bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATG5 is instrumental in the transition from autophagy to apoptosis during the degeneration of tick salivary glands
Authors: Wang Yanan , Zhang Houshuang , Luo Li , Zhou Yongzhi , Cao Jie , Xuan Xuenan , Suzuki Hiroshi , Zhou Jinlin 
Published: May 2020

AbstractFemale tick salivary glands undergo rapid degeneration several days post engorgement. This degeneration may be caused by the increased concentration of ecdysone in the hemolymph during the fast feeding period and both autophagy and apoptosis occur. In this work, we first proved ATG and Caspase gene expression peaks during degeneration of the tick salivary glands. We explored the regulatory role ofRhipicephalus haemaphysaloidesautophagy related 5 (RhATG5) in the degeneration of tick salivary glands. During the fast feeding phase, RhATG5 was cleaved and both calcium concentration and the transcription of RhCalpains increased in the salivary glands. Recombinant RhATG5 was cleaved by μ-Calpain only in the presence of calcium; the mutant RhATG5191-199Δwas not cleaved. Treatment with 20-hydroxyecdysone (20E) led to programmed cell death in the salivary glands of unfed ticksin vitro, RhATG8-phosphatidylethanolamine (PE) was upregulated in ticks treated with low concentration of 20E. Conversely, RhATG8-PE decreased and RhCaspase-7 increased in ticks treated with a high concentration of 20E and transformed autophagy to apoptosis. High concentrations of 20E led to the cleavage of RhATG5. Calcium concentration and expression of RhCalpains were also upregulated in the tick salivary glands. RNA interference (RNAi) of RhATG5in vitroinhibited both autophagy and apoptosis of the tick salivary glands. RNAi of RhATG5in vivosignificantly inhibited the normal feeding process. These results demonstrated that high concentrations of 20E led to the cleavage of RhATG5 by increasing the concentration of calcium and stimulated the transition from autophagy to apoptosis.
Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth
Authors: Das Manisit , Zhou Xuefei , Liu Yun , Das Anirban , Vincent Benjamin G. , Li Jingjing , Liu Rihe , Huang Leaf 
Published: May 2020

AbstractThe threshold for immunogenic clonal fraction in a heterogeneous solid tumor required to induce effective bystander killing of non-immunogenic subclones is unknown. Pancreatic cancer poses crucial challenges for immune therapeutic interventions due to low mutational burden and consequent lack of neoantigens. Here, we designed a model to incorporate artificial neoantigens into genes of interest in cancer cells and to test the potential of said antigens to actuate bystander killing. By precisely controlling the abundance of a neoantigen in the tumor, we studied the impact of neoantigen frequency on immune response and immune escape. Our results showed that a single, strong, widely expressed neoantigen could lead to a robust antitumor response when at least 80% of cancer cells express the neoantigen. Further, immunological assays revealed induction of T-cell responses against a non-target self-antigen on KRAS oncoprotein, when we inoculated animals with a high frequency of tumor cells expressing a test neoantigen. Using nanoparticle-based gene therapy, we successfully altered the tumor microenvironment by perturbing interleukin-12 and interleukin-10 gene expression. The subsequent remodeling of the microenvironment reduced the threshold of neoantigen frequency at which bioluminescent signal intensity for tumor burden decreased 1.5-logfold, marking a robust tumor growth inhibition, from 83% to as low as 29%. Our results thus suggest that bystander killing is rather inefficient in immunologically cold tumors like pancreatic cancer and requires an extremely high abundance of neoantigens. However, the bystander killing mediated antitumor response can be rescued, when supported by adjuvant immune therapy.
Modelling within-host macrophage dynamics in influenza virus infection
Authors: Li Ke , McCaw James M. , Cao Pengxing 
Published: May 2020

