bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low effective mechanical advantage of giraffes’ limbs during walking reveals trade-off between limb length and locomotor performance
Authors: Basu Christopher , Hutchinson John R. 
Published: April 2021

AbstractGiraffes (Giraffa camelopardalis) possess specialised locomotor morphology, namely elongate and gracile distal limbs. Whilst this contributes to their overall height (and enhanced feeding behaviour), we propose that the combination of long limb segments and modest muscle lever arms results in low effective mechanical advantage (EMA, the ratio of in-lever to out-lever moment arms), when compared with other cursorial mammals. To test this, we used a combination of experimentally measured kinematics and ground rection forces (GRFs), musculoskeletal modelling, and inverse dynamics to calculate giraffe forelimb EMA during walking. Giraffes walk with an EMA of 0.34 (±0.05 S.D.), with no evident association with speed within their walking gait. Giraffe EMA was markedly below the expectations extrapolated from other mammals ranging from 0.03 – 297 kg, and provides further evidence that EMA plateaus or even diminishes in mammals exceeding horse size. We further tested the idea that limb segment length is a factor which determines EMA, by modelling the GRF and muscle moment arms in the extinct giraffidSivatherium giganteumand the other extant giraffidOkapia johnstoni. GiraffaandOkapiashared similar EMA, despite a 4-6 fold difference in body mass (OkapiaEMA = 0.38). In contrastSivatherium, sharing a similar body mass toGiraffa, had greater EMA (0.59), which we propose reflects behavioural differences, such athletic performance. Our modelling approach suggests that limb length is a determinant of GRF moment arm magnitude, and that unless muscle moment arms scale isometrically with limb length, tall mammals are prone to low EMA.Significance StatementGiraffes are the tallest living animals - using their height to access food unavailable to their competitors. It is not clear how their specialized anatomy impacts their athletic ability. We made musculoskeletal models of the forelimbs from a giraffe and two close relatives, and used motion-capture and forceplate data to measure how efficient they are when walking in a straight line. A horse for example, uses just 1 unit of muscle force to oppose 1 unit of force on the ground. Giraffe limbs however are comparatively disadvantaged – their muscles must develop 3 units of force to oppose 1 unit of force at the ground. This explains why giraffes walk and run at relatively slow speeds.
ATXN10 is required for embryonic heart development and maintenance of epithelial cell phenotypes in the adult kidney and pancreas
Authors: Bentley-Ford Melissa R. , Andersen Reagan S. , Croyle Mandy J. , Haycraft Courtney J. , Clearman Kelsey R. , Foote Jeremy B. , Reiter Jeremy F. , Yoder Bradley K. 
Published: April 2021

AbstractAtxn10is a gene known for its role in cytokinesis during the cell cycle and is associated with Spinocerebellar Ataxia (SCA10), a slowly progressing cerebellar syndrome caused by an intragenic pentanucleotide repeat expansion.Atxn10is also implicated in the ciliopathy syndromes Nephronophthisis (NPHP) and Joubert Syndrome (JBTS), which are caused by disruption of cilia function leading to nephron loss, impaired renal function, and cerebellar hypoplasia. HowAtxn10disruption contributes to these disorders remains unknown. Here we generatedAtxn10congenital and conditional mutant mouse models. Our data indicate that while ATXN10 protein can be detected around the base of the cilium as well as in the cytosol, its loss does not cause overt changes in cilia formation or morphology. Congenital loss ofAtxn10results in embryonic lethality around E10.5 associated with pericardial effusion and loss of trabeculation. Similarly, tissue specific loss of ATXN10 in the developing endothelium (Tie2-Cre) and myocardium (cTnT-Cre) also results in embryonic lethality with severe cardiac malformations occurring in the latter. Using an inducible Cagg-CreER to disrupt Atxn10 systemically, we show that ATXN10 is also required for survival in adult mice. Loss of ATXN10 results in severe pancreatic and renal abnormalities leading to lethality within a few weeks post ATXN10 deletion in adult mice. Evaluation of these phenotypes further identified rapid epithelial to mesenchymal transition (EMT) in these tissues. In the pancreas, the phenotype includes signs of both acinar to ductal metaplasia and EMT with aberrant cilia formation and severe defects in glucose homeostasis related to pancreatic insufficiency or defects in feeding or nutrient intake. Collectively this study identifies ATXN10 as an essential protein for survival.
Actin-based myosin XXI (13) molecular motor is involved in early phase ofLeishmaniacytokinesis
Authors: Bajaj Rani , Gupta Chhitar M. 
Published: April 2021

