bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Basis of Host-Adaptation Interactions between Influenza Virus Polymerase PB2 Subunit and ANP32A
Authors: Zarco Aldo Camacho , Kalayil Sissy , Maurin Damien , Salvi Nicola , Delaforge Elise , Milles Sigrid , Jensen Malene Ringkjøbing , Hart Darren J. , Cusack Stephen , Blackledge Martin 
Published: March 2020

AbstractAvian influenza polymerase undergoes host adaptation in order to efficiently replicate in human cells. Adaptive mutants are localised on the C-terminal (627-NLS) domains of the PB2 subunit. In particular mutation of PB2 residue 627 from E to K in avian polymerase rescues activity in mammalian cells. A host transcription regulator ANP32A, comprising a long C-terminal intrinsically disordered domain (IDD), has also been shown to be responsible for this viral adaptation. Human ANP32A IDD lacks a 33 residue insertion compared to avian ANP32A, a deletion that restricts avian influenza polymerase activity in mammalian cells. We determined conformational descriptions of the highly dynamic complexes between 627E and 627K forms of the 627-NLS domains of PB2 and avian and human ANP32A. The negatively charged intrinsically disordered domain of human ANP32A transiently binds to a basic face of the 627 domain, exploiting multiple binding sites to maximize affinity for 627-NLS. This interaction also implicates residues 590 and 591 that are responsible for human-adaptation of the the 2009 pandemic influenza polymerase. The presence of 627E interrupts the polyvalency of the interaction, an effect that is compensated by extending the interaction surface and exploiting an avian-unique motif in the unfolded domain that interacts with the 627-NLS linker. In both cases the interaction favours the open, dislocated form of the 627-NLS domains. Importantly the two binding modes exploited by human- and avian-adapted PB2 are strongly abrogated in the cross interaction between avian polymerase and human ANP32A, suggesting that this molecular specificity may be related to species adaptation. The observed binding mode is maintained in the context of heterotrimeric influenza polymerase, placing ANP32A in the immediate vicinity of known host-adaptive PB2 mutants. This study provides a molecular framework for understanding the species-specific restriction of influenza polymerase by ANP32A and will inform the identification of new targets for influenza inhibition.
Start codon disruption with CRISPR/Cas9 prevents murine Fuchs’ endothelial corneal dystrophy
Authors: Uehara Hironori , Zhang Xiaohui , Pereira Felipe , Narendran Siddharth , Choi Susie , Bhuvanagiri Sai , Liu Jinlu , Kumar Sangeetha Ravi , Bohner Austin , Carroll Lara , Archer Bonnie , Zhang Yue , Liu Wei , Gao Guangping , Ambati Jayakrishna , Jun Albert S , Ambati Balamurali K. 
Published: March 2020

AbstractA missense mutation of collagen type VIII alpha 2 chain (COL8A2) gene leads to early onset Fuchs’ endothelial corneal dystrophy (FECD), which progressively impairs vision through loss of corneal endothelial cells. We demonstrate that CRISPR/Cas9-based postnatal gene editing achieves structural and functional rescue in a mouse model of FECD. A single intraocular injection of an adenovirus encoding both the Cas9 gene and guide RNA (Ad-Cas9-Col8a2gRNA), efficiently knocked down mutant COL8A2 expression in corneal endothelial cells, prevented endothelial cell loss, and rescued corneal endothelium pumping function in adult Col8a2 mutant mice. There were no adverse sequelae on histology or electroretinography. Col8a2 start codon disruption represents a non-surgical strategy to prevent vision loss in early-onset FECD. As this demonstrates the ability of Ad-Cas9-gRNA to restore phenotype in adult post-mitotic cells, this method may be widely applicable to adult-onset diseases, even in tissues affected with disorders of non-reproducing cells.
Stochastic Epigenetic Dynamics of Gene Switching
Authors: Bhattacharyya Bhaswati , Wang Jin , Sasai Masaki 
Published: March 2020

AbstractEpigenetic modifications of histones crucially affect the eukaryotic gene activity. We theoretically analyze the dynamical effects of histone modifications on gene switching by using the Doi-Peliti operator formalism of chemical reaction kinetics. The calculated probability flux in self-regulating genes shows a distinct circular flow around basins in the landscape of the gene state distribution, giving rise to hysteresis in gene switching. In contrast to the general belief that the change in the amount of transcription factor (TF) precedes the histone state change, the flux drives histones to be modified prior to the change in the amount of TF in the self-regulating circuits. The flux-landscape analyses elucidate the nonlinear nonequilibrium mechanism of epigenetic gene switching.
Population dynamics of decision making in temperate bacteriophages
Authors: Lang Moritz , Pleška Maroš , Guet Cǎlin C. 
Published: March 2020

