bluuebunny/crossref_metadata_2025_split huggingface dataset:
Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model
Authors: Driouich Jean-Sélim , Cochin Maxime , Lingas Guillaume , Moureau Grégory , Touret Franck , Petit Paul Rémi , Piorkowski Géraldine , Barthélémy Karine , Coutard Bruno , Guedj Jérémie , de Lamballerie Xavier , Solas Caroline , Nougairède Antoine 
Published: July 2020

AbstractDespite no or limited pre-clinical evidence, repurposed drugs are massively evaluated in clinical trials to palliate the lack of antiviral molecules against SARS-CoV-2. Here we used a Syrian hamster model to assess the antiviral efficacy of favipiravir, understand its mechanism of action and determine its pharmacokinetics. When treatment was initiated before or simultaneously to infection, favipiravir had a strong dose effect, leading to dramatic reduction of infectious titers in lungs and clinical alleviation of the disease. Antiviral effect of favipiravir correlated with incorporation of a large number of mutations into viral genomes and decrease of viral infectivity. The antiviral efficacy observed in this study was achieved with plasma drug exposure comparable with those previously found during human clinical trials and was associated with weight losses in animals. Thereby, pharmacokinetic and tolerance studies are required to determine whether similar effects can be safely achieved in humans.
Imaging LexA degradation in cells explains regulatory mechanisms and heterogeneity of the SOS response
Authors: Jones Emma C. , Uphoff Stephan 
Published: July 2020

ABSTRACTThe SOS response functions as the central regulator of DNA repair and mutagenesis in most bacteria and stands as a paradigm of gene networks controlled by a master transcriptional regulator, LexA. We developed a single-molecule imaging approach to directly monitor the LexA repressor inside liveEscherichia colicells, demonstrating key mechanisms by which DNA-binding and degradation of LexA regulates the SOS responsein vivo.Our approach revealed that self-cleavage of LexA occurs frequently during unperturbed growth and causes substantial heterogeneity in LexA abundances across cells. LexA variability underlies SOS gene expression heterogeneity and triggers spontaneous SOS pulses, which enhance bacterial survival in anticipation of stress.
Insights into the genomic evolution of insects from cricket genomes
Authors: Ylla Guillem , Nakamura Taro , Itoh Takehiko , Kajitani Rei , Toyoda Atsushi , Tomonari Sayuri , Bando Tetsuya , Ishimaru Yoshiyasu , Watanabe Takahito , Fuketa Masao , Matsuoka Yuji , Barnett Austen A. , Noji Sumihare , Mito Taro , Extavour Cassandra G. 
Published: July 2020

AbstractMost of our knowledge of insect genomes comes from Holometabolous species, which undergo the complete metamorphosis and have genomes under 2Gb with little signs of DNA methylation. In contrast, Hemiemetabolous insects undergo the ancestral incomplete metamorphosis and have larger genomes with high levels of DNA methylation. Hemimetabolous species from the Orthopteran order (grasshoppers and crickets) have some of the largest insect genomes. What drives the evolution of these unusual insect genome sizes, remains unknown. Here we report the sequencing, assembly and annotation of the 1.66-Gb genome of the Mediterranean field cricketGryllus bimaculatus, and the annotation of the 1.60-Gb genome of the Hawaiian cricketLaupala kohalensis.We compare these two cricket genomes with those of 14 additional insects, and find evidence that hemimetabolous genomes expanded due to transposable element activity. Based on the ratio of observed to expected CpG sites, we find higher conservation and stronger purifying selection of methylated genes than non-methylated genes. Finally, our analysis suggests an expansion of thepickpocketclass V gene family in crickets, which we speculate might play a role in the evolution of cricket courtship, including their characteristic chirping.
Quantitative benzimidazole resistance and fitness effects of parasitic nematode beta-tubulin alleles
Authors: Dilks Clayton M. , Hahnel Steffen R. , Sheng Qicong , Long Lijiang , McGrath Patrick T. , Andersen Erik C. 
Published: July 2020

