bluuebunny/crossref_metadata_2025_split huggingface dataset:
The genomics of trait combinations and their influence on adaptive divergence
Authors: Calvert McCall B. , Doellman Meredith M. , Feder Jeffrey L. , Hood Glen R. , Meyers Peter , Egan Scott P. , Powell Thomas H.Q. , Glover Mary M. , Tait Cheyenne , Schuler Hannes , Berlocher Stewart H. , Smith James J. , Nosil Patrik , Hahn Daniel A. , Ragland Gregory J. 
Published: June 2020

ABSTRACTUnderstanding rapid adaptation requires quantifying natural selection on traits and elucidating the genotype-phenotype relationship for those traits. However, recent studies have often failed to predict the direction of adaptive allelic variation in natural populations from laboratory studies. Here, we test for genomic signatures of genetic correlations to illustrate how multifarious, correlational selection may drive counterintuitive patterns of population divergence in the apple maggot fly,Rhagoletis pomonella(Diptera: Tephritidae). Apple-infesting populations with relatively early emerging adults have recently evolved from hawthorn-infesting populations consisting of relatively later emerging adults. Multiple studies have reported a paradoxical relationship between population differentiation and seasonal timing, as determined by the timing of diapause termination; alleles associated with late termination occur at higher frequencies in the earlier emerging apple-infesting populations compared to hawthorn-infesting populations. We present evidence that historical selection on diapause termination and another trait, initial diapause intensity, over geographic gradients generated genetic correlations between the traits in a direction antagonistic to contemporary selection on apple-infesting populations. Single nucleotide polymorphism in genomic regions of high linkage disequilibrium associated strongly with diapause termination and intensity, population divergence, geography, and evolutionary responses in laboratory selection experiments. These associations were consistent with geographically variable selection and with correlated evolutionary responses driving higher frequencies of late-associated alleles in the early emerging apple race. In contrast, loci associated only with diapause termination showed the expected pattern (more early-associated alleles in the apple race) in half of the population pairs. Our results suggest that selection on loci demonstrating antagonistic pleiotropy may often shape genomic footprints of rapid adaptation.
RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development
Authors: Mevel Renaud , Steiner Ivana , Mason Susan , Galbraith Laura C.A. , Patel Rahima , Fadlullah Muhammad ZH , Ahmad Imran , Leung Hing Y. , Oliveira Pedro , Blyth Karen , Baena Esther , Lacaud Georges 
Published: June 2020

ABSTRACTThe characterization of prostate epithelial hierarchy and lineage heterogeneity is critical to understand its regenerative properties and malignancies. Here, we report that the transcription factor RUNX1 marks a specific subpopulation of proximal luminal cells (PLCs), enriched in the periurethral region of the developing and adult mouse prostate, and distinct from the previously identified NKX3.1+luminal castration resistant cells. Using scRNA-seq profiling and genetic lineage tracing, we show that RUNX1+PLCs are unaffected by androgen deprivation, and do not contribute to the regeneration of the distal luminal compartments. Furthermore, we demonstrate that a transcriptionally similar RUNX1+population emerges at the onset of embryonic prostate specification to populate the proximal region of the ducts. Collectively, our results reveal that RUNX1+PLCs is an intrinsic castration-resistant and self-sustained lineage that emerges early during prostate development and provide new insights into the lineage relationships of the prostate epithelium.
Curvature effect of PE-included membrane on the behavior of cinnamycin on the membrane
Authors: Lee S-R. , Park Y. , Park J-W. 
Published: June 2020