AbstractDue to their ability to choose between lysis and lysogeny, temperate bacteriophages represent a classic model system to study the molecular basis of decision making. The coinfection of individual bacteria by multiple, genetically identical phages is known to alter the infection outcome and favor lysogeny over lytic development. However, it is not clear what role the ability of individual phages to sense and respond to coinfections plays in the phage-host infection dynamics at the population level. To address this question, we developed a full-stochastic model to capture the interaction dynamics between billions of bacteria and phages with single-cell and -phage resolution. While, at the level of individual bacteria, the probability of coinfections depends mainly on the phage concentration at the time of infection, the average number of coinfections at the population level is primarily determined by the relative growth rate of phage. Because the maximum attainable phage growth rate is constrained by basic life history parameters, the average number of coinfections has an upper bound of around two. However, for a broad range of conditions, the average number of coinfections stays well below this value. Consequently, we find that coinfections provide only very limited information to individual phages about the state of the infection at the population level. Nevertheless, this information can still provide a strong competitive advantage for phages that base fate decisions on the number of coinfections.
On the ecology and distribution of steelhead(Oncorhynchus mykiss)in California’s Eel River
Authors: Kannry Samantha H. , O’Rourke Sean M. , Kelson Suzanne J , Miller Michael R 
Published: March 2020

AbstractPreservation of life-history and other phenotypic complexity is central to the resilience of Pacific salmon stocks. Steelhead (Oncorhynchus mykiss) express a diversity of life history strategies such as the propensity to migrate (anadromy/residency) and the timing and state of maturation upon return to freshwater (run-timing), providing an opportunity to study adaptive phenotypic complexity. Historically, the Eel River supported upwards of one million salmon and steelhead, but the past century has seen dramatic declines of all salmonids in the watershed. Here we investigate life history variation in Eel River steelhead by using Rapture sequencing, on thousands of individuals, to genotype the region diagnostic for run-timing (GREB1L) and the region strongly associated with residency/anadromy (OMY5) in the Eel River and other locations, as well as determine patterns of overall genetic differentiation. Our results provide insight into many conservation related issues. For example, we found distinct segregation between winter and summer-run steelhead correlated with flow dependent barriers in major forks of the Eel; that summer-run steelhead inhabited the upper Eel prior to construction of an impassable dam, and that both life-history and overall genetic diversity have been maintained in the resident trout population above; and no evidence of the summer-run allele in the South Fork Eel, indicating that summer run-timing cannot be expected to arise from standing genetic variation in this and other populations that lack the summer-run phenotype. The results presented in this study provide valuable information for designing future restoration and management strategies forO. mykissin Northern California and beyond.
Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity
Authors: Cui Lu , Chen Shih-Yu , Lerbs Tristan , Lee Jin-Wook , Domizi Pablo , Gordon Sydney , Kim Yong-hun , Nolan Garry , Betancur Paola , Wernig Gerlinde 
Published: March 2020

AbstractIn pulmonary fibrosis, the transcription factor JUN is highly expressed in the fibrotic foci. Its induction in adult mice drives lung fibrosis, which is abrogated by administration of anti-CD47. Here, we use high-dimensional mass cytometry to profile protein expression and the secretome of individual fibroblasts and leukocytes from pulmonary fibrosis patients. We show thatJUNis activated in fibroblasts derived from fibrotic lungs which also demonstrated increased CD47 and PD-L1 expression. Using ATAC-seq and ChIP-seq, we found that activation ofJUNin fibroblasts rendered enhancers ofCD47andPD-L1accessible, an observation that reporter assays corroborated. Meanwhile we detected increased IL-6 signaling which amplified both JUN-mediatedCD47-enhancer activity and protein expression in fibrotic lung fibroblasts. Using anin vivomouse model of fibrosis, we found two distinct mechanisms by which blocking IL-6, CD47, and PD-L1 reversed fibrosis—increased phagocytosis of profibrotic fibroblasts and elimination of suppressive effects on adaptive immunity. Our results identify specific immune mechanisms that promote the fibrotic process and suggest a complementary therapeutic approach that could be used alongside conventional anti-fibrotics for pulmonary fibrosis diseases.
Conversion of marginal land into switchgrass conditionally accrues soil carbon and reduces methane consumption
Authors: Bates Colin T. , Escalas Arthur , Kuang Jialiang , Hale Lauren , Wang Yuan , Herman Don , Nuccio Erin E. , Wang Xiaoling , Fu Ying , Tian Renmao , Wang Gangsheng , Ning Daliang , Yang Yunfeng , Wu Liyou , Pett-Ridge Jennifer , Saha Malay , Craven Kelly , Firestone Mary , Zhou Jizhong 
Published: March 2020

