bluuebunny/crossref_metadata_2025_split huggingface dataset:
Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin
Authors: Bruyère Julie , Abada Yah-Se , Vitet Hélène , Fontaine Gaëlle , Deloulme Jean-Christophe , Cès Aurélia , Denarier Eric , Pernet-Gallay Karin , Andrieux Annie , Humbert Sandrine , Potier Marie Claude , Delatour Benoît , Saudou Frédéric 
Published: April 2020

AbstractStudies have suggested that amyloid precursor protein (APP) regulates synaptic homeostasis, but the evidence has not been consistent. In particular, signaling pathways controlling APP transport to the synapse in axons and dendrites remain to be identified. Having previously shown that Huntingtin (HTT), the scaffolding protein involved in Huntington’s disease, regulates neuritic transport of APP, we used a microfluidic corticocortical neuronal network-on-a-chip to examine APP transport and localization to the pre- and post-synaptic compartments. We found that HTT, upon phosphorylation by the Ser/Thr kinase Akt, regulates APP transport in axons but not dendrites. Expression of an unphosphorylatable HTT decreased axonal anterograde transport of APP, reduced presynaptic APP levels, and increased synaptic density. Ablatingin vivoHTT phosphorylation in APPPS1 mice, which overexpress APP, reduced presynaptic APP levels, restored synapse number and improved learning and memory. The Akt-HTT pathway and axonal transport of APP thus regulate APP presynaptic levels and synapse homeostasis.
Molecular Basis for the Adaptive Evolution of Environment Sensing by H-NS Proteins
Authors: Zhao Xiaochuan , Kharchenko Vladlena , Hameed Umar F. Shahul , Liao Chenyi , Huser Franceline , Remington Jacob M. , Radhakrishnan Anand K. , Jaremko Mariusz , Jaremko Łukasz , Arold Stefan T. , Li Jianing 
Published: April 2020

AbstractThe DNA-binding protein H-NS is a pleiotropic gene regulator in gram-negative bacteria. Through its capacity to sense temperature and other environmental factors, H-NS allows pathogens like Salmonella to adapt their gene expression, and hence toxicity and biological responses, to their presence inside or outside warm-blooded hosts. To investigate how this sensing mechanism may have evolved to fit different bacterial lifestyles, we compared H-NS orthologs from bacteria that infect humans, plants, and insects, and from bacteria that live on a deep-sea hypothermal vent. The combination of biophysical characterization, high-resolution proton-less NMR spectroscopy and molecular simulations revealed, at an atomistic level, how the same general mechanism was adapted to specific habitats and lifestyles. In particular, we demonstrate how environment-sensing characteristics arise from specifically positioned intra- or intermolecular electrostatic interactions. Our integrative approach clarified the mechanism for H-NS–mediated environmental sensing and suggests that it resulted from the exaptation of an ancestral protein feature.
Label-free single-instance protein detection in vitrified cells
Authors: Rickgauer J. Peter , Choi Heejun , Lippincott-Schwartz Jennifer , Denk Winfried 
Published: April 2020

AbstractA general method to map molecular interactions and conformational states in structurally intact cells would find wide application in biochemistry and cell biology. We used a library of images— calculated on the basis of known structural data—as search templates to detect targets as small as the “head” domain (350 kDa) of the ribosome’s small subunit in single-tilt electron cryo-micrographs by cellular high resolution template matching (cHRTM). Atomically precise position and orientation estimates reveal the conformation of individual ribosomes and enable the detection of specifically bound ligands down to 24 kDa. We show that highly head-swivelled states are likely to play a role in mRNA translocation in living cells. cHRTM outperforms cryo-electron tomography three-fold in sensitivity and completely avoids the vicissitudes of exogenous labelling.
Genetic dissection of glutamatergic neuron subpopulations and developmental trajectories in the cerebral cortex
Authors: Matho Katherine S. , Huilgol Dhananjay , Galbavy William , He Miao , Kim Gukhan , An Xu , Lu Jiangteng , Wu Priscilla , Di Bella Daniela J. , Shetty Ashwin S. , Palaniswamy Ramesh , Hatfield Joshua , Raudales Ricardo , Narasimhan Arun , Gamache Eric , Levine Jesse , Tucciarone Jason , Szelenyi Eric , Harris Julie A. , Mitra Partha P. , Osten Pavel , Arlotta Paola , Huang Z. Josh 
Published: April 2020