AbstractThe behavior of the cinnamycin on the biomimetic membrane was studied with respect to the curvature of the phosphatidylethanolamine(PE)-included membrane with the adhesion measured by the atomic force microscope(AFM). The membrane was formed through vesicle fusion on the hydrophobic surface of the sphere spheres, which was used to define the curvature of the membrane. The hydrophobicity was generated by the reaction of alkyl-silane and analyzed with the X-ray photoelectron spectrometer. The cinnamycin, immobilized covalently to the AFM tip coated with 1-mercapto-1-undecanol that was observed inert to any adhesion to the membrane, showed that the adhesion became stronger with the increase in the curvature. The correlation between the adhesion and the curvature was linearly proportional. Previously, it was found that the cinnamycin was bound to PE headgroup and the binding was enhanced by the interaction of the hydrophobic area located at one side of the cinnamycin. Therefore, the linear proportionality seems to suggest that the interaction is related to the one dimensional orientation of the binding.Statement of SignificanceThe behavior of the cinnamycin was studied on the phosphatidylethanolamine(PE)-included membrane with respect to the curvature of the membrane. The cinnamycin, immobilized covalently to the atomic force microscope, showed that the adhesion became stronger linearly with the increase in the curvature. Previously, it was found that the specific binding between the cinnamycin and PE headgroup was enhanced by the interaction of the hydrophobic area located at one side of the cinnamycin. Therefore, the linear proportionality seems to suggest that the interaction is related to the one dimensional orientation of the binding.
Short sequence motif dynamics in the SARS-CoV-2 genome suggest a role for cytosine deamination in CpG reduction
Authors: Sadykov Mukhtar , Mourier Tobias , Guan Qingtian , Pain Arnab 
Published: June 2020

AbstractRNA viruses use CpG reduction to evade the host cell defense, but the driving mechanisms are still largely unknown. In an attempt to address this we used a rapidly growing genomic dataset of SARS-CoV-2 with relevant metadata information. Remarkably, by simply ordering SARS-CoV-2 genomes by their date of collection, we find a progressive increase of C-to-U substitutions resulting in 5'-UCG-3' motif reduction that in turn have reduced the CpG frequency over just a few months of observation. This is consistent with APOBEC-mediated RNA editing resulting in CpG reduction, thus allowing the virus to escape ZAP-mediated RNA degradation. Our results thus link the dynamics of target sequences in the viral genome for two known host molecular defense mechanisms, mediated by the APOBEC and ZAP proteins.
An in-silico based clinical insight on the effect of noticeable CD4 conserved residues of SARS-CoV-2 on the CD4-MHC-II interactions
Authors: C Selvaa Kumar , Kumar Senthil Arun , Dasgupta Debjani , Wei Haiyan 
Published: June 2020

AbstractThe study is aimed to unveil the conserved residues of CD4 in the context of its purposeful interaction with MHC-II at the receptor-binding domain (RBD) of SARS-CoV-2 compared with the envelope (Env) glycoprotein (gp) 120 of HIV-1. The paired CD4 conserved residues, including the matched CD4 interacting MHC-II epitopes of the structural viral protein domains, were chosen for the protein modelling using the SWISS-MODEL online server. Energy minimization and structural validation of the modelled viral protein domains, including the CD4 and MHC-II protein were achieved by CHIMERA and PROCHECK-Ramachandran Plot respectively. Protein-protein docking was performed by the HADDOCK online tool. The binding affinity score was measured using the PRODIGY online server.As per our docking report, the Env gp120 of HIV-1 with three identical and three conserved residues of CD4 exhibited the highest binding affinity (−13.9 kcal/mol) with MHC-II than the second-highest RBD-S1-SARS-CoV-2 (−12.5 kcal/mol) with three identical and a single conserved residue of CD4. With a noticeable single salt bridge formation identified at the interacting residues Lys305 (of Env gp120-HIV-1) and Glu139 (of MHC-II); the Env gp120 interaction with MHC-II occupied the crucial His144 and Glu194 (salt-bridge) interacting residues of CD4 with the measured buried surface area 2554.8±40.8 Å2. Similarly, the RBD-S1-SARS-CoV-2-MHC-II complex showed two salt bridge formations at the residue sites: 1) Arg567 (of SARS-CoV-2)-Glu194 (of MHC-II) 2) 2) Asp568(of SARS-CoV-2)-Arg165 (of MHC-II) with the increased buried surface area of 1910.9±97.1 Å2over the SARS-CoV score 1708.2±50.8 Å2; that camouflaged all crucial CD4 interacting residues of MHC-II. In conclusion, the noticeable conserved residues of CD4 at the RBD-S1 sites of SARS-CoV-2 could interrupt the aspired CD4-MHC-II interactions of adaptive immune activation.
Functional partnership between carbonic anhydrase and malic enzyme in promoting gluconeogenesis inLeishmania major
Authors: Mondal Dipon Kumar , Pal Dhiman Sankar , Abbasi Mazharul , Datta Rupak 
Published: June 2020