AbstractHuman respiratory disease associated with influenza virus infection is of significant public health concern. Macrophages, as part of the front line of host innate cellular defence, have been shown to play an important role in controlling viral replication. However, fatal outcomes of infection, as evidenced in patients infected with highly pathogenic viral strains, are often associated with prompt activation and excessive accumulation of macrophages. Activated macrophages can produce a large amount of pro-inflammatory cytokines, which leads to severe symptoms and at times death. However, the mechanism for rapid activation and excessive accumulation of macrophages during infection remains unclear. It has been suggested that the phenomena may arise from complex interactions between macrophages and influenza virus. In this work, we develop a novel mathematical model to study the relationship between the level of macrophage activation and the level of viral shedding in influenza virus infection. Our model combines a dynamic model of viral infection, a dynamic model of macrophages and the essential interactions between the virus and macrophages. Our model predicts that the level of macrophage activation can be negatively correlated with the level of viral shedding when viral infectivity is sufficiently high. We further identify that temporary depletion of resting macrophages in response to viral infection is a major driver in our model for the negative relationship between macrophage activation and viral shedding, providing new insight into the mechanisms that regulate macrophage activation. Our model serves as a framework to study the complex dynamics of virus-macrophage interactions and provides a mechanistic explanation for existing experimental observations, contributing to an enhanced understanding of the role of macrophages in influenza viral infection.
Disrupted Endothelial Cell Heterogeneity and Network Organization Impairs Vascular Function in Prediabetic Obesity
Authors: Wilson Calum , Zhang Xun , Lee Matthew D. , MacDonald Margaret , Heathcote Helen H. , Alorfi Nasser M.N. , Buckley Charlotte , Dolan Sharon , McCarron John G. 
Published: May 2020

AbstractRationaleObesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations giving rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that, rather than being a population of uniformly responding cells, neighboring endothelial cells are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function.ObjectiveTo investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contributes to impaired vascular reactivity in obesity.Methods and ResultsTo study obesity-related vascular function without the complications associated with diabetes, we induced a state of prediabetic obesity in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and network-level calcium responses. Obesity did not alter the slope of this relationship, but impaired network-level endothelial calcium responses. The network itself was comprised of structural and functional components. The structural component, a hexagonal lattice network of endothelial cells, was unchanged in obesity. The functional network contained sub-populations of clustered agonist-sensing cells from which signals were communicate through the network. In obesity there were fewer but larger clusters of agonist-sensing cells and communication path lengths between clusters was increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone.Specialized subpopulations of endothelial cells had increased agonist sensitivity. These agonist-responsive cells were spatially clustered in a non-random manner and drove network level calcium responses. Communication between adjacent cells was unaltered in obesity, but there was a decrease in the size of the agonist-sensitive cell population and an increase in the clustering of agonist-responsive cellsConclusionsThe distribution of cells in the endothelial network is critical in determining overall vascular function. Altered cell heterogeneity and arrangement in obesity decrease endothelial function and provide a novel framework for understanding compromised endothelial function in cardiovascular disease.
Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism
Authors: Ewan Eric E. , Avraham Oshri , Carlin Dan , Goncalves Tassia Mangetti , Zhao Guoyan , Cavalli Valeria 
Published: May 2020

AbstractRegeneration failure after spinal cord injury (SCI) results in part from the lack of a pro-regenerative response in injured neurons, but the response to SCI has not been examined specifically in injured sensory neurons. Using RNA sequencing of dorsal root ganglion, we determined that thoracic SCI elicits a transcriptional response distinct from sciatic nerve injury (SNI). Both SNI and SCI induced upregulation of ATF3 and Jun, yet this response failed to promote growth in sensory neurons after SCI. RNA sequencing of purified sensory neurons one and three days after injury revealed that unlike SNI, the SCI response is not sustained. Both SCI and SNI elicited the expression of ATF3 target genes, with very little overlap between conditions. Pathway analysis of differentially expressed ATF3 target genes revealed that fatty acid biosynthesis and terpenoid backbone synthesis were downregulated after SCI but not SNI. Pharmacologic inhibition of fatty acid synthase, the enzyme generating palmitic acid, decreased axon growth and regeneration in vitro. These results supports the notion that decreased expression of lipid metabolism-related genes after SCI, including fatty acid synthase, may restrict axon regenerative capacity after SCI.
The evolution of sex allocation in metapopulations
Authors: Roux Camille , Mullon Charles , Pannell John R. 
Published: May 2020

AbstractSelection in inbred populations is expected to favor female-biased sex ratios in dioecious populations as a result of local mate competition, a prediction that finds strong support in situations where females have control of the sex ratio. Local mate competition due to inbreeding should also promote female-biased sex allocation in hermaphrodites, with reduced emphasis on the production and dispersal of sperm or pollen relative to that of eggs, ovules or seeds. While inbreeding can be the direct result of the mating system in local populations, it can also be brought about by population turnover in metapopulations with frequent local extinction and recolonization. This effect of population turnover has previously been considered for species with separate sexes. Here, we use both formal analysis and individual-based simulations to explore the effect of population turnover on sex allocation in partially self-fertilizing hermaphroditic metapopulations. Using simulations, we also assess the extent to which different genetic measures of inbreeding and population differentiation predict the equilibrium sex allocation. We find that population turnover can select for strongly female-biased sex allocation in hermaphroditic metapopulations, particularly if amongdeme dispersal is low, even where local demes are fully outcrossing. In such situations,FSTis a good predictor of the equilibrium sex allocation, and much better than the alternative differentiation measuresGSTand Jost’sD. Our study extends predictions for sex allocation in subdivided populations to hermaphroditic species, and draws attention in general to the power of Wright’s hierarchical inbreeding statistics to predict the sex allocation in metapopulations at equilibrium.
Light pollution affects West Nile virus exposure risk across Florida
Authors: Kernbach Meredith E. , Martin Lynn B. , Unnasch Thomas R. , Hall Richard J. , Jiang Rays H.Y. , Francis Clinton D. 
Published: May 2020