AbstractSwitchgrass (Panicum virgatumL.) is a perennial C4grass native to tallgrass prairies of the Central US, and a promising bioenergy feedstock. Switchgrass can be cultivated on soils with low nutrient contents and its rooting depth, of up to 2 m, has brought attention to the crop as a potential mechanism to sequester and build soil carbon (C). Switchgrass, therefore, offers multifaceted benefits on degraded soils by enhancing soil organic matter content. However, to evaluate the sustainability of switchgrass-based biofuel production, it is crucial to understand the impacts of land conversion and switchgrass establishment on biotic/abiotic characteristics of various soils. In this study, we characterized the ecosystem-scale consequences of switchgrass growing at two highly-eroded, ‘Dust Bowl’ remnant field sites from Oklahoma US, with silt-loam (SL) or clay-loam (CL) soil textures having low nitrogen (N), phosphorus (P), and C contents. Paired plots at each site, including fallow control and switchgrass-cultivated, were assessed. Our results indicated that switchgrass significantly increased soil C at the SL site and reduced microbial diversity at the CL site. The CL site exhibited significantly higher CO2flux and higher respiration from switchgrass plots. Strikingly, switchgrass significantly reduced the CH4consumption by an estimated 39% for the SL site and 47% for the CL site. Structural equation modeling identified soil temperature, P content, and soil moisture levels as the most influential factors regulating both CO2and CH4fluxes. CO2flux was also influenced by microbial biomass while CH4flux was influenced by microbial diversity. Together, our results suggest that site selection by soil type is a crucial factor in improving soil C stocks and mitigating greenhouse gas (GHG) fluxes, especially considering our finding that switchgrass reduced methane consumption, implying that carbon balance considerations should be accounted for to fully evaluate the sustainability of switchgrass cultivation.
Scleraxis is required for the growth of adult tendons in response to mechanical loading
Authors: Gumucio Jonathan P , Schonk Martin M , Kharaz Yalda A , Comerford Eithne , Mendias Christopher L 
Published: March 2020

AbstractScleraxis is a basic helix-loop-helix transcription factor that plays a central role in promoting tenocyte proliferation and matrix synthesis during embryonic tendon development. However, the role of scleraxis in the growth and adaptation of adult tendons is not known. We hypothesized that scleraxis is required for tendon growth in response to mechanical loading, and that scleraxis promotes the specification of progenitor cells into tenocytes. We conditionally deleted scleraxis in adult mice using a tamoxifen-inducible Cre-recombinase expressed from theRosa26locus (ScxΔ), and then induced tendon growth inScx+andScxΔadult mice via plantaris tendon mechanical overload. Compared to the wild typeScx+group,ScxΔmice demonstrated blunted tendon growth. Transcriptional and proteomic analyses revealed significant reductions in cell proliferation, protein synthesis, and extracellular matrix genes and proteins. Our results indicate that scleraxis is required for mechanically-stimulated adult tendon growth by causing the commitment of CD146+pericytes into the tenogenic lineage, and by promoting the initial expansion of newly committed tenocytes and the production of extracellular matrix proteins.
A multiscale 3D chemotaxis assay reveals bacterial navigation mechanisms
Authors: Grognot Marianne , Taute Katja M. 
Published: March 2020

AbstractHow bacteria navigate environmental chemical gradients has implications ranging from health to climate science. The underlying behavioral mechanisms are unknown for most species due to a lack in techniques bridging scales from individual 3D motility behavior to the statistical power required to assess the resulting performance. We present the first demonstration of such a multiscale 3D chemotaxis assay and reveal thatCaulobacter crescentuschemotaxis breaks with theEscherichia coliparadigm.
A full-length transcriptome dataset of normal andNosema ceranae-challenged midgut tissues of eastern honeybee workers
Authors: Du Yu , Fan Yuanchan , Chen Huazhi , Wang Jie , Xiong Cuiling , Zheng Yanzhen , Chen Dafu , Guo Rui 
Published: March 2020