AbstractLeishmaniahas a remarkable ability to proliferate under widely fluctuating levels of essential nutrients, such as glucose. For this the parasite is heavily dependent on its gluconeogenic machinery. One perplexing aspect of gluconeogenesis inLeishmaniais the lack of the crucial pyruvate carboxylase (PC) gene. PC-catalyzed conversion of pyruvate to oxaloacetate is a key entry point through which gluconeogenic amino acids are funnelled into this pathway. Absence of PC inLeishmaniathus raises question about the mechanism of pyruvate entry into the gluconeogenic route. We report here that this task is accomplished inLeishmania majorthrough a novel functional partnership between its mitochondrial malic enzyme (LmME) and cytosolic carbonic anhydrase (LmCA1). Using a combination of pharmacological inhibition studies with genetic manipulation, we showed that both these enzymes are necessary in promoting gluconeogenesis and supporting parasite growth under glucose limiting condition. Functional crosstalk between LmME and LmCA1 was evident when it was observed that the growth retardation caused by inhibition of any one of these enzymes could be protected to a significant extent by overexpressing the other enzyme. We also found that while LmCA1 exhibited constitutive expression, LmME protein level was strongly upregulated in low glucose condition. Notably, both LmME and LmCA1 were found to be important for survival ofLeishmaniaamastigotes within host macrophages. Taken together, our results indicate that LmCA1 by virtue of its CO2concentrating ability stimulates LmME-catalyzed pyruvate carboxylation, thereby driving gluconeogenesis through pyruvate-malate-oxaloacetate bypass pathway. Additionally, our study establishes LmCA1 and LmME as promising therapeutic targets.
Oscillatory correlates of auditory working memory examined with human electrocorticography
Authors: Kumar Sukhbinder , Gander Phillip E. , Berger Joel I. , Billig Alexander J. , Nourski Kirill V. , Oya Hiroyuki , Kawasaki Hiroto , Howard Matthew A. , Griffiths Timothy D. 
Published: June 2020

AbstractThis work examines how sounds are held in auditory working memory (AWM) in humans by examining oscillatory local field potentials (LFPs) in candidate brain regions. Previous fMRI studies by our group demonstrated blood oxygenation level-dependent (BOLD) response increases during maintenance in auditory cortex, inferior frontal cortex and the hippocampus using a paradigm with a delay period greater than 10s. The relationship between such BOLD changes and ensemble activity in different frequency bands is complex, and the long delay period raised the possibility that long-term memory mechanisms were engaged. Here we assessed LFPs in different frequency bands in six subjects with recordings from all candidate brain regions using a paradigm with a short delay period of 3 s. Sustained delay activity was demonstrated in all areas, with different patterns in the different areas. Enhancement in low frequency (delta) power and suppression across higher frequencies (beta/gamma) were demonstrated in primary auditory cortex in medial Heschl’s gyrus (HG) whilst non-primary cortex showed patterns of enhancement and suppression that altered at different levels of the auditory hierarchy from lateral HG to superior- and middle-temporal gyrus. Inferior frontal cortex showed increasing suppression with increasing frequency. The hippocampus and parahippocampal gyrus showed low frequency increases and high frequency decreases in oscillatory activity. The work demonstrates sustained activity patterns that can only be explained by AWM maintenance, with prominent low-frequency increases in medial temporal lobe regions.
The 20-hydroxyecdysone agonist, halofenozide, promotes anti-Plasmodiumimmunity inAnopheles gambiaevia the ecdysone receptor
Authors: Reynolds Rebekah A. , Kwon Hyeogsun , Alves e Silva Thiago Luiz , Olivas Janet , Vega-Rodriguez Joel , Smith Ryan C. 
Published: June 2020

