bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of noncanonical antigens to virulence and adaptive immunity in human infection with enterotoxigenicE. coli
Authors: Kuhlmann FM , Laine RO , Afrin S , Nakajima R , Akhtar M , Vickers T , Parker K , Nizam NN , Grigura V , Goss CW , Felgner PL , Rasko DA , Qadri F , Fleckenstein JM 
Published: October 2020

AbstractEnterotoxigenicE. coli(ETEC) contribute significantly to the substantial burden of infectious diarrhea among children living in low and middle income countries. In the absence of a vaccine for ETEC, children succumb to acute dehydration as well as non-diarrheal sequelae related to these infections including malnutrition. The considerable diversity of ETEC genomes has complicated canonical vaccine development approaches focused on a subset of antigens known as colonization factors (CFs). To identify additional conserved immunogens, we mined genomic sequences of 89 ETEC isolates, bioinformatically selected potential surface-exposed pathovar-specific antigens conserved in more than 40% of the genomes (n=118), and assembled the representative proteins onto microarrays, complemented with known or putative colonization factor subunit molecules (n=52), and toxin subunits to interrogate samples from individuals with acute symptomatic ETEC infections. Surprisingly, in this open-aperture approach, we found that immune responses were largely constrained to a small number of antigens including individual colonization factor antigens and EtpA, an extracellular adhesin. In a Bangladeshi cohort of naturally infected children < 2 years of age, both EtpA and a second noncanonical antigen, EatA, elicited significant serologic responses that were associated with protection from symptomatic illness. In addition, children infected with ETEC isolates bearing eitheretpA or eatAgenes were significantly more likely to develop symptomatic disease. These studies support a role for more recently discovered noncanonical antigens in virulence and the development of adaptive immune responses during ETEC infections, findings that may inform vaccine design efforts to complement existing approaches.
Patterns of Multimorbidity and Risk of Severe SARS-CoV-2 Infection: an observational study in the U.K
Authors: Chudasama Yogini V , Zaccardi Francesco , Gillies Clare L , Razieh Cameron , Yates Thomas , Kloecker David E , Rowlands Alex V , Davies Melanie J , Islam Nazrul , Seidu Samuel , Forouhi Nita G , Khunti Kamlesh 
Published: October 2020

ABSTRACTBackgroundPre-existing comorbidities have been linked to SARS-CoV-2 infection but evidence is sparse on the importance and pattern of multimorbidity (2 or more conditions) and severity of infection indicated by hospitalisation or mortality. We aimed to use a multimorbidity index developed specifically for COVID-19 to investigate the association between multimorbidity and risk of severe SARS-CoV-2 infection.MethodsWe used data from the UK Biobank linked to laboratory confirmed test results for SARS-CoV-2 infection and mortality data from Public Health England between March 16 and July 26, 2020. By reviewing the current literature on COVID-19 we derived a multimorbidity index including: 1) angina; 2) asthma; 3) atrial fibrillation; 4) cancer; 5) chronic kidney disease; 6) chronic obstructive pulmonary disease; 7) diabetes mellitus; 8) heart failure; 9) hypertension; 10) myocardial infarction; 11) peripheral vascular disease; 12) stroke. Adjusted logistic regression models were used to assess the association between multimorbidity and risk of severe SARS-CoV-2 infection (hospitalisation or death). Potential effect modifiers of the association were assessed: age, sex, ethnicity, deprivation, smoking status, body mass index, air pollution, 25‐hydroxyvitamin D, cardiorespiratory fitness, high sensitivity C-reactive protein.ResultsAmong 360,283 participants, the median age was 68 [range, 48-85] years, most were White (94.5%), and 1,706 had severe SARS-CoV-2 infection. The prevalence of multimorbidity was more than double in those with severe SARS-CoV-2 infection (25%) compared to those without (11%), and clusters of several multimorbidities were more common in those with severe SARS-CoV-2 infection. The most common clusters with severe SARS-CoV-2 infection were stroke with hypertension (79% of those with stroke had hypertension); diabetes and hypertension (72%); and chronic kidney disease and hypertension (68%). Multimorbidity was independently associated with a greater risk of severe SARS-CoV-2 infection (adjusted odds ratio 1.91 [95% confidence interval 1.70, 2.15] compared to no multimorbidity). The risk remained consistent across potential effect modifiers, except for greater risk among men.ConclusionThe risk of severe SARS-CoV-2 infection is higher in individuals with multimorbidity, indicating the need to target research and resources in people with SARS-CoV-2 infection and multimorbidity.
Alpha globin variation in the long-tailed macaque suggests malaria selection
Authors: Faust C.L. , Rangkuti F. , Preston S. G. , Boyd A. , Flammer P. , Bia B. , Rose N. J. , Piel F. B. , Smith A. L. , Dobson A.P. , Gupta S. , Penman B. S. 
Published: October 2020