AbstractEmerging infectious diseases (EIDs), including zoonotic arboviruses, present a global health threat. Multiple components of human land use change have been linked to arboviral emergence, but one pervasive factor that has received comparatively little attention is light pollution. Although often considered a component of built environments, artificial light at night (ALAN) outpaces the growth and spatial extent of urbanization, and thus affects areas where human population density and anthropogenic land changes are modest. West Nile virus (WNV) emergence has been described as peri-urban, but recent research suggests that its relative ubiquity in human-altered environments might actually be due to ALAN. Indeed, we found previously that experimental ALAN exposure enhanced avian competence to transmit WNV to mosquitoes. In the present study, we asked whether such organismal effects manifest ecologically by determining whether WNV exposure among sentinel chickens in Florida is related to local ALAN conditions. We found strong support for a nonlinear relationship between ALAN and WNV exposure in chickens with peak WNV risk occurring at low ALAN levels. Importantly, effects of ALAN on WNV exposure were stronger than other aspects of urbanization; only ambient temperature in the month prior to sampling had a comparable effect to ALAN. These results represent the first field evidence that ALAN might affect infectious disease exposure risk. We advocate for further research on how ALAN influences zoonotic risk, as well as efforts to study alternative nighttime lighting methods to reduce such risk.Significance StatementLight pollution associated with human development is a globally pervasive and rapidly expanding anthropogenic stressor; but despite documented effects on host immune functions and vector behaviors, how it affects infectious disease risk is unknown. Using data from the Florida Department of Health arbovirus surveillance program, we show that light pollution is a stronger predictor of variation in West Nile virus (WNV) exposure risk than many other previously implicated anthropogenic and natural environmental variables. Light pollution effects are nonlinear, so risk is highest in areas with dim light pollution. Our results highlight a new way that light pollution might affect human and wildlife health.
Joint probabilistic modeling of paired transcriptome and proteome measurements in single cells
Authors: Gayoso Adam , Steier Zoë , Lopez Romain , Regier Jeffrey , Nazor Kristopher L , Streets Aaron , Yosef Nir 
Published: May 2020

AbstractThe paired measurement of RNA and surface protein abundance in single cells with CITE-seq is a promising approach to connect transcriptional variation with cell phenotypes and functions. However, each data modality exhibits unique technical biases, making it challenging to conduct a joint analysis and combine these two views into a unified representation of cell state. Here we present Total Variational Inference (totalVI), a framework for the joint probabilistic analysis of paired RNA and protein data from single cells. totalVI probabilistically represents the data as a composite of biological and technical factors such as limited sensitivity of the RNA data, background in the protein data, and batch effects. To evaluate totalVI, we performed CITE-seq on immune cells from murine spleen and lymph nodes with biological replicates and with different antibody panels measuring over 100 surface proteins. With this dataset, we demonstrate that totalVI provides a cohesive solution for common analysis tasks like the integration of datasets with matched or unmatched protein panels, dimensionality reduction, clustering, evaluation of correlations between molecules, and differential expression testing. totalVI enables scalable, end-to-end analysis of paired RNA and protein data from single cells and is available as open-source software.
Computational analysis of ligand dose range thermal proteome profiles
Authors: Kurzawa Nils , Becher Isabelle , Sridharan Sindhuja , Franken Holger , Mateus André , Anders Simon , Bantscheff Marcus , Huber Wolfgang , Savitski Mikhail M. 
Published: May 2020

AbstractDetecting ligand-protein interactions in living cells is a fundamental challenge in molecular biology and drug research. Proteome-wide profiling of thermal stability as a function of ligand concentration promises to tackle this challenge. We present a statistical analysis method with reliable control of the false discovery rate and apply it to several datasets probing epigenetic drugs. We detect off-target drug engagement in unrelated protein families.
Intra-genome variability in the dinucleotide composition of SARS-CoV-2
Authors: Digard Paul , Lee Hui Min , Sharp Colin , Grey Finn , Gaunt Eleanor 
Published: May 2020