AbstractMosquito physiology and immunity are integral determinants of malaria vector competence. This includes the principal role of hormonal signaling inAnopheles gambiaeinitiated shortly after blood-feeding, which stimulates immune induction and promotes vitellogenesis through the function of 20-hydroxyecdysone (20E). Previous studies demonstrated that manipulating 20E signaling through the direct injection of 20E or the application of a 20E agonist can significantly impactPlasmodiuminfection outcomes, reducing oocyst numbers and the potential for malaria transmission. In support of these findings, we demonstrate that a 20E agonist, halofenozide, is able to induce anti-Plasmodiumimmune responses that limitPlasmodiumookinetes. We demonstrate that halofenozide requires the function of ultraspiracle (USP), a component of the canonical heterodimeric ecdysone receptor, to induce malaria parasite killing responses. Additional experiments suggest that the effects of halofenozide treatment are temporal, such that its application only limits malaria parasites when applied prior to infection. Unlike 20E, halofenozide does not influence cellular immune function or AMP production. Together, our results further demonstrate the potential of targeting 20E signaling pathways to reduce malaria parasite infection in the mosquito vector and provide new insight into the mechanisms of halofenozide-mediated immune activation that differ from 20E.
Genetic dissection of Down syndrome-associated alterations in APP/amyloid-β biology using mouse models
Authors: Tosh Justin L. , Rhymes Ellie , Mumford Paige , Whittaker Heather T. , Pulford Laura J. , Noy Sue J. , Cleverley Karen , Walker Matthew C. , Tybulewicz Victor L.J. , Wykes Rob C. , Fisher Elizabeth M.C , Wiseman Frances K. 
Published: June 2020

AbstractIndividuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 geneAPP(amyloid precursor protein) and the extra copy or ‘dose’ ofAPPis thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other thanAPP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to anAPPtransgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation andAPPtransgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other thanAPP, likely modulate Alzheimer’s disease in people who have Down syndrome.
Structural Diversity and Phylogenetic Distribution of Valyl tRNA-like Structures in Viruses
Authors: Sherlock Madeline E. , Hartwick Erik W. , MacFadden Andrea , Kieft Jeffrey S. 
Published: June 2020

ABSTRACTViruses commonly use specifically folded RNA elements that interact with both host and viral proteins to perform functions important for diverse viral processes. Examples are found at the 3′ termini of certain positive-sense ssRNA virus genomes where they partially mimic tRNAs, including being aminoacylated by host cell enzymes. Valine-accepting tRNA-like structures (TLSVal) are an example that share some clear homology to canonical tRNAs but have several important structural differences. Although many examples of TLSValhave been identified, we lacked a full understanding of their structural diversity and phylogenetic distribution. To address this, we undertook an in-depth bioinformatic and biochemical investigation of these RNAs, guided by recent high-resolution structures of a TLSVal. We cataloged many new examples in plant-infecting viruses but also in unrelated insect-specific viruses. Using biochemical and structural approaches, we verified the secondary structure of representative TLSValsubstrates and tested their ability to be valylated, finding structural heterogeneity within this class. In a few cases, large stem-loop structures are inserted within distinct variable regions located in an area of the TLS distal to known host cell factor binding sites. In addition, we identified one virus whose TLS has switched its anticodon away from valine; the implications of this remain unclear. These results refine our understanding of the structural and functional mechanistic details of tRNA mimicry and how this may be used in viral infection.
POLArIS, a versatile probe for molecular orientation, revealed actin filaments associated with microtubule asters in early embryos
Authors: Sugizaki Ayana , Sato Keisuke , Chiba Kazuyoshi , Saito Kenta , Kawagishi Masahiko , Tomabechi Yuri , Mehta Shalin B. , Ishii Hirokazu , Sakai Naoki , Shirouzu Mikako , Tani Tomomi , Terada Sumio 
Published: June 2020

AbstractBiomolecular assemblies govern the physiology of cells. Their function often depends on the changes in molecular arrangements of constituents, both in the positions and orientations. While recent advancements of fluorescence microscopy including super-resolution microscopy have enabled us to determine the positions of fluorophores with unprecedented accuracy, monitoring orientation of fluorescently labeled molecules within living cells in real-time is challenging. Fluorescence polarization microscopy (FPM) reports the orientation of emission dipoles and is therefore a promising solution. For imaging with FPM, target proteins need labeling with fluorescent probes in a sterically constrained manner, but due to difficulties in the rational three-dimensional design of protein connection, universal method for constrained tagging with fluorophore was not available. Here we report POLArIS, a genetically encoded and versatile probe for molecular orientation imaging. Instead of using a direct tagging approach, we used a recombinant binder connected to a fluorescent protein in a sterically constrained manner and can target arbitrary biomolecules by combining with phage-display screening. As an initial test case of POLArIS, we developed POLArISact, which specifically binds to F-actin in living cells. We confirmed that the orientation of F-actin can be monitored by observing cells expressing POLArISactwith FPM. In living starfish early embryos expressing POLArISact, we found actin filaments radially extending from centrosomes in association with microtubule asters during mitosis. By taking advantage of the genetically encoded nature, POLArIS can be used in a variety of living specimens including whole bodies of developing embryos and animals, and also expressed in a cell-type/tissue specific manner.
SARS-CoV-2 infection of African green monkeys results in mild respiratory disease discernible by PET/CT imaging and prolonged shedding of infectious virus from both respiratory and gastrointestinal tracts
Authors: Hartman Amy L. , Nambulli Sham , McMillen Cynthia M. , White Alexander G. , Tilston-Lunel Natasha L. , Albe Joseph R. , Cottle Emily , Dunn Matthew , Frye L. James , Gilliland Theron H. , Olsen Emily L. , O’Malley Katherine J. , Schwarz Madeline M. , Tomko Jaime A. , Walker Reagan C. , Xia Mengying , Hartman Matthew S. , Klein Edwin , Scanga Charles A. , Flynn JoAnne L. , Klimstra William B. , McElroy Anita K. , Reed Douglas S. , Duprex W. Paul 
Published: June 2020