ABSTRACTApis cerana ceranais a subspecies of eastern honeybee,Apis cerana, and it plays a vital role in ecological maintenance in China. However,A. c. ceranais threatened by many pathogenic microorganisms includingNosema ceranae, a widespread fungal parasite that infected worldwide colonies. In this article, un-challenged (AcCK1, AcCK2) andN. ceranae-challenged midguts ofA. c. ceranaworkers (AcT1, AcT2) were sequenced utilizing Nanopore long-read sequencing technology. Totally, 11,727,628, 6,996,395, 14,383,735 and 11,580,154 raw reads were yielded from AcCK1, AcCK2, AcT1 and AcT2; the average lengths were 1147 bp, 908 bp, 992 bp and 1077 bp, and the average N50 were 1308 bp, 911 bp, 1079 bp and 1192 bp. The length distribution of was ranged 1 kb to more than 10 kb. Additionally, the quality (Q) score distribution of raw reads was among Q7~Q17. Further, 11,617,144, 6,940,895, 14,277,240 and 11,501,562 clean reads were respectively obtained from AcCK1, AcCK2, AcT1 and AcT2, and among them 78.40%, 82.50%, 79.05% and 80.20% were identified as full-length clean reads. In addition, full-length clean reads from AcCK1, AcT1, AcT2 and AcCK2 were ranged from 1 kb to more than 10 kb in length. Finally, the length distribution of redundant reads-removed full-length transcripts was among 1 kb~5 kb.Value of the data♦This dataset enables better understanding the complexity ofA. c. ceranatranscriptome.♦Current dataset contributes to identification of genes and transcripts engaged in response of eastern honeybee toN. ceranaestress.♦The data provides a valuable genetic resource for deciphering alternative splicing and polyadenylation ofA. c. ceranamRNAs involved in host response toN. ceranaechallenge.♦The reported data is beneficial for uncovering the molecular mechanism regulating interaction between eastern honeybee and microsporidian.
In VivoEfficacy and PK/PD Modeling of KBP-7072, An Aminomethylcycline Antibiotic, in Neutropenic Pneumonia and Thigh Infection Models
Authors: Tan Xiaojuan , Zhang Min , Liu Qingmei , Wang Ping , Zhou Tian , Benn Vincent , Yang Fred 
Published: March 2020

ABSTRACTKBP-7072 is a novel aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative multidrug resistant bacterial isolates and strains.Antibacterial activity and the PK/PD relationship were assessed usingin vivoinfection models. Six to 8-week-old female CD-1 mice were randomized to oral KBP-7072, minocycline and vehicle in aKlebsiella pneumoniaemurine model, and KBP-7072, linezolid and vehicle for aStreptococcus pneumoniaemurine model. Each animal was inoculated withK. pneumoniaeorS. pneumoniaeplaced on the tip of the nares. KBP-7072 and antibiotics were started 3 hours post inoculation and continued for 3 days forK. pneumoniae, and were started 18 hours post inoculation and continued for 3 days forS. pneumoniae. Animals were euthanized at 0 (control group), 24, 48 or 72 hours post final dose.In vivoefficacy and PK/PD parameters were determined inStaphylococcus aureusisolate (6424MRSA-363),K. pneumoniaeisolate (6680kpn-522), andE. coliisolate (6691eco-558) murine thigh infection models.In vivoefficacy and PK/PD parameters (fAUC/MIC,fCmax/MIC and %T>MICfree) were calculated. Respiratory infection occurred in all inoculated mice. KBP-7072 produced a significant (p<0.05 to <0.001) dose-dependent decrease in colony forming units (CFUs) at all doses and a dose-dependent increase in survival rate (p<0.001 vs. vehicle). The median survival in all KBP-7072-treated groups was significantly greater vs. comparators (p<0.001). These results demonstrate potentin vivoefficacy for KBP-7072 and determined that the AUC/MIC parameter was optimal for assessing bacteriostatic and bactericidal effects of KBP-7072.
A Novel Triage Tool of Artificial Intelligence-Assisted Diagnosis Aid System for Suspected COVID-19 Pneumonia in Fever Clinics
Authors: Feng Cong , Wang Lili , Chen Xin , Zhai Yongzhi , Zhu Feng , Chen Hua , Wang Yingchan , Su Xiangzheng , Huang Sai , Tian Lin , Zhu Weixiu , Sun Wenzheng , Zhang Liping , Han Qingru , Zhang Juan , Pan Fei , Chen Li , Zhu Zhihong , Xiao Hongju , Liu Yu , Liu Gang , Chen Wei , Li Tanshi 
Published: March 2020