AbstractCpG dinucleotides are under-represented in the genomes of single stranded RNA viruses, and coronaviruses, including SARS-CoV-2, are no exception to this. Artificial modification of CpG frequency is a valid approach for live attenuated vaccine development, and if this is to be applied to SARS-CoV-2, we must first understand the role CpG motifs play in regulating SARS-CoV-2 replication. Accordingly, the CpG composition of the newly emerged SARS-CoV-2 genome was characterised in the context of other coronaviruses. CpG suppression amongst coronaviruses does not significantly differ according to genera of virus, but does vary according to host species and primary replication site (a proxy for tissue tropism), supporting the hypothesis that viral CpG content may influence cross-species transmission. Although SARS-CoV-2 exhibits overall strong CpG suppression, this varies considerably across the genome, and the Envelope (E) open reading frame (ORF) and ORF10 demonstrate an absence of CpG suppression. While ORF10 is only present in the genomes of a subset of coronaviruses, E is essential for virus replication. Across theCoronaviridae, E genes display remarkably high variation in CpG composition, with those of SARS and SARS-CoV-2 having much higher CpG content than other coronaviruses isolated from humans. Phylogeny indicates that this is an ancestrally-derived trait reflecting their origin in bats, rather than something selected for after zoonotic transfer. Conservation of CpG motifs in these regions suggests that they have a functionality which over-rides the need to suppress CpG; an observation relevant to future strategies towards a rationally attenuated SARS-CoV-2 vaccine.
Refined measurement of SecA-driven protein transport reveals indirect coupling to ATP turnover
Authors: Allen William J. , Watkins Daniel W. , Dillingham Mark S. , Collinson Ian 
Published: May 2020

AbstractThe universally conserved Sec system is the primary method cells utilise to transport proteins across membranes. Until recently, measuring the activity – a prerequisite for understanding how biological systems works – has been limited to discontinuous protein transport assays with poor time resolution, or used as reporters large, non-natural tags that interfere with the process. The development of an assay based on a split super-bright luciferase (NanoLuc) changed this. Here, we exploit this technology to unpick the steps that constitute post-translational transport in bacteria. Under the conditions deployed, transport of the model pre-protein substrate proSpy occurs at 200 amino acids per minute with the data best fit by a series of large, ∼30 amino acid, steps each coupled to many (100s) ATP hydrolysis events. Prior to that, there is no evidence for a distinct, rate-limiting initiation event. Kinetic modelling suggests that SecA-driven transport activity is facilitated by the substrate (polypeptide) concentration gradient – in keeping with classical membrane transporters. Furthermore, the features we describe are consistent with a non-deterministic motor mechanism, such as a Brownian ratchet.
Cotranslational protein folding can promote the formation of correct folding intermediate
Authors: Tao P. , Xiao Y. 
Published: May 2020

AbstractCotranslational folding is vital for proteins to form correct structures in vivo. However, it is still unclear how a nascent chain folds at atomic resolution during the translation process. Previously, we have built a model of ribosomal exit tunnel and investigated cotranslational folding of a three-helices protein by using all-atom molecular dynamics simulations. Here we shall study the cotranslational folding of three mainly-β proteins using the same method and find that cotranslational folding can enhance helical population in most cases and reduce nonnative long-range contacts before emerging from the ribosomal exit tunnel. After exiting the tunnel, all proteins fall into local minimal states and structural ensembles in cotranslational folding are more helical than in free folding. Importantly, for GTT WW domain, one local minimal state in cotranslational folding is known as correct folding intermediate, which is not found in free folding. This result suggests that cotranslational folding may directly increase folding efficiency by accelerating sampling more than by avoiding the misfolded state, which is a mainstream viewpoint in present. In addition, our method can serve as a general scheme to study cotranslational folding process of proteins.Statement of SignificanceIn cell, the formations of correct three-dimensional structures of proteins, namely protein folding, are essential to human health. Misfolding can lead to serious diseases such as Alzheimer’s disease and mad cow disease. As the first step of in vivo folding, the effect of cotranslational folding on the correct folding of proteins has been the focus of scientific research in this century. Although some experiments have shown that cotranslational folding can improve the efficiency of folding, its microscopic mechanism is not yet clear. In this paper, we study the process of cotranslational folding of three proteins by using all-atom molecular dynamics simulations, and try to reveal some aspects of the mechanism of cotranslational folding from a microscopic perspective.