AbstractLeishmaniagenome encodes for two isoforms of myosin, but only Myosin XXI (Myo21), which is a novel form of myosin in that it contains two ubiquitin associated-like (UBA) domains towards the end of its tail structure, is expressed in both the promastigote and amastigote forms of this protozoan. Earlier studies have shown that inLeishmaniapromastigotes Myo21 besides localizing throughout the cell body and flagellum, it is prominently localized to the base of the flagellum. It has further been shown that this protein in the promastigotes plays an important role in regulating the cell morphology, motility, flagellum dynamics, growth and intracellular trafficking, As Myo21 depletion has been shown to result in reduced cell growth in culture, we considered it of interest to investigate whether the observed effect of Myo21 on the cell growth is mediated through its possible role inLeishmaniacell division cycle. For this, we prepared heterozygous Myo21 mutants ofLeishmaniapromastigotes (Myo21+/−cells) and then analyzed their morphology, growth and cell division cycle, using wild typeLeishmaniapromastigotes (Myo21+/+cells) as control. The cell division cycle was analyzed by employing flow cytometry and immunofluorescence microscopy. Flow cytometric analysis revealed that the G2/M to G1 phase transition in Myo21+/−cell is significantly delayed, as compared to Myo21+/+cells. Immunofluorescence confocal microscopic analysis indicated that Myo21+/−cells encountered a significant delay in initiation of cytokinesis, which was mainly due to delay in the flagellar pocket division. Further analysis revealed that actin-based Myo21 motor is essentially required in the initiation phase ofLeishmaniacytokinesis.
Blood vessels regulate primary motor neuronal pathfinding in zebrafish via exosome contained microRNA-22
Authors: Sheng Jiajing , Gong Jie , Shi Yunwei , Wang Xin , Liu Dong 
Published: April 2021

AbstractA precise neuro-vascular communication is crucial to orchestrate directional migration and patterning of the complex vascular network and neural system. However, how blood vessels are involved in shaping the proper neuronal formation has not been fully understood. So far, limited studies have reported the discovery and functions of microRNAs (miRNAs) in guiding vascular and neural pathfinding. Currently, we showed that the deficiency of miRNA-22a, an endothelial-enriched miRNA, caused dramatic pathfinding defects both in intersegmental vessels (ISVs) and primary motor neurons (PMNs) in zebrafish embryos. Furthermore, we found the specific inhibition of miR-22a in ECs resulted in the patterning defects of both ISVs and PMNs. However, neuronal block of miR-22a mainly led to the axonal defects of PMN. Then we demonstrated that endothelial miR-22a regulates PMNs axonal navigation via exosome pathway. Sema4c was identified as a potential target of miR-22a through transcriptomic analysis andin silicoanalysis. Furthermore, luciferase assay and EGFP sensor assayin vivoconfirmed the binding of miR-22a with 3’-UTR ofsema4c. In addition, Down-regulation ofsema4cin the miR-22a morphants significantly neutralized the aberrant patterning of vascular and neural networks. Our study revealed that miR-22a acted as a dual guidance cue coordinating vascular and neuronal patterning and expanded the repertoire of guidance molecules, which might be of use therapeutically to guide vessels and nerves in the relevant diseases that affect both systems.
Cluster Size Distribution of Cells Disseminating from a Primary Tumor
Authors: Mukherjee Mrinmoy , Levine Herbert 
Published: April 2021

AbstractThe first stage of the metastatic cascade often involves motile cells emerging from a primary tumor either as single cells or as clusters. These cells enter the circulation, transit to other parts of the body and finally are responsible for growth of secondary tumors in distant organs. The mode of dissemination is believed to depend on the EMT nature (epithelial, hybrid or mesenchymal) of the cells. Here, we calculate the cluster size distribution of these migrating cells, using a mechanistic computational model, in presence of different degree of EMT-ness of the cells; EMT is treated as given rise to changes in their active motile forces (μ) and cell-medium surface tension (Γ). We find that, for (μ > μmin, Γ > 1), when the cells are hybrid in nature, the mean cluster size,, whereμminincreases with increase in Γ. For Γ ≤ 0,, the cells behave as completely mesenchymal. In presence of spectrum of hybrid states with different degree of EMT-ness (motility) in primary tumor, the cells which are relatively more mesenchymal (higherμ) in nature, form larger clusters, whereas the smaller clusters are relatively more epithelial (lowerμ). Moreover, the heterogeneity inμis comparatively higher for smaller clusters with respect to that for larger clusters. We also observe that more extended cell shapes promote the formation of smaller clusters. Overall, this study establishes a framework which connects the nature and size of migrating clusters disseminating from a primary tumor with the phenotypic composition of the tumor, and can lead to the better understanding of metastasis.Author summaryIn the process of metastasis, tumor cells disseminate from the primary tumor either as single cells or multicellular clusters. These clusters are potential contributor to the initiation of secondary tumor in distant organs. Our computational model captures the size distribution of migrating clusters depending on the adhesion and motility of the cells (which determine the degree of their EMT nature). Furthermore, we investigate the effect of heterogeneity of cell types in the primary tumor on the resultant heterogeneity of cell types in clusters of different sizes. We believe that the understanding the formation and nature of these clusters, dangerous actors in the deadly aspect of cancer progression, will be useful for improving prognostic methods and eventually better treatments.
Genome-wide mutational signatures of immunological diversification in normal lymphocytes
Authors: Machado Heather E , Mitchell Emily , Øbro Nina F , Kübler Kirsten , Davies Megan , Maura Francesco , Leongamornlert Daniel , Sanders Mathijs A. , Cagan Alex , McDonald Craig , Belmonte Miriam , Shepherd Mairi S. , Osborne Robert J. , Mahbubani Krishnaa , Martincorena Iñigo , Laurenti Elisa , Green Anthony R , Getz Gad , Polak Paz , Saeb-Parsy Kourosh , Hodson Daniel J , Kent David , Campbell Peter J 
Published: April 2021

AbstractA lymphocyte suffers many threats to its genome, including programmed mutation during differentiation, antigen-driven proliferation and residency in diverse microenvironments. After developing protocols for single-cell lymphocyte expansions, we sequenced whole genomes from 717 normal naive and memory B and T lymphocytes and hematopoietic stem cells. Lymphocytes carried more point mutations and structural variation than stem cells, accruing at higher rates in T than B cells, attributable to both exogenous and endogenous mutational processes. Ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every one on-targetIGVmutation during the germinal center reaction. Structural variation was 16-fold higher in lymphocytes than stem cells, with ~15% of deletions being attributable to off-target RAG activity.One Sentence Summary:The mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.
Aqnr-plasmid allows aminoglycosides to induce SOS inEscherichia coli
Authors: Babosan Anamaria , Skurnik David , Muggeo Anaëlle , Pier Gerald B. , Baharoglu Zeynep , Jové Thomas , Ploy Marie-Cécile , Griveau Sophie , Bedioui Fethi , Vergnolle Sébastien , Moussalih Sophie , de Champs Christophe , Mazel Didier , Guillard Thomas 
Published: April 2021

AbstractThe plasmid-mediated quinolone resistance (PMQR) genes have been shown to promote high-level bacterial resistance to fluoroquinolone antibiotics, potentially leading to clinical treatment failures.InEscherichia coli, sub-inhibitory concentrations (sub-MIC) of the widely used fluoroquinolones are known to induce the SOS response. Interestingly, the expression of several PMQRqnrgenes is controlled by the SOS master regulator.During the characterization of a smallqnrD-plasmid carried inE. coli,we observed that the aminoglycosides become able to induce the SOS response in this species, thus leading to the transcription ofqnrD.We found that induction of the SOS response is due to nitric oxide (NO) accumulation in presence of sub-MIC of aminoglycosides. We demonstrated that the NO accumulation is driven by two plasmid genes, ORF3 and ORF4, whose products act at two levels. ORF3 encode aFAD-binding oxidoreductase which helps NO synthesis, while ORF4 code for anFNR-type transcription factor, related to an O2-responsive regulator ofhmpexpression, able to repress the Hmp-mediated NO detoxification pathway ofE. coli.Thus, this discovery, that other major classes of antibiotics may induce the SOS response could have worthwhile implications for antibiotic stewardship efforts in preventing the emergence of resistance.
UnderstandingLactobacillus paracaseiandStreptococcus oralisbiofilm interactions through agent-based modeling
Authors: Archambault Linda , Koshy-Chenthittayil Sherli , Thompson Angela , Dongari-Bagtzoglou Anna , Laubenbacher Reinhard , Mendes Pedro 
Published: April 2021

ABSTRACTAs common commensals residing on mucosal tissues,Lactobacillusspecies are known to encourage health, while recent findings highlight the pathogenic roles ofStreptococcusspecies in these environments. In this study we used a combination ofin vivoimaging experiments and computational modeling to explore biofilm interactions betweenStreptococcus oralis, an accessory pathogen in oral Candidiasis, andLactobacillus paracasei, an organism with known probiotic properties. A computational agent-based model was created where the two species only interact by competing for space and nutrients. Quantification of bacterial growth in live biofilms indicated thatS. oralisbiomass and cell numbers were much lower than predicted by the model. Two subsequent models were then created to examine more complex interactions between these species, one whereL. paracaseisecretes a surfactant, and another whereL. paracaseisecretes an inhibitor ofS. oralisgrowth. Further biofilm experiments support the hypothesis thatL. paracaseimay secrete an inhibitor ofS. oralisgrowth, although they do not exclude that a surfactant could also be involved. This contribution shows how agent-based modeling and experiments can be used in synergy to address multiple species biofilm interactions, with important roles in mucosal health and disease.IMPORTANCEWe previously discovered a role of the oral commensalStreptococcus oralisas an accessory pathogen.S. oralisincreases the virulence ofCandida albicansinfections in murine oral candidiasis and epithelial cell models through mechanisms which promote the formation of tissue-damaging biofilms.Lactobacillusspecies have known inhibitory effects on biofilm formation of many microbes, includingStreptococcusspecies. Agent-based modeling has great advantages as a means of exploring multifaceted relationships between organisms in complex environments such as biofilms. Here we used an iterative collaborative process between experimentation and modeling to reveal aspects of the mostly unexplored relationship betweenS. oralisandL. paracaseiin biofilm growth. The inhibitory nature ofL. paracaseionS. oralisin biofilms may be exploited as a means of preventing or alleviating mucosal fungal infections.
Early life stress affects the miRNA cargo in epididymal extracellular vesicles in mouse
Authors: Alshanbayeva Anar , Tanwar Deepak K. , Roszkowski Martin , Manuella Francesca , Mansuy Isabelle M. 
Published: April 2021

AbstractSperm RNA can be modified by environmental factors and has been implicated in communicating signals about changes in a father’s environment to the offspring. The RNA composition of sperm is influenced during its final stage of maturation in the epididymis by extracellular vesicles released by epididymal cells. We studied the effect of exposure to stress in postnatal life on the transcriptome of epididymal extracellular vesicles using a mouse model of transgenerational transmission. We found that the small RNA signature of epididymal extracellular vesicles, particularly miRNAs, is altered in adult males exposed to postnatal stress. miRNAs changes correlate with differences in the expression of their target genes in sperm and zygotes generated from that sperm. These results suggest that stressful experiences in early life can have persistent biological effects on the male reproductive tract that may in part be responsible for the transmission of the effects of exposure to the offspring.Summary SentencemiRNA cargo of extracellular vesicles in cauda epididymis is changed by paternal exposure to early life stress, which correlates with differences in the expression of their target genes in sperm and zygotes generated from that sperm
WGDI: A user-friendly toolkit for evolutionary analyses of whole-genome duplications and ancestral karyotypes
Authors: Sun Pengchuan , Jiao Beibei , Yang Yongzhi , Shan Lanxing , Li Ting , Li Xiaonan , Xi Zhenxiang , Wang Xiyin , Liu Jianquan 
Published: April 2021

AbstractEvidence of whole-genome duplications (WGDs) and subsequent karyotype changes has been detected in most major lineages of life on Earth. To clarify the complex resulting multiple-layered patterns of gene collinearity in genome analyses there is a need for convenient and accurate toolkits. To meet this need, we introduce here WGDI (Whole-GenomeDuplicationIntegrated analysis), a Python-based command-line tool that facilitates comprehensive analysis of recursive polyploidizations and cross-species genome alignments. WGDI supports three main workflows (polyploid inference, hierarchical inference of genomic homology, and ancestral chromosomal karyotyping) that can improve detection of WGD and characterization of related events. It incorporates a more sensitive and accurate collinearity detection algorithm than previous softwares, and can accelerate WGD-related karyotype research. As a freely available toolkit at GitHub (https://github.com/SunPengChuan/wgdi), WGDI outperforms similar tools in terms of efficiency, flexibility and scalability. In an illustrative example of its application, WGDI convincingly clarified karyotype evolution inAquilegia coeruleaandVitis viniferafollowing WGDs and rejected the hypothesis thatAquilegiacontributed as a parental lineage to the allopolyploid origin of core dicots.
Melbournevirus-encoded histone doublets are recruited to virus particles and form destabilized nucleosome-like structures
Authors: Liu Yang , Toner Chelsea Marie , Philippe Nadege , Jeudy Sandra , Zhou Keda , Bowerman Samuel , White Alison , Edwards Garrett , Abergel Chantal , Luger Karolin 
Published: April 2021

SummaryThe organization of genomic DNA into defined nucleosomes has long been viewed as a hallmark of eukaryotes. This paradigm has been challenged by the identification of ‘minimalist’ histones in archaea, and more recently by the discovery of genes that encode fused remote homologs of the four eukaryotic histones inMarseilleviridae, a subfamily of giant viruses that infect amoebae. We demonstrate that viral doublet histones localize to the cytoplasmic viral factories after virus infection, and ultimately to mature virions. CryoEM structures of viral nucleosome-like particles show strong similarities to eukaryotic nucleosomes, despite the limited sequence identify. The unique connectors that link the histone chains contribute to the observed instability of viral nucleosomes, and some histone tails assume structural roles. Our results further expand the range of ‘organisms’ that have nucleosomes and suggest a specialized function of histones in the biology of these unusual viruses.One Sentence SummarySome large DNA viruses encode fused histone doublets that are targeted to viral factories and assemble into open nucleosome-like structures.