bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenic measles viruses cannot evolve to bypass vaccine-induced neutralizing antibodies
Authors: Muñoz-Alía Miguel Ángel , Nace Rebecca A. , Zhang Lianwen , Russell Stephen J. 
Published: October 2020

AbstractAfter centuries of pestilence and decades of global vaccination, measles serotypes capable of evading vaccine-induced immunity have not emerged. Here, by systematically building mutations into the H-glycoprotein of an attenuated measles strain and assaying for serum neutralization, we show that virus evolution is severely constrained by the existence of numerous codominant H-glycoprotein antigenic sites, some critical for binding to pathogenicity receptors SLAMF1 and Nectin-4. We further demonstrate the existence in serum of protective neutralizing antibodies targeting codominant F-glycoprotein epitopes. Calculations suggest that evolution of pathogenic measles viruses capable of escaping serum neutralization in vaccinated individuals is a near-zero probability scenario.
echolocatoR: an automated end-to-end statistical and functional genomic fine-mapping pipeline
Authors: Schilder Brian M. , Humphrey Jack , Raj Towfique 
Published: October 2020

AbstractSummaryecholocatoRintegrates a diverse suite of statistical and functional fine-mapping tools in order to identify, test enrichment in, and visualize high-confidence causal consensus variants in any phenotype. It requires minimal input from users (a summary statistics file), can be run in a single R function, and provides extensive access to relevant datasets (e.g. reference linkage disequilibrium (LD) panels, quantitative trait loci (QTL) datasets, genome-wide annotations, cell type-specific epigenomics, thereby enabling rapid, robust and scalable end-to-end fine-mapping investigations.Availability and implementationecholocatoRis an open-source R package available through GitHub under the MIT license:https://github.com/RajLabMSSM/echolocatoR
homologizer: Phylogenetic phasing of gene copies into polyploid subgenomes
Authors: Freyman William A. , Johnson Matthew G. , Rothfels Carl J. 
Published: October 2020

SummaryOrganisms such as allopolyploids and F1 hybrids contain multiple distinct subgenomes, each potentially with its own evolutionary history. These organisms present a challenge for multilocus phylogenetic inference and other analyses since it is not apparent which gene copies from different loci are from the same subgenome and thus share an evolutionary history.Here we introducehomologizer, a flexible Bayesian approach that uses a phylogenetic framework to infer the phasing of gene copies across loci into their respective subgenomes.Through the use of simulation tests we demonstrate thathomologizeris robust to a wide range of factors, such as incomplete lineage sorting and the phylogenetic informativeness of loci. Furthermore, we establish the utility ofhomologizeron real data, by analyzing a multilocus dataset consisting of nine diploids and 19 tetraploids from the fern family Cystopteridaceae.Finally, we describe howhomologizermay potentially be used beyond its core phasing functionality to identify non-homologous sequences, such as hidden paralogs or contaminants.
The Biogeography of Fungal Communities Across Different Chinese Wine-producing Regions Associated with Environmental Factors and Spontaneous Fermentation Performance
Authors: Li Ruilong , Yang Siyu , Lin Mengyuan , Guo Sijiang , Han Xiaoyu , Ren Mengmeng , Du Le , Song Yinghui , You Yilin , Zhan Jicheng , Huang Weidong 
Published: October 2020