AbstractInfections by parasitic nematodes inflict a huge burden on the health of humans and livestock throughout the world. Anthelmintic drugs are the first line of defense against these infections. Unfortunately, resistance to these drugs is rampant and continues to spread. To improve treatment strategies, we must understand the genetics and molecular mechanisms that underlie resistance. Studies of the fungusAspergillus nidulansand the free-living nematodeCaenorhabditis elegansdiscovered that a beta-tubulin gene is mutated in benzimidazole (BZ) resistant strains. In parasitic nematode populations, three canonical beta-tubulin alleles, F200Y, E198A, and F167Y, have long been correlated with resistance. Additionally, improvements in sequencing technologies have identified new alleles - E198V, E198L, E198K, E198I, and E198Stop - also correlated with BZ resistance. However, none of these alleles have been proven to cause resistance. To empirically demonstrate this point, we independently introduced the three canonical alleles as well as two of the newly identified alleles, E198V and E198L, into the BZ susceptibleC. elegansN2 genetic background. These genome-edited strains were exposed to both albendazole and fenbendazole to quantitatively measure animal responses to BZs. We used a range of doses for each BZ compound to define response curves and found that all five of the alleles conferred resistance to BZ compounds equal to a loss of the entire beta-tubulin gene. These results prove that the parasite beta-tubulin alleles cause resistance. The E198V allele is found at low frequencies in natural parasite populations, suggesting that it could affect fitness. We performed competitive fitness assays and demonstrated that the E198V allele reduces animal health, supporting the hypothesis that this allele is less fit in field populations. Overall, we present a powerful platform to quantitatively assess anthelmintic resistance and effects of specific resistance alleles on organismal fitness in the presence or absence of the drug.HighlightsAll three canonical parasitic nematode beta-tubulin alleles (F167Y, E198A, F200Y) and two newly identified alleles (E198V, E198L) confer equal levels of benzimidazole resistance in a defined genetic background using single-generation, high-replication drug response assays.Beta-tubulin variants are strongly selected in albendazole conditions in multigenerational competitive fitness assays, but these alleles confer different levels of benzimidazole resistance over time.Only the E198V allele confers a fitness cost in control (non-benzimidazole) conditions as compared to all other tested beta-tubulin alleles, suggesting that this intermediate allele might only be found in field populations at low frequency because it causes reduced fitness.Graphical Abstract
Repeated loss of variation in insect ovary morphology highlights the role of developmental constraint in life-history evolution
Authors: Church Samuel H. , de Medeiros Bruno A. S. , Donoughe Seth , Márquez Reyes Nicole L. , Extavour Cassandra G. 
Published: July 2020

AbstractThe number of offspring an organism can produce is a key component of its evolutionary fitness and life-history. Here we perform a test of the hypothesized trade off between the number and size of offspring using thousands of descriptions of the number of egg-producing compartments in the insect ovary (ovarioles), a common proxy for potential offspring number in insects. We find evidence of a negative relationship between egg size and ovariole number when accounting for adult body size. However in contrast to prior claims, we note that this relationship is not generalizable across all insect clades, and we highlight several factors that may have contributed to this size-number trade off being stated as a general rule in previous studies. We reconstruct the evolutionary history of the nurse cell arrangement within the ovariole, and show that the diversification of ovariole number and egg size have both been largely independent of nurse cell presence or position within the ovariole. Instead we show that ovariole number evolution has been shaped by a series of transitions between variable and invariant states, with multiple independent lineages evolving to have almost no variation in ovariole number. We highlight the implications of these invariant lineages on our understanding of the specification of ovariole number during development, as well as the importance of considering developmental processes in theories of life-history evolution.
ATP-Citrate lyase fuels axonal transport across species
Authors: Even Aviel , Morelli Giovanni , Le Bail Romain , Shilian Michal , Turchetto Silvia , Broix Loïc , Brandis Alexander , Inbar Shani , Chariot Alain , Saudou Frédéric , Dietrich Paula , Dragatsis Ioannis , Brone Bert , Rigo Jean-Michel , Weil Miguel , Nguyen Laurent 
Published: July 2020