ABSTRACTDiverse types of glutamatergic pyramidal neurons (PyNs) mediate the myriad processing streams and output channels of the cerebral cortex, yet all derive from neural progenitors of the embryonic dorsal telencephalon. Here, we establish genetic strategies and tools for dissecting and fate mapping PyN subpopulations based on their developmental and molecular programs. We leverage key transcription factors and effector genes to systematically target the temporal patterning programs in progenitors and differentiation programs in postmitotic neurons. We generated over a dozen temporally inducible mouse Cre and Flp knock-in driver lines to enable combinatorial targeting of major progenitor types and projection classes. Intersectional converter lines confer viral access to specific subsets defined by developmental origin, marker expression, anatomical location and projection targets. These strategies establish an experimental framework for understanding the hierarchical organization and developmental trajectory of PyN subpopulations that assemble cortical processing networks and output channels.
Female-specific upregulation of insulin pathway activity mediates the sex difference inDrosophilabody size plasticity
Authors: Millington Jason W. , Chao Chien , Sun Ziwei , Basner-Collins Paige J. , Brownrigg George P. , Wat Lianna W. , Hudry Bruno , Miguel-Aliaga Irene , Rideout Elizabeth J. 
Published: April 2020

ABSTRACTNutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work inDrosophilashowed that body size plasticity was higher in females, yet the mechanisms underlying the sex difference in body size plasticity remain unclear. Here, we discover that a protein-rich diet augments body size in females and not males because of a female-specific increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This increased IIS activity was triggered by a diet-induced increase instunted, and requiredDrosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, we show that sex determination genetransformerregulates the diet-induced increase instuntedand IIS activity, and mediates the sex difference in body size plasticity. This identifies one sex-specific mechanism underlying the nutrient-dependent regulation of IIS activity and body size plasticity, providing vital insight into conserved mechanisms that mediate sex differences in phenotypic plasticity.
Actin in Dendritic Spines Self-Organizes into a Critical State
Authors: Bonilla-Quintana Mayte , Wörgötter Florentin , D’Este Elisa , Tetzlaff Christian , Fauth Michael 
Published: April 2020

SummaryIt is known that dendritic spines change their size and shape spontaneously and sometimes to a large degree, but the function of this remains unclear. Here, we quantify these changes using time-series analysis of confocal data and demonstrate that spine size can follow different autoregressive integrated moving average (ARIMA) models and that shape- and size-changes are not correlated. We capture this behavior with a biophysical model, based on the spines’ actin dynamics, and find the presence of 1/fnoise. When investigating its origins, the model predicts that actin in the dendritic spines self-organizes into a critical state, which creates a fine balance between static actin filaments and free monomers. We speculate that such a balance might be functionally beneficially to allow a spine to quickly reconfigure itself after LTP induction.
RADSex: a computational workflow to study sex determination using Restriction Site-Associated DNA Sequencing data
Authors: Feron Romain , Pan Qiaowei , Wen Ming , Imarazene Boudjema , Jouanno Elodie , Anderson Jennifer , Herpin Amaury , Journot Laurent , Parrinello Hugues , Klopp Christophe , Kottler Verena A. , Roco Alvaro S. , Du Kang , Kneitz Susanne , Adolfi Mateus , Wilson Catherine A. , McCluskey Braedan , Amores Angel , Desvignes Thomas , Goetz Frederick W. , Takanashi Ato , Kawaguchi Mari , Detrich H. William , Oliveira Marcos , Nobrega Rafael , Sakamoto Takashi , Nakamoto Masatoshi , Wargelius Anna , Karlsen Ørjan , Wang Zhongwei , Stöck Matthias , Waterhouse Robert M. , Braasch Ingo , Postlethwait John H. , Schartl Manfred , Guiguen Yann 
Published: April 2020

ABSTRACTThe study of sex determination and sex chromosome organisation in non-model species has long been technically challenging, but new sequencing methodologies are now enabling precise and high-throughput identification of sex-specific genomic sequences. In particular, Restriction Site-Associated DNA Sequencing (RAD-Seq) is being extensively applied to explore sex determination systems in many plant and animal species. However, software designed to specifically search for sex-biased markers using RAD-Seq data is lacking. Here, we present RADSex, a computational analysis workflow designed to study the genetic basis of sex determination using RAD-Seq data. RADSex is simple to use, requires few computational resources, makes no prior assumptions about type of sex-determination system or structure of the sex locus, and offers convenient visualization through a dedicated R package. To demonstrate the functionality of RADSex, we re-analyzed a published dataset of Japanese medaka, Oryzias latipes, where we uncovered a previously unknown Y chromosome polymorphism. We then used RADSex to analyze new RAD-Seq datasets from 15 fish species spanning multiple systematic orders. We identified the sex determination system and sex-specific markers in six of these species, five of which had no known sex-markers prior to this study. We show that RADSex greatly facilitates the study of sex determination systems in non-model species and outperforms the commonly used RAD-Seq analysis software STACKS. RADSex in speed, resource usage, ease of application, and visualization options. Furthermore, our analysis of new datasets from 15 species provides new insights on sex determination in fish.
The kinase Isr1 negatively regulates hexosamine biosynthesis inS. cerevisiae
Authors: Alme Emma B , Stevenson Erica , Krogan Nevan J , Swaney Danielle L , Toczyski David P 
Published: April 2020

AbstractTheS. cerevisiae ISR1gene encodes a putative kinase with no ascribed function. Here, we show that Isr1 acts as a negative regulator of the highly-conserved hexosamine biosynthesis pathway (HBP), which converts glucose into uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the carbohydrate precursor to protein glycosylation, GPI-anchor formation, and chitin biosynthesis. Overexpression ofISR1is lethal and, at lower levels, causes sensitivity to tunicamycin and resistance to calcofluor white, implying impaired protein glycosylation and reduced chitin deposition. Gfa1 is the first enzyme in the HBP and is conserved from bacteria and yeast to humans. The lethality caused byISR1overexpression is rescued by co-overexpression ofGFA1or exogenous glucosamine, which bypassesGFA1’sessential function. Gfa1 is phosphorylated in anISR1-dependent fashion and mutation ofISR1-dependent sites ameliorates the lethality associated withISR1overexpression. Isr1 contains a phosphodegron that is phosphorylated by Pho85 and subsequently ubiquitinated by the SCF-Cdc4 complex, largely confining Isr1 protein levels to the time of bud emergence. Mutation of this phosphodegron stabilizes Isr1 and recapitulates the overexpression phenotypes. As Pho85 is a cell cycle and nutrient responsive kinase, this tight regulation of Isr1 may serve to dynamically regulate flux through the HBP and modulate how the cell’s energy resources are converted into structural carbohydrates in response to changing cellular needs.Author SummaryProtein phosphorylation is an essential regulatory mechanism that controls most cellular processes, integrating a variety of environmental signals to drive cellular growth. Yeast encode over 100 kinases, yet many remain poorly characterized. TheS. cerevisiaegeneISR1encodes a putative kinase with no ascribed function. Here, we show thatISR1decreases the synthesis of a critical structural carbohydrate, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), by mediating inhibition of one of the enzymes responsible for its synthesis, Gfa1. UDP-GlcNAc is the precursor to protein glycosylation, GPI anchor formation, and chitin synthesis, the first two of which are essential and conserved in humans. Throughout the cell cycle, and in response to changing environmental conditions, the cell must balance its use of glucose for energy production and generation of these structural carbohydrates. Here we show that Isr1 is regulated by both cell cycle and nutrient changes, and is rapidly degraded in a phosphorylation dependent manner. Isr1-mediated inhibition of UDP-GlcNAc synthesis may serve as a mechanism of dynamically regulating how the cell utilizes glucose in response to its environment.
The tomato DELLA protein PROCERA promotes ABA responses in guard cells by upregulating ABA transporter
Authors: Shohat Hagai , Illouz-Eliaz Natanella , Kanno Yuri , Seo Mitsunori , Weiss David 
Published: April 2020

AbstractPlants reduce transpiration to avoid drought stress by stomatal closure. While abscisic acid (ABA) has a central role in the regulation of stomatal closure under water-deficit conditions, we demonstrated in tomato that the gibberellin (GA) response inhibitor, the DELLA protein PROCERA (PRO), promotes ABA-induced stomatal closure and gene transcription in guard cells. To study how PRO affects stomatal closure, we performed RNAseq analysis of isolated guard cells and identified the ABA transportersABA-IMPORTING TRANSPORTER1.1(AIT1.1) andAIT1.2, also called in ArabidopsisNPF4.6, as upregulated by PRO. Tomato has fourAIT1genes, but onlyAIT1.1andAIT1.2were upregulated by PRO, and onlyAIT1.1exhibited high expression in guard cells. Functional analysis ofAIT1.1in yeast confirmed its activity as an ABA transporter, possibly importer. CRISPR-Cas9-defrivedait1.1mutant exhibited increased transpiration, larger stomatal aperture and reduced response to ABA. Moreover,ait1.1suppressed the promoting effects of PRO on ABA-induced stomatal closure and gene expression in guard cells. The negative interaction between GA and ABA has been studied for many years in numerous plant species. These studies suggest that the crosstalk is mediated by changes in hormone biosynthesis and signaling. Our results suggest that it is also mediated by changes in hormone transport.One-sentence SummaryThe tomato DELLA protein PROCERA promoted abscisic acid-induced stomatal closure and gene expression by upregulating the expression of the ABA transporterABA-IMPORTING TRANSPORTER1 in guard cells.
Quantification of lysogeny caused by phage coinfections in microbial communities from biophysical principles
Authors: Luque Antoni , Silveira Cynthia 
Published: April 2020

AbstractTemperate phages can integrate in their bacterial host genome to form a lysogen, often modifying the phenotype of the host. Lysogens are dominant in the microbial-dense environment of the mammalian-gut. This observation contrasts with the long-standing hypothesis of lysogeny being favored in microbial communities with low densities. Here we hypothesized that phage coinfections—the most studied molecular mechanism of lysogeny in lambda phage—increases at high microbial abundances. To test this hypothesis, we developed a biophysical model of coinfection and stochastically sampled ranges of phage and bacterial concentrations, adsorption rates, lysogenic commitment times, and community diversity from marine and gut microbiomes. Based on lambda experiments, a Poisson process assessed the probability of lysogeny via coinfection in these ecosystems. In 90% of the sampled marine ecosystems, lysogeny stayed below 10% of the bacterial community. In contrast, 25% of the sampled gut communities stayed above 25% of lysogeny, representing an estimated nine trillion lysogens formed via phage coinfection in the human gut every day. The prevalence of lysogeny in the gut was a consequence of the higher densities and faster adsorption rates. In marine communities, which were characterized by lower densities and phage adsorption rates, lysogeny via coinfection was still possible for communities with long lysogenic commitments times. Our study suggests that physical mechanisms can favor coinfection and cause lysogeny at poor growth conditions (long commitment times) and in rich environments (high densities and adsorption rates).ImportancePhage integration in bacterial genomes manipulate microbial dynamics from the oceans to the human gut. This phage-bacteria interaction, called lysogeny, is well-studied in laboratory models, but its environmental drivers remain unclear. Here we quantified the frequency of lysogeny via phage coinfection—the most studied mechanism of lysogeny—by developing a biophysical model that incorporated a meta-analysis of the properties of marine and gut microbiomes. Lysogeny was found to be more frequent in high-productive environments like the gut, due to higher phage and bacterial densities and faster phage adsorption rates. At low cell densities, lysogeny via coinfection was possible for hosts with long duplication times. Our research bridges the molecular understanding of lysogeny with the ecology of complex microbial communities.
Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model
Authors: Dent Matthew , Hamorsky Krystal , Vausselin Thibaut , Dubuisson Jean , Miyata Yoshinari , Morikawa Yoshio , Matoba Nobuyuki 
Published: April 2020