AbstractChinese Marselan grapes are believed to possess the potential to become a characteristic regional variety, whose quality is internationally recognized. The fermentation-related mycobiota from six climatically diverse Marselan-producing regions in China were analyzed via high-throughput sequencing (HTS), while the influence of environmental factors was evaluated as well. The results implied that the phyla Ascomycota and genusAureobasidiumdominated the fungal communities in 166 Marselan must and ferment samples. Significant differences were detected in the fungal microbiota from the regions, as well as the wineries, while these discrepancies decreased as the fermentation progressed. Moreover, the difference in fungal communities between the wineries exceeded the variation involving the regions, and higher diversity was identified in the types of species than in the compositions. Geoclimatic elements (Gc) and physicochemical indexes (Pi) exerted a significant effect on the fungal must consortium, explaining 58.17% of the taxonomic information. Therefore, a correlation was proposed between the spontaneous fermentation performance, as well as the polyphenol (PP) content, and their association with fungal taxonomic composition. In addition to enriching the knowledge regarding the wine microbiome and its influencing factors, this study may provide a new strategy for harnessing autochthonous “microbial terroir”.ImportanceWine microbiome and their metabolism play a crucial role in wine quality. Chinese wine-producing regions are widely distributed with diverse geoclimatic conditions, this study reports a most comprehensive biogeography of fermentation-related fungal communities performed to date, taking the Chinese promising Marselan grape variety as the research object. It reveals significant differences in the fungal microbiota of Marselan must and ferment from different regions and wineries, and higher otherness between species type than that between species composition. The study also reports the main geoclimatic and physicochemical factors shaping fungal flora. Moreover, a correlation was proposed among the spontaneous fermentation performance with fungal taxonomic composition and polyphenol content. Taken together, the results shed light on the wine fungal communities and its influencing factors, which is crucial for vineyard and fermentation microorganism management, and may also provide a new strategy for harnessing autochthonous “microbial terroir” by utilizing spontaneous fermentation.
B LYMPHOCYTES, BUT NOT DENDRITIC CELLS, EFFICIENTLY HIV-1TRANS-INFECT NAÏVE CD4+T CELLS: IMPLICATIONS FOR THE VIRAL RESERVOIR
Authors: Gerberick Abigail , DeLucia Diana C. , Piazza Paolo , Alaoui-El-Azher Mounia , Rinaldo Charles R. , Sluis-Cremer Nicolas , Rappocciolo Giovanna 
Published: October 2020

AbstractInsight into the establishment and maintenance of HIV-1 infection in resting CD4+T cell subsets is critical for the development of therapeutics targeting the HIV-1 reservoir. Although the frequency of HIV-1 infection, as quantified by the frequency of HIV-1 DNA, is lower in CD4+naïve T cells (TN) compared to the memory T cell subsets, recent studies have shown that TNcells harbor a large pool of replication-competent virus. Interestingly, however, TNcells are highly resistant to direct (cis) HIV-1 infectionin vitro, in particular to R5-tropic HIV-1, as TNcells do not express CCR5. In this study, we investigated whether TNcells could be efficiently HIV-1trans-infected by professional antigen-presenting B lymphocytes and myeloid dendritic cells (DC) in the absence of global T cell activation. We found that B cells, but not DC, have a unique ability to efficientlytransinfect TNcellsin vitro. In contrast, both B cells and DC mediated HIV-1transinfection of memory and activated CD4+T cells. Moreover, we found that TNisolated from HIV-1-infected nonprogressors (NP) harbor significantly disproportionately lower levels of HIV-1 DNA compared to TNisolated from progressors. This is consistent with our previous finding that APC derived from NP do not efficientlytrans-infect CD4+T cells due to alterations in APC cholesterol metabolism and cell membrane lipid raft organization. These findings support that B cell-mediatedtransinfection of TNcells with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression.ImportanceThe latent human immunodeficiency virus type 1 (HIV-1) reservoir in persons on antiretroviral therapy represents a major barrier to a cure. Although most studies have focused on the HIV-1 reservoir in the memory T cell subset, replication competent HIV-1 has been isolated from naïve T cells, and CCR5-tropic HIV-1 has been recovered from CCR5negTNcells from ART-suppressed HIV-1-infected individuals. In this study, we showed that CCR5negTNcells are efficientlytransinfected with R-5 tropic HIV-1 by B lymphocytes, but not by myeloid dendritic cells. Furthermore, we found that TNisolated from NP harbor no or significantly less copies of HIV-1 DNA compared to ART-suppressed progressors. These findings support that B cell-mediatedtransinfection of TNcells with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression. Understanding the establishment and maintenance of the HIV-1 latent reservoir is fundamental for the design of effective treatments for viral eradication.
SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and alters gene expression via direct interaction with host mRNAs
Authors: Nabeel-Shah Syed , Lee Hyunmin , Ahmed Nujhat , Marcon Edyta , Farhangmehr Shaghayegh , Pu Shuye , Burke Giovanni L. , Ashraf Kanwal , Wei Hong , Zhong Guoqing , Tang Hua , Yang Jianyi , Blencowe Benjamin J. , Zhang Zhaolei , Greenblatt Jack F. 
Published: October 2020

AbstractThe COVID-19 pandemic has caused over one million deaths thus far. There is an urgent need for the development of specific viral therapeutics and a vaccine. SARS-CoV-2 nucleocapsid (N) protein is highly expressed upon infection and is essential for viral replication, making it a promising target for both antiviral drug and vaccine development. Here, starting from a functional proteomics workflow, we initially catalogued the protein-protein interactions of 21 SARS-CoV-2 proteins in HEK293 cells, finding that the stress granule resident proteins G3BP1 and G3BP2 copurify with N with high specificity. We demonstrate that N protein expression in human cells sequesters G3BP1 and G3BP2 through its physical interaction with these proteins, attenuating stress granule (SG) formation. The ectopic expression of G3BP1 in N-expressing cells was sufficient to reverse this phenotype. Since N is an RNA-binding protein, we performed iCLIP-sequencing experiments in cells, with or without exposure to oxidative stress, to identify the host RNAs targeted by N. Our results indicate that SARS-CoV-2 N protein binds directly to thousands of mRNAs under both conditions. Like the G3BPs stress granule proteins, N was found to predominantly bind its target mRNAs in their 3’UTRs. RNA sequencing experiments indicated that expression of N results in wide-spread gene expression changes in both unstressed and oxidatively stressed cells. We suggest that N regulates host gene expression by both attenuating stress granules and binding directly to target mRNAs.
The Oscillatory Effects of Rhythmic Median Nerve Stimulation
Authors: Houlgreave Mairi S. , Maiquez Barbara Morera , Brookes Matthew J. , Jackson Stephen R. 
Published: October 2020

AbstractEntrainment of brain oscillations can be achieved using rhythmic non-invasive brain stimulation, and stimulation of the motor cortex at a frequency associated with sensorimotor inhibition can impair motor responses. Despite the potential for therapeutic application, these techniques do not lend themselves to use outside of a clinical setting. Here, the aim was to investigate whether rhythmic median nerve stimulation (MNS) could be used to entrain oscillations related to sensorimotor inhibition. MEG data were recorded from 20 participants during 400 trials, where for each trial 10 pulses of MNS were delivered either rhythmically or arrhythmically at 12 or 20Hz. Our results demonstrate a frequency specific increase in relative amplitude in the contralateral somatosensory cortex during rhythmic but not arrhythmic stimulation. This was coupled with an increase in inter-trial phase coherence at the same frequency, suggesting that the oscillations synchronised with the pulses of MNS. While the results show that 20Hz rhythmic peripheral nerve stimulation can produce entrainment, the response to 12Hz stimulation was largely due to the presence of rhythmic sensory evoked potentials. Regardless, rhythmic MNS resulted in synchronous firing of neuronal populations within the contralateral somatosensory cortex meaning these neurons were ‘occupied’ in processing of the afferent input. Therefore, MNS could prove therapeutically useful in disorders associated with hyperexcitability within the sensorimotor cortices.
Functional Molecular Switches of Mammalian G Protein-Coupled Bitter-Taste Receptors
Authors: Topin Jérémie , Bouysset Cédric , Pacalon Jody , Kim Yiseul , Rhyu MeeRa , Fiorucci Sébastien , Golebiowski Jérôme 
Published: October 2020