AbstractMicrotubule (MT)-based transport is an evolutionary conserved processed finely tuned by posttranslational modifications. Among them, α-tubulin acetylation, which is catalyzed by the α-tubulin N-acetyltransferase 1, Atat1, promotes the recruitment and processivity of molecular motors along MT tracks. However, the mechanisms that controls Atat1 activity remains poorly understood. Here, we show that a pool of vesicular ATP-citrate lyase Acly acts as a rate limiting enzyme to modulate Atat1 activity by controlling availability of Acetyl-Coenzyme-A (Acetyl-CoA). In addition, we showed that Acly expression is reduced upon loss of Elongator activity, further connecting Elongator to Atat1 in the pathway regulatingα-tubulin acetylation and MT-dependent transport in projection neurons, across species. Remarkably, comparable defects occur in fibroblasts from Familial Dysautonomia (FD) patients bearing an autosomal recessive mutation in the gene coding for the Elongator subunit ELP1. Our data may thus shine new light on the pathophysiological mechanisms underlying FD.
Survival of the salient: Emotion rescues otherwise forgettable memories via neural reactivation and post-encoding hippocampal connectivity
Authors: Clewett David , Dunsmoor Joseph , Bachman Shelby , Phelps Elizabeth , Davachi Lila 
Published: July 2020

AbstractEmotion’s selective effects on memory go beyond the simple enhancement of threatening or rewarding stimuli. They can also rescue otherwise forgettable memories that share overlapping features. Here, we use functional magnetic resonance imaging (fMRI) to examine the brain mechanisms that support this retrograde memory enhancement. In a two-phase incidental encoding paradigm, participants first view images of neutral tools and animals. During Phase 1, these images are intermixed with neutral scenes, which provides a unique ‘context tag’ for this specific phase of encoding. A few minutes later, during Phase 2, new pictures from one category are paired with a mild shock (fear-conditioned stimulus; CS+), while pictures from the other category are not shocked. fMRI analyses reveal that, across participants, retroactive memory benefits for Phase 1 CS+ items are associated with greater phasic reinstatement of the prior mental context during Phase 2 CS+ items. We also see that greater VTA/SN activation during Phase 2 CS+ items relates to this retroactive memory enhancement, suggesting that emotion promotes both the encoding and ongoing consolidation of overlapping representations. Additionally, we find that emotional experience-dependent changes in post-encoding hippocampal functional coupling with CS+ category-selective cortex relate to the magnitude of the retroactive memory effect. These hippocampal connectivity patterns also mediate the relationship between dopaminergic emotional encoding effects and across-participant variability in the retroactive memory benefit. Collectively, our findings suggest that an interplay between online and offline brain mechanisms may enable emotion to preserve seemingly mundane memories that become significant in the future.
Reversible auto-inhibitory regulation ofEscherichia colimetallopeptidase BepA for selective β-barrel protein degradation
Authors: Daimon Yasushi , Narita Shin-ichiro , Miyazaki Ryoji , Hizukuri Yohei , Mori Hiroyuki , Tanaka Yoshiki , Tsukazaki Tomoya , Akiyama Yoshinori 
Published: July 2020

AbstractEscherichia coliperiplasmic zinc-metallopeptidase BepA normally functions by promoting maturation of LptD, a β-barrel outer membrane protein involved in biogenesis of lipopolysaccharides, but degrades it when its membrane assembly is hampered. These processes should be properly regulated to ensure normal biogenesis of LptD, but the underlying mechanism of regulation, however, remains to be elucidated. A recently solved BepA structure has revealed unique features, in particular the active site is buried in the protease domain and conceivably inaccessible for substrate degradation. Additionally, the His-246 residue in the loop region containing helix α9 (α9/H246 loop), which has a potential flexibility and covers the active site, coordinates the zinc ion as the fourth ligand to exclude a catalytic water molecule, thereby suggesting that the crystal structure of BepA represents a latent form. To examine the roles of the α9/H246 loop in the regulation of the BepA activity, we constructed BepA mutants with a His-246 mutation or a deletion of the α9/H246 loop and analyzed their activitiesin vivoandin vitro. These mutants exhibited an elevated protease activity and, unlike the wild-type BepA, degraded LptD that is in the normal assembly pathway. In contrast, tethering of the α9/H246 loop repressed the LptD degradation, which suggests that the flexibility of this loop is important to the exhibition of the protease activity. Based on these results, we propose that the α9/H246 loop undergoes a reversible structural change that enables His-246-mediated switching (histidine switch) of its protease activity, which is important for regulated degradation of stalled/misassembled LptD.
Rapid degradation of GRASP55 and GRASP65 reveals their immediate impact on the Golgi structure
Authors: Zhang Yijun , Seemann Joachim 
Published: July 2020

AbstractGRASP65 and GRASP55 have been implicated in stacking of Golgi cisternae and lateral linking of stacks within the Golgi ribbon. However, loss of gene function approaches by RNAi or gene knockout to dissect their respective roles often resulted in conflicting conclusions. Here, we gene-edited GRASP55 and/or GRASP65 with a degron tag in human fibroblasts, allowing for the induced rapid degradation by the proteasome. We show that acute depletion of either GRASP55 or GRASP65 does not affect the Golgi ribbon, while chronic degradation of GRASP55 disrupts lateral connectivity of the Golgi ribbon. Acute double depletion of both GRASPs coincides with the loss of the vesicle tethering proteins GM130, p115 and Golgin-45 from the Golgi and compromises ribbon linking. Furthermore, neither GRASP55 and/or GRASP65 are required for maintaining stacks orde novoassembly of stacked cisternae at the end of mitosis. These results demonstrate that both GRASPs are dispensable for Golgi stacking, but are involved in maintaining the integrity of Golgi ribbon together with GM130 and Golgin-45.
Development of a growth coupled dynamic regulation network balancing malonyl-CoA node to enhance (2S)-naringenin synthesis inE. coli
Authors: Zhou Shenghu , Yuan Shuo-Fu , Nair Priya H , Alper Hal S , Deng Yu , Zhou Jingwen 
Published: July 2020

AbstractGenerally, high- and low-performance nongenetic variants and young and aged cells co-existed in culture at all growth phases. In this regard, individually and dynamically regulating the metabolic flux of single cells based on their cellular state is highly useful for improving the performance of populations. However, balancing the trade-offs between biomass formation and compound over-production requires sophisticated dynamic regulation networks (DRNs) which can be challenging. Here, we developed a growth coupled NCOMB (Naringenin-Coumaric acid-Malonyl-CoA-Balanced) DRN with systematic optimization of (2S)-naringenin andp-coumaric acid-responsive regulation pathways for real-time control of intracellular supply of malonyl-CoA. In doing so, the acyl carrier protein was used as a new critical node for fine-tuning malonyl-CoA consumption instead of fatty acid synthase. Following directed evolution of the NCOMB DRN, we obtained a strain with cumulative 8.4-fold improvement in (2S)-naringenin production with balanced cell growth, demonstrating the high efficiency of this system for improving pathway production.
Effectiveness of Ivermectin as add-on Therapy in COVID-19 Management (Pilot Trial)
Authors: Gorial Faiq I , Mashhadani Sabeeh , Sayaly Hend M , Dakhil Basim Dhawi , AlMashhadani Marwan M. , Aljabory Adnan M , Abbas Hassan M , Ghanim Mohammed , Rasheed Jawad I 
Published: July 2020

AbstractBackgroundTo date no effective therapy has been demonstrated for COVID-19. In vitro, studies indicated that ivermectin (IVM) has antiviral effect.ObjectivesTo assess the effectiveness of ivermectin (IVM) as add-on therapy to hydroxychloroquine (HCQ) and azithromycin (AZT) in treatment of COVID-19.MethodsThis Pilot clinical trial conducted on hospitalized adult patients with mild to moderate COVID-19 diagnosed according to WHO interim guidance. Sixteen Patients received a single dose of IVM 200Mcg /kg on admission day as add on therapy to hydroxychloroquine (HCQ)and Azithromycin (AZT) and were compared with 71 controls received HCQ and AZT matched in age, gender, clinical features, and comorbidities.The primary outcome was percentage of cured patients, defined as symptoms free to be discharged from the hospital and 2 consecutive negative PCR test from nasopharyngeal swabs at least 24 hours apart. The secondary outcomes were time to cure in both groups and evaluated by measuring time from admission of the patient to the hospital till discharge.ResultsOf 87 patients included in the study,t he mean age ± SD (range) of patients in the IVM group was similar to controls [44.87 ± 10.64 (28-60) vs 45.23 ± 18.47 (8-80) years, p=0.78] Majority of patients in both groups were male but statistically not significant [11(69%) versus 52 (73%), with male: female ratio 2.21 versus 2.7-, p=0.72)All the patients of IVM group were cured compared with the controls [16 (100 %) vs 69 (97.2 %)]. Two patients died in the controls. The mean time to stay in the hospital was significantly lower in IVM group compared with the controls (7.62 ± 2.75 versus 13.22 ±5.90 days, p=0.00005, effect size= 0.82). No adverse events were observedConclusionsAdd-on use of IVM to HCQ and AZT had better effectiveness, shorter hospital stay, and relatively safe compared with controls. however, a larger prospective study with longer follow up may be needed to validate these results.
Loss of PRC2 subunits primes lineage choice during exit of pluripotency
Authors: Loh Chet H , Perino Matteo , Bark Magnus R , Veenstra Gert Jan C 
Published: July 2020