AbstractVaccines are urgently needed to combat the global coronavirus disease 2019 (COVID-19) pandemic, and testing of candidate vaccines in an appropriate non-human primate (NHP) model is a critical step in the process. Infection of African green monkeys (AGM) with a low passage human isolate of SARS-CoV-2 by aerosol or mucosal exposure resulted in mild clinical infection with a transient decrease in lung tidal volume. Imaging with human clinical-grade18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) co-registered with computed tomography (CT) revealed pulmonary lesions at 4 days post-infection (dpi) that resolved over time. Infectious virus was shed from both respiratory and gastrointestinal (GI) tracts in all animals in a biphasic manner, first between 2-7 dpi followed by a recrudescence at 14-21 dpi. Viral RNA (vRNA) was found throughout both respiratory and gastrointestinal systems at necropsy with higher levels of vRNA found within the GI tract tissues. All animals seroconverted simultaneously for IgM and IgG, which has also been documented in human COVID-19 cases. Young AGM represent an excellent species to study mild/subclinical COVID-19 disease and have shed light on unknown aspects of long-term virus shedding. They are ideally suited for preclinical evaluation of candidate vaccines and therapeutic interventions.One Sentence SummarySubclinical infection of African green monkeys infected with SARS-CoV-2 results in prolonged shedding of infectious virus from both respiratory and gastrointestinal tracts.
Structural templates for imaging EEG cortical sources in infants
Authors: O’Reilly Christian , Larson Eric , Richards John E. , Elsabbagh Mayada 
Published: June 2020

AbstractElectroencephalographic (EEG) source reconstruction is a powerful approach that helps to unmix scalp signals, mitigates volume conduction issues, and allows anatomical localization of brain activity. Algorithms used to estimate cortical sources require an anatomical model of the head and the brain, generally reconstructed using magnetic resonance imaging (MRI). When such scans are unavailable, a population average can be used for adults, but no average surface template is available for cortical source imaging in infants. To address this issue, this paper introduces a new series of 12 anatomical models for subjects between zero and 24 months of age. These templates are built from MRI averages and volumetric boundary element method segmentation of head tissues available as part of the Neurodevelopmental MRI Database. Surfaces separating the pia mater, the gray matter, and the white matter were estimated using the Infant FreeSurfer pipeline. The surface of the skin as well as the outer and inner skull surfaces were extracted using a cube marching algorithm followed by Laplacian smoothing and mesh decimation. We post-processed these meshes to correct topological errors and ensure watertight meshes. The use of these templates for source reconstruction is demonstrated and validated using 100 high-density EEG recordings in 7-month-old infants. Hopefully, these templates will support future studies based on EEG source reconstruction and functional connectivity in healthy infants as well as in clinical pediatric populations. Particularly, they should make EEG-based neuroimaging more feasible in longitudinal neurodevelopmental studies where it may not be possible to scan infants at multiple time points.Graphical abstractHighlightsTwelve surface templates for infants in the 0-2 years old range are proposedThese templates can be used for EEG source reconstruction using existing toolboxesA relatively modest impact of age differences was found in this age rangeCorrelation analysis confirms increasing source differences with age differencesSources reconstructed with infants versus adult templates significantly differ