AbstractHuman haemoglobin variants, such as sickle, confer protection against death from malaria; consequently, frequencies of such variants are often greatly elevated in humans from malaria endemic regions. Among non-human primates, the long-tailed macaque,Macaca fascicularis, also displays substantial haemoglobin variation. Almost allM. fascicularishaemoglobin variation is in the alpha globin chain, encoded by two linked genes:HBA1andHBA2. We demonstrate that alpha globin variation inM. fasciculariscorrelates with the strength of malaria selection. We identify a range of missense mutations inM. fascicularisalpha globin and demonstrate that some of these exhibit a strikingHBA1orHBA2specificity, a pattern consistent with computational simulations of selection on genes exhibiting copy number variation. We propose thatM. fascicularisaccumulated amino acid substitutions in its alpha globin genes under malaria selection, in a process that closely mirrors, but does not entirely converge with, human malaria adaptation.
PEPATAC: An optimized pipeline for ATAC-seq data analysis with serial alignments
Authors: Smith Jason P. , Corces M. Ryan , Xu Jin , Reuter Vincent P. , Chang Howard Y. , Sheffield Nathan C. 
Published: October 2020

MotivationAs chromatin accessibility data from ATAC-seq experiments continues to expand, there is continuing need for standardized analysis pipelines. Here, we present PEPATAC, an ATAC-seq pipeline that is easily applied to ATAC-seq projects of any size, from one-off experiments to large-scale sequencing projects.ResultsPEPATAC leverages unique features of ATAC-seq data to optimize for speed and accuracy, and it provides several unique analytical approaches. Output includes convenient quality control plots, summary statistics, and a variety of generally useful data formats to set the groundwork for subsequent project-specific data analysis. Downstream analysis is simplified by a standard definition format, modularity of components, and metadata APIs in R and Python. It is restartable, fault-tolerant, and can be run on local hardware, using any cluster resource manager, or in provided Linux containers. We also demonstrate the advantage of aligning to the mitochondrial genome serially, which improves the accuracy of alignment statistics and quality control metrics. PEPATAC is a robust and portable first step for any ATAC-seq project.AvailabilityBSD2-licensed code and documentation athttps://pepatac.databio.org.
Widespread effects of DNA methylation and intra-motif dependencies revealed by novel transcription factor binding models
Authors: Grau Jan , Schmidt Florian , Schulz Marcel H. 
Published: October 2020

AbstractSeveral studies suggested that transcription factor (TF) binding to DNA may be impaired or enhanced by DNA methylation. We present MeDeMo, a toolbox for TF motif analysis that combines information about DNA methylation with models capturing intra-motif dependencies. In a large-scale study using ChIP-seq data for 335 TFs, we identify novel TFs that are affected by DNA methylation. Overall, we find that CpG methylation decreases the likelihood of binding for the majority of TFs. For a considerable subset of TFs, we show that intra-motif dependencies are pivotal for accurately modelling the impact of DNA methylation on TF binding.
Combination of arsenic trioxide epigallocatechin-3-gallate and Resveratrol synergistically suppresses the growth and invasion in Brain tumor cell lines
Authors: Sajjadi Roshanak S. , Ahmadi Samaneh , Mantashloo Marziye , Layeghi Sepideh Mehrpour , Asgari Yazdan , Ghorbani Mohammad , Mohammadi Seyed Danial , Saffari Mojtaba 
Published: October 2020

AbstractThe glioblastoma multiform has some properties including rapid growth, invasion, treatment resistance, and recurrence. Therefore, new therapies need to be developed that can be approved for using in patients. The previous study showed Arsenic Trioxide inhibits aggressive behavior in glioblastoma cells. Also, (–)-epigallocatechin-3-gallate prevents cellular proliferation, and invasion in multiple glioma cells. Resveratrol decreases cellular proliferation, induces cell death, and impaired the invasiveness of glioma cells. