bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lamin A/C functions independently from mechanical signaling during adipogenesis
Authors: Goelzer Matthew , Dudakovic Amel , Olcum Melis , Sen Buer , Ozcivici Engin , Rubin Janet , van Wijnen Andre J , Uzer Gunes 
Published: September 2020

AbstractMesenchymal stem cells (MSC) maintain the musculoskeletal system by differentiating into multiple cell types including osteocytes and adipocytes. Mechanical signals, including strain and low intensity vibration (LIV), are important regulators of MSC differentiation. Lamin A/C is a vital protein for nuclear architecture that supports chromatin organization, as well as mechanical integrity and mechano-sensitivity of the nucleus in MSCs. Here, we investigated whether Lamin A/C and mechano-responsiveness are functionally coupled during adipogenesis. Lamin depletion in MSCs using siRNA increased nuclear area, height and volume and decreased circularity and stiffness, while phosphorylation of focal adhesions and dynamic substrate strain in response to LIV remained intact. Lamin A/C depletion decelerates adipogenesis as reflected by delayed appearance of key biomarkers (e.g., adiponectin/ADIPOQ). Based on RNA-seq data, reduced Lamin A/C levels decrease the activation of the adipocyte transcriptome that is normally observed in response to adipogenic cues mediating differentiation of MSCs. Mechanical stimulation via daily LIV application reduced the expression levels of ADIPOQ in both control and Lamin A/C depleted cells. Yet, treatment with LIV did not induce major transcriptome changes in either control or Lamin A/C depleted MSCs, suggesting that the biological effects of LIV on adipogenesis may not occur at the transcriptional level. We conclude that while Lamin A/C activation is essential for normal adipogenesis, it is dispensible for activation of focal adhesions by dynamic vibration induced mechanical signals.
The ontogeny of multisensory peripersonal space in human infancy: From visual-tactile links to conscious expectations
Authors: Orioli Giulia , Parisi Irene , van Velzen José L. , Bremner Andrew J. 
Published: September 2020

AbstractThe influence of visual object motion on the processing of bodily events offers a marker for the development of human infants’ perception of themselves in peripersonal space. We presented 4- (n = 20) and 8-month-old (n = 20) infants with an unattended visual object moving towards or away from their body followed by a vibrotactile stimulus on their hands. The 4-month-olds’ somatosensory evoked potentials (SEPs) were modulated by approaching visual motion, demonstrating the early ontogeny of the cortical multisensory foundations of peripersonal space representations. We also observed rapid changes in these markers within the 8-month-old age group: as infants approach 9 months, salient SEP components were increasingly enhanced by (unexpected) tactile stimuli following receding visual motion. These findings provide important clues to the ontogeny of human self-awareness in the first year of life, and suggest important postnatal developments in infants’ expectations about interactions between the body and the external world.
Generating single-sex litters: development of CRISPR-Cas9 genetic tools to produce all-male offspring
Authors: Douglas Charlotte , Maciulyte Valdone , Zohren Jasmin , Snell Daniel M. , Ojarikre Obah A. , Ellis Peter J.I. , Turner James M.A. 
Published: September 2020

AbstractAnimals are extremely useful genetic tools in science and global resources in agriculture. However, a single sex is often required in surplus, and current genetic methods for producing all-female or all-male litters are inefficient. Using the mouse as a model, we developed a synthetic, two-part bicomponent strategy for generating all-male litters. We achieved this using CRISPR-Cas9 genome editing technology to generate large stable knock-ins on the autosomes and X chromosome. The bicomponent system functions via the sex-specific co-inheritance of a Cas9 transgene and an sgRNA transgene targeting the essentialTopoisomerase 1gene. This technology proved to be highly efficient in generating on-target mutations, resulting in embryonic lethality of the target sex. Our study is the first to successfully generate all-male mammalian litters using a CRISPR-Cas9 bicomponent system and provides great strides towards generating single-sex litters for laboratory or agricultural research.
The role of Anti-Mullerian hormone in predicting fertilization and pregnancy rates following in vitro fertilization-embryo transfer (IVF-ET) and intracytoplasmic sperm injection (ICSI) cycles at a public fertility centre in Nigeria
Authors: Usman Safiyya Faruk , Ladipo Olubunmi Peter , Momoh J.A.F , Agboghoroma Chris Ovoroyeguono , Abubakar Nabila Datti 
Published: September 2020

AbstractObjectiveTo determine the role of Anti-Mullerian Hormone (AMH) in predicting fertilization and pregnancy rates following in vitro fertilization-embryo transfer (IVF-ET) and intracytoplasmic sperm injection (ICSI) treatment cycles.MethodsThis was a prospective cohort study of one hundred and fifty consecutive women undergoing IVF-ET/ICSI that were recruited from February 1, 2017 to October 31, 2018 at the Fertility centre of the National Hospital, Abuja, Nigeria. Participants’ plasma AMH were assayed and were followed up till achieving fertilization and pregnancy. Association between AMH levels, fertilization and pregnancy rates was assessed using univariable and multivariable logistic regression modelling to adjust for confounding variables.ResultsThe mean age and mean AMH level of the participants were 36 ± 4.2 years and 1.74 ± 2.35ng/ml respectively. There was a statistically significant association between AMH level and age (P <0.001), duration of infertility (P =0.026), cause of infertility (P =0.035), number of oocytes retrieved (P =<0.001), number of embryos generated (P =<0.001) and type of treatment (P =<0.001). However, there was no significant difference in the fertilization rates (adjusted odds ratio [AdjOR] 0.36, 95% confidence interval [CI] 0.23–4.30; P =0.533) and pregnancy rates (AdjOR 0.26, 95% CI 0.04–2.00; P =0.210) at different plasma levels of AMH.ConclusionPlasma AMH level was not a predictor of fertilization and pregnancy rates among our cohort of patients who had IVF/ICSI treatment cycles.
Plasmodium falciparumguanylyl cyclase-alpha and the activity of its appended P4-ATPase domain are essential for cGMP synthesis and blood stage egress
Authors: Nofal Stephanie D. , Patel Avnish , Blackman Michael J. , Flueck Christian , Baker David A. 
Published: September 2020

AbstractIn malaria parasites, guanylyl cyclases (GCs), which synthesise cyclic GMP (cGMP), are associated with a P4-ATPase-like domain in a unique bifunctional configuration. P4-ATPases generate membrane bilayer lipid asymmetry by translocating phospholipids from the outer to the inner leaflet. Here we investigate the role ofPlasmodium falciparumguanylyl cyclase alpha (GCα) and its associated P4-ATPase module, showing that asexual blood stage parasites lacking both the cyclase and P4-ATPase domains are unable to egress from host erythrocytes. GCα-null parasites cannot synthesise cGMP, or mobilise calcium, a cGMP-dependent protein kinase (PKG)-driven requirement for egress. Using chemical complementation with a cGMP analogue and point mutagenesis of a crucial conserved residue within the P4-ATPase domain, we show that ATPase activity is up stream of and linked to cGMP synthesis. Collectively, our results demonstrate that GCα is a critical regulator of PKG and that its associated P4-ATPase domain plays a primary role in generating cGMP for merozoite egress.
The structural basis of the oncogenic mutant K-Ras4B homodimers
Authors: Kosoglu Kayra , Omur Meltem Eda , Jang Hyunbum , Nussinov Ruth , Keskin Ozlem , Gursoy Attila 
Published: September 2020

AbstractRas proteins activate their effectors through physical interactions in response to the various extracellular stimuli at the plasma membrane. Oncogenic Ras forms dimer and nanoclusters at the plasma membrane, boosting the downstream MAPK signal. It was reported that K-Ras4B can dimerize through two major interfaces: (i) the effector lobe interface, mapped to Switch I and effector binding regions; (ii) the allosteric lobe interface involving α3 and α4 helices. Recent experiments showed that constitutively active, oncogenic mutant K-Ras4BG12Ddimers are enriched in the plasma membrane. Here, we perform molecular dynamics simulations of K-Ras4BG12Dhomodimers aiming to quantify the two major interfaces in atomic level. To examine the effect of mutations on dimerization, two double mutations, K101D/R102E on the allosteric lobe and R41E/K42D on the effector lobe interfaces were added to the K-Ras4BG12Ddimer simulations. We observed that the effector lobe K-Ras4BG12Ddimer is stable, while the allosteric lobe dimer alters its helical interface during the simulations, presenting multiple conformations. The K101D/R102E mutations slightly weakens the allosteric lobe interface. However, the R41E/K42D mutations disrupt the effector lobe interface. Using the homo-oligomers prediction server, we obtained trimeric, tetrameric, and pentameric complexes with the allosteric lobe K-Ras4BG12Ddimers. However, the allosteric lobe dimer with the K101D/R102E mutations is not capable of generating multiple higher order structures. Our detailed interface analysis may help to develop inhibitor design targeting functional Ras dimerization and high order oligomerization at the membrane signaling platform.
Exploratory polarization facilitates mating partner selection inSaccharomyces cerevisiae
Authors: Clark-Cotton Manuella R. , Henderson Nicholas T. , Pablo Michael , Ghose Debraj , Elston Timothy C. , Lew Daniel J. 
Published: September 2020

AbstractYeast decode pheromone gradients to locate mating partners, providing a model for chemotropism. How yeast polarize toward a single partner in crowded environments is unclear. Initially, cells often polarize in unproductive directions, but then they relocate the polarity site until two partners’ polarity sites align, whereupon the cells “commit” to each other by stabilizing polarity to promote fusion. Here we address the role of the early mobile polarity sites. We found that commitment by either partner failed if just one partner was defective in generating, orienting, or stabilizing its mobile polarity sites. Mobile polarity sites were enriched for pheromone receptors and G proteins, and we suggest that such sites engage in an exploratory search of the local pheromone landscape, stabilizing only when they detect elevated pheromone levels. Mobile polarity sites were also enriched for pheromone secretion factors, and simulations suggest that only focal secretion at polarity sites would produce high pheromone concentrations at the partner’s polarity site, triggering commitment.
The SARS-CoV-2 multibasic cleavage site facilitates early serine protease-mediated entry into organoid-derived human airway cells
Authors: Mykytyn Anna Z. , Breugem Tim I. , Riesebosch Samra , Schipper Debby , van den Doel Petra B. , Rottier Robbert J. , Lamers Mart M. , Haagmans Bart L. 
Published: September 2020

AbstractAfter the SARS-CoV outbreak in 2003, a second zoonotic coronavirus named SARS-CoV-2, emerged late 2019 in China and rapidly caused the COVID-19 pandemic leading to a public health crisis of an unprecedented scale. Despite the fact that SARS-CoV-2 uses the same receptor as SARS-CoV, transmission and pathogenesis of both viruses seem to be quite distinct. A remarkable feature of the SARS-CoV-2 spike is the presence of a multibasic cleavage site, which is absent in the SARS-CoV spike. The viral spike protein not only attaches to the entry receptor, but also mediates fusion after cleavage by host proteases. Here, we report that the SARS-CoV-2 spike multibasic cleavage site increases infectivity on differentiated organoid-derived human airway cells. Compared with SARS-CoV, SARS-CoV-2 entered faster into the lung cell line Calu-3, and more frequently formed syncytial cells in differentiated organoid-derived human airway cells. Moreover, the multibasic cleavage site increased entry speed and plasma membrane serine protease usage relative to endosomal entry using cathepsins. Blocking serine protease activity using the clinically approved drug camostat mesylate effectively inhibited SARS-CoV-2 entry and replication in differentiated organoid-derived human airway cells. Our findings provide novel information on how SARS-CoV-2 enters relevant airway cells and highlight serine proteases as an attractive antiviral target.Significance StatementHighly pathogenic coronaviruses have spilled from animals to humans three times in the past two decades. Late 2019, SARS-CoV-2 emerged in China and was declared a pandemic by March 2020. The other two highly pathogenic coronaviruses, SARS-CoV and MERS-CoV, emerged in 2002 and 2012, respectively, but did not attain sustained human-to-human transmission. Given the high diversity of coronaviruses in animals, urbanization and increased air travel, future coronavirus pandemics are likely to occur intermittently. Identifying which factors determine pandemic potential and pathogenicity are therefore of key importance to global health. Additionally, there is an urgent need to rapidly translate fundamental knowledge to the clinic, a process that is expedited through the use of relevant cell culture systems.
Vimentin intermediate filaments mediate cell shape on visco-elastic substrates
Authors: Swoger Maxx , Gupta Sarthak , Charrier Elisabeth E. , Bates Michael , Hehnly Heidi , Patteson Alison E. 
Published: September 2020

AbstractThe ability of cells to take and change shape is a fundamental feature underlying development, wound repair, and tissue maintenance. Central to this process is physical and signaling interactions between the three cytoskeletal polymeric networks: F-actin, microtubules, and intermediate filaments (IFs). Vimentin is an IF protein that is essential to the mechanical resilience of cells and regulates cross-talk amongst the cytoskeleton, but its role in how cells sense and respond to the surrounding extracellular matrix is largely unclear. To investigate vimentin’s role in substrate sensing, we designed polyacrylamide hydrogels that mimic the elastic and viscoelastic nature of in vivo tissues. Using wild-type and vimentin-null mouse embryonic fibroblasts, we show that vimentin enhances cell spreading on viscoelastic substrates, even though it has little effect in the limit of purely elastic substrates. Our results provide compelling evidence that the vimentin cytoskeletal network is a physical modulator of how cells sense and respond to mechanical properties of their extracellular environment.
Loss ofPrdm12during development, but not in mature nociceptors, causes defects in pain sensation
Authors: Landy Mark A. , Goyal Megan , Casey Katherine M. , Liu Chen , Lai Helen C. 
Published: September 2020

SummaryPrdm12is as a key transcription factor in nociceptor neurogenesis. Mutations ofPrdm12cause Congenital Insensitivity to Pain (CIP) due to failure of nociceptor development. However, precisely how deletion ofPrdm12during development or adulthood affects nociception is unknown. Here, we employ tissue- and temporal-specific knockout mouse models to test the function ofPrdm12during development and in adulthood. We find that constitutive loss ofPrdm12causes deficiencies in proliferation during sensory neurogenesis. We also demonstrate that conditional knockout from dorsal root ganglia (DRGs) during embryogenesis causes defects in nociception. In contrast, we find that in adult DRGs,Prdm12is dispensable for pain sensation and injury-induced hypersensitivity. Using transcriptomic analysis, we found unique changes in adultPrdm12knockout DRGs compared to embryonic knockout, and that PRDM12 is likely a transcriptional activator in the adult. Overall, we find that the function of PRDM12 changes over developmental time.
Plasmodium vinckei genomes provide insights into the pan-genome and evolution of rodent malaria parasites
Authors: Ramaprasad Abhinay , Klaus Severina , Douvropoulou Olga , Culleton Richard , Pain Arnab 
Published: September 2020

AbstractBackgroundRodent malaria parasites (RMPs) serve as tractable tools to study malaria parasite biology and host-parasite-vector interactions. Plasmodium vinckei is the most geographically widespread of the four RMP species collected in sub-Saharan Central Africa. Several P. vinckei isolates are available but relatively less characterized than other RMPs, thus hindering their use in experimental studies. We have generated a comprehensive resource for P. vinckei comprising of high-quality reference genomes, genotypes, gene expression profiles and growth phenotypes for ten P. vinckei isolates.ResultsThe P. vinckei subspecies have diverged widely from their common ancestor and have undergone genomic structural variations. The subspecies from Katanga, P. v. vinckei, has a uniquely smaller genome, a reduced multigene family repertoire and is also amenable to genetic manipulation making it an ideal parasite for reverse genetics. Comparing P. vinckei genotypes reveals region-specific selection pressures particularly on genes involved in mosquito transmission. The erythrocyte membrane antigen 1 and fam-c families have expanded considerably among the lowland forest-dwelling P. vinckei parasites. Genetic crosses can be established in P. vinckei but are limited at present by low transmission success under the experimental conditions tested in this study.ConclusionsPlasmodium vinckei isolates display a large degree of phenotypic and genotypic diversity and could serve as a resource to study parasite virulence and immunogenicity. Inclusion of P. vinckei genomes provide new insights into the evolution of RMPs and their multigene families. Amenability to genetic crossing and genetic manipulation make them also suitable for classical and functional genetics to study Plasmodium biology.
Reconstructing the history of founder events using genome-wide patterns of allele sharing across individuals
Authors: Tournebize Rémi , Chu Gillian , Moorjani Priya 
Published: September 2020

AbstractFounder events play a critical role in shaping genetic diversity, impacting the fitness of a species and disease risk in humans. Yet our understanding of the prevalence and distribution of founder events in humans and other species remains incomplete, as most existing methods for characterizing founder events require large sample sizes or phased genomes. To learn about the frequency and evolutionary history of founder events, we introduceASCEND(Allele Sharing Correlation for the Estimation of Non-equilibrium Demography), a flexible two-locus method to infer the age and strength of founder events. This method uses the correlation in allele sharing across the genome between pairs of individuals to recover signatures of past bottlenecks. By performing coalescent simulations, we show thatASCENDcan reliably estimate the parameters of founder events under a range of demographic scenarios, with genotype or sequence data. We applyASCENDto ~5,000 worldwide human samples (~3,500 present-day and ~1,500 ancient individuals), and ~1,000 domesticated dog samples. In both species, we find pervasive evidence of founder events in the recent past. In humans, over half of the populations surveyed in our study had evidence for a founder events in the past 10,000 years, associated with geographic isolation, modes of sustenance, and historical invasions and epidemics. We document that island populations have historically maintained lower population sizes than continental groups, ancient hunter-gatherers had stronger founder events than Neolithic Farmers or Steppe Pastoralists, and periods of epidemics such as smallpox were accompanied by major population crashes. Many present-day groups--including Central & South Americans, Oceanians and South Asians--have experienced founder events stronger than estimated in Ashkenazi Jews who have high rates of recessive diseases due to their history of founder events. In dogs, we uncovered extreme founder events in most groups, more than ten times stronger than the median strength of founder events in humans. These founder events occurred during the last 25 generations and are likely related to the establishment of dog breeds during Victorian times. Our results highlight a widespread history of founder events in humans and dogs, and provide insights about the demographic and cultural processes underlying these events.
The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics
Authors: Giblin William , Bringman-Rodenbarger Lauren , Guo Angela H. , Kumar Surinder , Monovich Alexander C. , Mostafa Ahmed M. , Skinner Mary E. , Azar Michelle , Mady Ahmed S.A. , Chung Carolina H. , Kadambi Namrata , Melong Keith-Allen , Lee Ho-Joon , Zhang Li , Sajjakulnukit Peter , Trefely Sophie , Varner Erika L. , Iyer Sowmya , Wang Min , Wilmott James S. , Soyer H. Peter , Sturm Richard A. , Pritchard Antonia L. , Andea Aleodor , Scolyer Richard A. , Stark Mitchell S. , Scott David A. , Fullen Douglas R. , Bosenberg Marcus W. , Chandrasekaran Sriram , Nikolovska-Coleska Zaneta , Verhaegen Monique E. , Snyder Nathaniel W. , Rivera Miguel N. , Osterman Andrei L. , Lyssiotis Costas A. , Lombard David B. 
Published: September 2020

AbstractCutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieves a durable remission. SIRT5 is a member of the sirtuin family of protein deacylases that regulate metabolism and other biological processes. GermlineSirt5deficiency is associated with mild phenotypes in mice. Here we show that SIRT5 is required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye and is incurable once metastatic. Likewise, SIRT5 is required for efficient tumor formation by melanoma xenografts and in an autochthonous mouseBraf;Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we find that SIRT5 is required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably includeMITF, a key lineage-specific survival oncogene in melanoma, and thec-MYCproto-oncogene. SIRT5 may represent a novel, druggable genotype-independent addiction in melanoma.
Leading the innovation: role of trust and job crafting as sequential mediators relating servant leadership and innovative work behavior
Authors: Khan Muhammad Mumtaz , Mubarik Muhammad Shujaat , Islam Tahir 
Published: September 2020

PurposeThe purpose of the study is to ascertain the role of servant leadership in causing innovative work behavior. The study also examines the mediating role of job crafting and sequential mediating role of trust and job crafting between servant leadership and innovative work behavior.Design/methodology/approachThe data were collected from 258 knowledge workers employed in software houses in Pakistan through survey design. The data analysis was done through structural equation modeling.FindingsThe results of the analysis of 258 respondents show that servant leadership is related with trust, job crafting and innovative work behavior. The mediation analysis revealed that job crafting mediates the relation between servant leadership and innovative work behavior. Finally, the relation between servant leadership and innovative work behavior was found to be sequentially mediated by trust and job crafting.Originality/valueThe current study contributes to delineating the linking mechanism between servant leadership and innovative work behavior. The main contributions of the study are exploring the mediating role of job crafting along with the sequential mediating role of trust and job crafting.