AbstractPolycomb Repressive Complex 2 (PRC2) is crucial for the coordinated expression of genes during early embryonic development, catalyzing histone H3 lysine 27 trimethylation. There are two distinct PRC2 complexes, PRC2.1 and PRC2.2, which contain respectively MTF2 and JARID2 in ES cells. Very little is known about the roles of these auxiliary PRC2 subunits during the exit of pluripotency. In this study, we explored their roles in lineage specification and commitment, using single-cell transcriptomics and mouse embryoid bodies derived fromMtf2andJarid2null embryonic stem cells (ESCs). We observed that the loss ofMtf2resulted in enhanced and faster differentiation towards cell fates from all germ layers, while theJarid2null cells were predominantly directed towards early differentiating precursors and neuro-ectodermal fates. Interestingly, we found that these effects are caused by derepression of developmental regulators that were poised for activation in pluripotent cells and gained H3K4me3 at their promoters in the absence of PRC2 repression. Upon lineage commitment, the differentiation trajectories were relatively similar to those of wild type cells. Together, our results uncovered a major role for MTF2-containing PRC2.1 in balancing poised lineage-specific gene activation, providing a threshold for lineage choice during the exit of pluripotency.HighlightsEnhanced and faster differentiation into all three germ layers inMtf2null embryoid bodiesJarid2null cells enriched for early differentiating precursors and neuro-ectodermal cell fatesMTF2 is critical for the balance of activation and repression of key developmental regulatorsPRC2 coordinates lineage choice and execution of the lineage-specific program by thresholding of lineage-priming
Gendered institutions and female entrepreneurship: a fuzzy-set QCA approach
Authors: Li Yaokuang , Wu Juan , Zhang Daru , Ling Li 
Published: July 2020

PurposeThis paper aims to examine the contextual embeddedness of female entrepreneurship through a focus on gendered institutions. Specifically, it draws upon Scott’s (1995) institutional categories and explores how the three dimensions of gendered institutions combine to explain both a high level of female Total Early-stage Entrepreneurship Activity (TEA) rates and female/male TEA ratios.Design/methodology/approachCollecting data from the Global Entrepreneurship Research Association, the World Economic Forum and the World Bank for 63 countries, this study uses the fuzzy-set qualitative comparative analysis (fsQCA) method to explore causal complexity between the regulative, normative and cognitive dimensions of gendered institutions (conditions) and the female TEA rates and the female/male TEA ratios (outcomes).FindingsFirst, this study confirms the complex interactions occurring among institutional components. Second, the results highlight the key role that gender equality in entrepreneurial cognitions plays in achieving high female entrepreneurship. Third, configurations for the high female TEA rates and the female/male TEA ratios share a high similarity.Practical implicationsThe study provides policymakers with a holistic viewpoint and alternate solutions with the aim of promoting female entrepreneurship in their respective countries.Originality/valueThe study highlights gendered institutions beyond general institutions, enriching the literature on the gender and institutional determinants of female entrepreneurship. Furthermore, the application of the fsQCA method in the study helps to enhance the understanding of how institutional components complexly interact to shape female entrepreneurship.