ABSTRACTInfection with hepatitis C virus (HCV) remains to be a major cause of morbidity and mortality worldwide despite the recent advent of highly effective direct-acting antivirals. The envelope glycoproteins of HCV are heavily glycosylated with a high proportion of high-mannose glycans (HMGs), which serve as a shield against neutralizing antibodies and assist in the interaction with cell-entry receptors. However, currently there is no approved therapeutic targeting this potentially druggable biomarker. Here, we investigated the therapeutic potential of the lectibody Avaren-Fc (AvFc), a HMG-binding lectin-Fc fusion protein.In vitroassays showed AvFc’s capacity to neutralize cell culture-derived HCV in a genotype independent manner with IC50values in the low nanomolar range. A histidine buffer-based AvFc formulation was developed for in vivo studies using the PXB human liver chimeric mouse model. Systemic administration of AvFc was well tolerated; after 11 consecutive doses every other day at 25 mg/kg, there were no significant changes in body or liver weights, nor any impact noted in blood human albumin levels or serum alanine aminotransferase activity. Gross necropsy and liver pathology further confirmed the lack of discernible toxicity. This treatment regimen successfully prevented genotype 1a HCV infection in all animals, while an AvFc mutant lacking HMG binding activity failed to block the infection. These results suggest that targeting envelope HMGs is a promising therapeutic approach against HCV infection. In particular, AvFc may provide a safe and efficacious means to prevent recurrent infection upon liver transplantation in HCV-related end-stage liver disease patients.
Circulating microRNA-762 upregulates colorectal cancer might through Wnt-1/β-catenin signaling
Authors: Lai Peng-Sheng , Chang Wei-Min , Chen Ying-Yin , Lin Yi-Feng , Liao Hui-Fen , Chen Chung-Yu 
Published: April 2020

ABSTRACTBackgroundA number of microRNAs (miRNAs) have been demonstrated to be correlated with the diagnosis, progression and prognosis of colorectal cancer (CRC). However, the key miRNAs and the associated signaling pathways that regulate the growth and metastasis of CRC remain unclear.MethodsThe circulating miRNAs from BALB/c mice with CRC CT26 cell implantation were assayed by microarray. Then, mmu-miR-762 mimic and inhibitor were transfected to CT26 cells for analysis of cell viability, invasion, and epithelial-mesenchymal transition (EMT), cell cycle, and regulatory molecule expression. Human subjects were included for comparison the circulating has-miR-762 levels in CRC patients and control donors, as well as the patients with and without distant metastasis.ResultsThe miRNA levels in mice with CRC cell implantation indicated that plasma mmu-miR-762 was upregulated. Transfection of mmu-miR-762 mimic to CT26 cells increased cell viability, invasion, and EMT, whereas transfection of mmu-miR-762 inhibitor decreased the above abilities. Cells treated with high-concentration mmu-miR-762 inhibitor induced cell cycle arrest at G0/G1 phase. Western blot analysis showed that mmu-miR-762 mimic transfection upregulated the expression of Wnt-1 and β-catenin. Further analysis was performed to demonstrate the correlation of has-miR-762 with CRC patients. The results showed that serum has-miR-762 levels in CRC patients were higher than in control donors. Among the CRC patients, patients with distant metastasis showed higher serum has-miR-762 levels than patients without distant metastasis.ConclusionsThe present study demonstrated that circulating miR-762 might be a biomarker with upregulation of CRC cell growth and invasion through the Wnt/β-catenin signaling.
Multiple environmental parameters impact core lipid cyclization in Sulfolobus acidocaldarius
Authors: Cobban Alec , Zhang Yujiao , Zhou Alice , Weber Yuki , Pearson Ann , Leavitt William D. 
Published: April 2020

ABSTRACTEnvironmental reconstructions based on microbial lipids require understanding the coupling between environmental conditions and membrane physiology. The paleotemperature proxy TEX86is built on the observation that archaea alter the number of five- and six-membered rings in the hydrophobic core of their glycerol dibiphytanyl glycerol tetraether (GDGT) membrane lipids when growing at different temperatures. However, recent work with these archaea also highlights a role for other factors, such as pH or energy availability in determining the degree of core lipid cyclization. To better understand the role of these variables we cultivated a model Crenarchaeon,Sulfolobus acidocaldarius, over a range in temperature, pH, oxygen flux, or agitation speed, and quantified the changes in growth rate, biomass yield, and core lipid compositions. The average degree of cyclization in core lipids correlated with growth rate under most conditions. When considered alongside other experimental findings from both the thermoacidophilic and mesoneutrophilic archaea, the results suggest the cyclization of archaeal lipids records a universal response to energy availability at the cellular level. Although we isolated the effects of individual parameters, there remains a need for multi-factor experiments (e.g., pH + temperature + redox) to establish a robust framework to interpret biomarker records of environmental change.