SummaryBackgroundCurrently, the prevention and control of the novel coronavirus disease (COVID-19) outside Hubei province in China, and other countries have become more and more critically serious. We developed and validated a diagnosis aid model without computed tomography (CT) images for early identification of suspected COVID-19 pneumonia (S-COVID-19-P) on admission in adult fever patients and made the validated model available via an online triage calculator.MethodsPatients admitted from Jan 14 to February 26, 2020 with the epidemiological history of exposure to COVID-19 were included [Model development (n = 132) and validation (n = 32)]. Candidate features included clinical symptoms, routine laboratory tests, and other clinical information on admission. Features selection and model development were based on the least absolute shrinkage and selection operator (LASSO) regression. The primary outcome was the development and validation of a diagnostic aid model for S-COVID-19-P early identification on admission.ResultsThe development cohort contained 26 S-COVID-19-P and 7 confirmed COVID-19 pneumonia cases. The final selected features included 1 variable of demographic information, 4 variables of vital signs, 5 variables of blood routine values, 7 variables of clinical signs and symptoms, and 1 infection-related biomarker. The model performance in the testing set and the validation cohort resulted in the area under the receiver operating characteristic (ROC) curves (AUCs) of 0.841 and 0.938, the F-1 score of 0.571 and 0.667, the recall of 1.000 and 1.000, the specificity of 0.727 and 0.778, and the precision of 0.400 and 0.500. The top 5 most important features were Age, IL-6, SYS_BP, MONO%, and Fever classification. Based on this model, an optimized strategy for S-COVID-19-P early identification in fever clinics has also been designed.ConclusionsS-COVID-19-P could be identified early by a machine-learning model only used collected clinical information without CT images on admission in fever clinics with a 100% recall score. The well-performed and validated model has been deployed as an online triage tool, which is available athttps://intensivecare.shinyapps.io/COVID19/.
Thioproline formation as a driver of formaldehyde toxicity inEscherichia coli
Authors: Patterson Jenelle A. , He Hai , Folz Jacob S. , Li Qiang , Wilson Mark A. , Fiehn Oliver , Bruner Steven D. , Bar-Even Arren , Hanson Andrew D. 
Published: March 2020

ABSTRACTFormaldehyde (HCHO) is a reactive carbonyl compound that formylates and cross-links proteins, DNA, and small molecules. It is of specific concern as a toxic intermediate in the design of engineered pathways involving methanol oxidation or formate reduction. The high interest in engineering these pathways is not, however, matched by engineering-relevant information on precisely why HCHO is toxic or on what damage-control mechanisms cells deploy to manage HCHO toxicity. The only well-defined mechanism for managing HCHO toxicity is formaldehyde dehydrogenase-mediated oxidation to formate, which is counterproductive if HCHO is a desired pathway intermediate. We therefore sought alternative HCHO damage-control mechanisms via comparative genomic analysis. This analysis associated homologs of theEscherichia coli pepPgene with HCHO-related one-carbon metabolism. Furthermore, deletingpepPincreased the sensitivity ofE. colito supplied HCHO but not other carbonyl compounds. PepP is a proline aminopeptidase that cleaves peptides of the general formula X-Pro-Y, yielding X + Pro-Y. HCHO is known to react spontaneously with cysteine to form the close proline analog thioproline (thiazolidine-4-carboxylate), which is incorporated into proteins and hence into proteolytic peptides. We therefore hypothesized that thioproline-containing peptides are toxic and that PepP cleaves these aberrant peptides. Supporting this hypothesis, PepP cleaved the model peptide Ala-thioproline-Ala as efficiently as Ala-Pro-Alain vitroandin vivo, and deletingpepPincreased sensitivity to supplied thioproline. Our data thus (i) provide biochemical genetic evidence that thioproline formation contributes substantially to HCHO toxicity and (ii) make PepP a candidate damage-control enzyme for engineered pathways having HCHO as an intermediate.