stress is attracting attention as new anticancer treatments. One of the downstream responses to endoplasmic reticulum stress is endoplasmic reticulum-associated degradation (ERAD), a major degradation pathway that facilitates proteasome-dependent degradation of unfolded or misfolded proteins. Recently, SVIP, an endogenous ERAD inhibitor, has been implicated in cancer progression, especially in glioma, prostate, and head and neck cancers. Here, the data of several RNA-seq and gene array studies were combined to evaluate the SVIP gene expression analysis on a variety of cancers, with a particular focus on breast cancer. SVIP was found to be overexpressed in primary breast tumors compared to normal tissues correlated well with its promoter methylation status and genetic alterations. Similarly, immunoblotting analysis showed that SVIP was expressed significantly higher in breast cancer cell lines compared to non-tumorigenic epithelial cell line. On the other hand, the expression of the key proteins of gp78-mediated ERAD did not exhibit such a pattern. Interestingly, silencing of SVIP enhanced the proliferation of p53 wt MCF7 cells but not p53 mutant T47D cells, however increased migration ability of both cell lines. Interestingly, SVIP expression is high in primary breast tumors but low in breast metastatic tumors. This correlates well with a lower probability of survival of breast cancer patients with lower SVIP expression compared to the patients with overexpressed SVIP. Overall, our data revealing the differential expression and function of SVIP on breast cancer cell lines together within silicodata analysis suggest that SVIP may have complex functions in breast cancer progression and has the potential to be a therapeutic target for breast cancer.
Phenotypic link between protein efficiency and pig welfare suggests no apparent trade-offs for mitigating nitrogen pollution
Authors: Roch Lea , Ewaoluwagbemiga Esther Oluwada , Kasper Claudia 
Published: March 2023

AbstractPig manure contributes significantly to environmental pollution through nitrogen compounds. Reducing protein in feed can help, but it may lead to damaging behaviors if pigs’ nutritional needs are not met. Breeding pigs for higher protein efficiency (PE) is a long-term solution to reduce nitrogen pollution, but concerns about pig welfare remain. We studied 95 pigs involved in a project on the genetic basis of PE on a 20% protein restricted diet to investigate the phenotypic connection between PE and welfare. These pigs represented natural PE variations in the population. At around 100 days, before their PE was known, we observed their behaviors. Only three pigs engaged in tail biting and manipulation of vulnerable regions, but this was not associated with PE. There was no clear link between PE and manipulating pen mates’ less vulnerable regions. Such behaviors are normal but can cause stress and injury if carried out excessively due to boredom or stress. Overall, pigs with higher PE showed no major behavioral abnormalities in this study. Considering the lack of genetic knowledge, the risk of increased harmful behaviors when selecting for higher PE appears low when inferred from this purely phenotypic association.
Widespread CRISPR repeat-like RNA regulatory elements in CRISPR-Cas systems
Authors: Shmakov Sergey A. , Barth Zachary K. , Makarova Kira S. , Wolf Yuri I. , Brover Vyacheslav , Peters Joseph E. , Koonin Eugene V. 
Published: March 2023

AbstractCRISPR-casloci typically contain CRISPR arrays with unique spacers separating direct repeats. Spacers along with portions of adjacent repeats are transcribed and processed into CRISPR(cr) RNAs that target complementary sequences (protospacers) in mobile genetic elements, resulting in cleavage of the target DNA or RNA. Additional, standalone repeats in some CRISPR-casloci produce distinct cr-like RNAs implicated in regulatory or other functions. We developed a computational pipeline to systematically predict crRNA-like elements by scanning for standalone repeat sequences that are conserved in closely related CRISPR-casloci. Numerous crRNA-like elements were detected in diverse CRISPR-Cas systems, mostly, of type I, but also subtype V-A. Standalone repeats often form mini-arrays containing two repeat-like sequence separated by a spacer that is partially complementary to promoter regions ofcasgenes, in particularcas8, or cargo genes located within CRISPR-Cas loci, such as toxins-antitoxins. We show experimentally that a mini-array from a type I-F1 CRISPR-Cas system functions as a regulatory guide. We also identified mini-arrays in bacteriophages that could abrogate CRISPR immunity by inhibiting effector expression. Thus, recruitment of CRISPR effectors for regulatory functions via spacers with partial complementarity to the target is a common feature of diverse CRISPR-Cas systems.
Insights into the function of the chloroplastic ribosome-associated GTPase HflX inArabidopsis thaliana
Authors: Mehrez Marwa , Lecampion Cécile , Ke Hang , Gorsane Faten , Field Ben 
Published: March 2023

AbstractRibosome-associated GTPases are conserved enzymes that participate in ribosome biogenesis and ribosome function. In bacteria, recent studies have identified HflX as a ribosome-associated GTPase that is involved in both ribosome biogenesis and recycling under stress conditions. Plants possess a chloroplastic HflX homolog, but its function remains unknown. Here, we characterised the role of HflX in the plantArabidopsis thaliana. Our findings demonstrate that HflX does not have a detectable role in plant growth and development, nor does it play a distinct role in acclimation to several different stresses, including heat, manganese, cold, and salt stress. However, we found that HflX is required for plant resistance to chloroplast translational stress mediated by the antibiotic lincomycin. Our results suggest that HflX is a chloroplast ribosome-associated protein that may play a role in the surveillance of translation. These findings provide new insight into the function of HflX as a ribosome-associated GTPase in plants and highlight the importance of investigating conserved proteins in different organisms to gain a comprehensive understanding of their biological roles.