AbstractBitter taste receptors (TAS2Rs) are a poorly understood subgroup of G protein-coupled receptors (GPCRs). The experimental structure of these receptors has yet to be determined, and key-residues controlling their function remain mostly unknown. We designed an integrative approach to improve comparative modeling of TAS2Rs. Using current knowledge on class A GPCRs and existing experimental data in the literature as constraints, we pinpointed conserved motifs to entirely re-align the amino-acid sequences of TAS2Rs. We constructed accurate homology models of human TAS2Rs. As a test case, we examined the accuracy of the TAS2R16 model with site-directed mutagenesis andin vitrofunctional assays. This combination ofin silicoandin vitroresults clarify sequence-function relationships and identify the functional molecular switches that encode agonist sensing and downstream signaling mechanisms within mammalian TAS2Rs sequences.ClassificationBiological sciences, Computational biology, and bioinformatics
Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer
Authors: Baca Sylvan C. , Takeda David Y. , Seo Ji-Heui , Hwang Justin , Ku Sheng Yu , Arafeh Rand , Arnoff Taylor , Agarwal Supreet , Bell Connor , O’Connor Edward , Qiu Xintao , Alaiwi Sarah Abou , Corona Rosario I. , Fonseca Marcos A. S. , Giambartolomei Claudia , Cejas Paloma , Lim Klothilda , He Monica , Sheahan Anjali , Nassar Amin , Berchuck Jacob E. , Brown Lisha , Nguyen Holly M. , Coleman Ilsa M. , Kaipainen Arja , De Sarkar Navonil , Nelson Peter S. , Morrissey Colm , Korthauer Keegan , Pomerantz Mark M. , Ellis Leigh , Pasaniuc Bogdan , Lawrenson Kate , Kelly Kathleen , Zoubeidi Amina , Hahn William C. , Beltran Himisha , Long Henry W. , Brown Myles , Corey Eva , Freedman Matthew L. 
Published: October 2020

AbstractLineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer1,2. An archetypal example is the development of neuroendocrine prostate cancer (NEPC) after treatment of prostate adenocarcinoma (PRAD) with inhibitors of androgen signaling. NEPC is an aggressive variant of prostate cancer that aberrantly expresses genes characteristic of neuroendocrine (NE) tissues and no longer depends on androgens. To investigate the epigenomic basis of this resistance mechanism, we profiled histone modifications in NEPC and PRAD patient-derived xenografts (PDXs) using chromatin immunoprecipitation and sequencing (ChIP-seq). We identified a vast network ofcis-regulatory elements (N~15,000) that are recurrently activated in NEPC. The FOXA1 transcription factor (TF), which pioneers androgen receptor (AR) chromatin binding in the prostate epithelium3,4, is reprogrammed to NE-specific regulatory elements in NEPC. Despite loss of dependence upon AR, NEPC maintains FOXA1 expression and requires FOXA1 for proliferation and expression of NE lineage-defining genes. Ectopic expression of the NE lineage TFs ASCL1 and NKX2-1 in PRAD cells reprograms FOXA1 to bind to NE regulatory elements and induces enhancer activity as evidenced by histone modifications at these sites. Our data establish the importance of FOXA1 in NEPC and provide a principled approach to identifying novel cancer dependencies through epigenomic profiling.
External light dark cycle shapes gut microbiota through intrinsically photosensitive retinal ganglion cells
Authors: Lee Chi-Chan , Lu Tsung-Hao , Lee I-Chi , Zou Yan-Fang , Yu Hon-Tsen , Chen (Alen) Shih-Kuo 
Published: October 2020

AbstractGut microbiota has been shown to involve in many physiological functions such as metabolism, brain development, and neuron degeneration disease. Intriguingly, many microbes in the digestive tract do not maintain a constant level of their relative abundance but show daily oscillations under normal conditions. Recent evidence indicates that chronic jetlag, constant darkness, or deletion of the circadian core gene can alter the composition of gut microbiota and dampen the daily oscillation of gut microbes. These studies suggest that the interaction between the host circadian clock and the light-dark cycle plays an important role in gut homeostasis and microbiota. However, how or whether environmental factors such as the light-dark cycle could modulate gut microbiota is still poorly understood. Using genetic mouse models and 16s rRNA metagenomic analysis, we found that light-dark cycle information transmitted by the ipRGC-sympathetic circuit was essential for daily oscillations of gut microbes under temporal restricted high fat diet condition. Furthermore, aberrant light exposure such as dim light at night (dLAN), acting through intrinsically photosensitive retinal ganglion cells (ipRGCs), could alter the composition, relative abundance, and daily oscillations of gut microbiota. Together, our results indicate that external stimulation, such as light-dark cycle information, through the sensory system can modulate gut microbiota in the direction from the brain to the gut.
Performance and impact of using a rapid molecular test to detectChlamydia trachomatisandNeisseria gonorrhoeaein women suspected of having pelvic inflammatory disease
Authors: Munrós J , Vergara A , Bataller E , Restovic G , García-Lorenzo B , Álvarez-Martínez MJ , Mira A , Carmona F , Vila J , Bosch J 
Published: October 2020

ABSTRACTObjectiveThe diagnosis of pelvic inflammatory disease (PID) is challenging. Testing forChlamydia trachomatis(CT) andNeisseria gonorrhoeae(NG) in the lower genital tract is recommended, since a positive result supports the diagnosis. The aim of this study was to investigate the prevalence of CT/NG infection in women suspected of having PID and the usefulness of a rapid molecular test to detect CT/NG.MethodsThis observational study included 3 groups of patients: mild-to-moderate PID (n=33), severe PID (n=29) and non-specific lower abdominal pain (NSAP) (n=13). CT/NG infection were analyzed using a standard and a rapid test. A cost analysis was carried out.ResultsThe presence of CT/NG was determined in 75 endocervical and urine samples. Endocervical samples of 19 patients (25.3%) were CT/ NG positive (two cases of co-infection). NG was not detected in urine in one case. Concordance between rapid and standard tests was 100%. However, the mean time to achieve results was shorter with the rapid test: 2.22vs.24.37 hours, respectively (p< 0.001). No significant differences were observed in the presence of CT/NG in mild-to-moderate compared to severe PID. Costs differed according only to disease severity but to the presence of CT/NG. Only one patient with NSAP was positive for CT.ConclusionsRapid molecular tests could help with the diagnosis of PID in sexually active women in clinical settings in which a standard technique is not available. Nonetheless, a positive test for CT/NG may not be determinant of the clinical management. The only cost difference relates to disease severity.
PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma
Authors: Edge Sarah D. , Renard Isaline , Pyne Emily , Moody Hannah , Roy Rajarshi , Beavis Andrew W. , Archibald Stephen J. , Cawthorne Christopher J. , Maher Stephen G. , Pires Isabel M. 
Published: October 2020

AbstractObjectivesNeoadjuvant chemo-radiotherapy (neo-CRT) prior to surgery is the standard of care for oesophageal adenocarcinoma (OAC) patients. Unfortunately, most patients fail to respond to treatment. MiR-187 was previously shown to be downregulated in neo-CRT non-responders, whistin vitromiR-187 overexpression enhanced radio-sensitivity and upregulatedPTEN. This study evaluates the role of miR-187 and downstream PI3K signalling in radiation response in OAC.MethodsThe effect of miR-187 overexpression on downstream PI3K signalling was evaluated in OAC cell lines by qPCR and western blotting.PTENexpression was analysed in OAC pre-treatment biopsies of neo-CRT responders and non-responders. Pharmacological inhibition of PI3K using GDC-0941 was evaluated in combination with radiotherapy in 2D and 3D OAC modelsin vitroand as a single agentin vivo. Radiation responsein vitrowas assessed via clonogenic assay.ResultsPTENexpression was significantly decreased in neo-CRT non-responders. MiR-187 overexpression significantly upregulatedPTENexpression and inhibited downstream PI3K signallingin vitro. GDC-0941 significantly reduced viability and enhanced radiation responsein vitroand led to tumour growth inhibition as a single agentin vivo.ConclusionsTargeting of PI3K signalling is a promising therapeutic strategy for OAC patients who have repressed miR-187 expression and do not respond to conventional neo-CRT.Advances in knowledgeThis is the first study evaluating the effect of PI3K inhibition on radio-sensitivity in OAC, with a particular focus on patients that do not respond to neo-CRT. We have shown for the 1sttime that targeting of PI3K signalling is a promising alternative therapeutic strategy for OAC patients who do not respond to conventional neo-CRT.
Evolution of Antibiotic Tolerance Shapes Resistance Development in ChronicPseudomonas aeruginosaInfections
Authors: Santi Isabella , Manfredi Pablo , Maffei Enea , Egli Adrian , Jenal Urs 
Published: October 2020

AbstractThe widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we usedin vitroevolution and analyzed inpatient microevolution ofPseudomonas aeruginosa, an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistancein vitroand we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections,P. aeruginosafirst acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multi-drug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections.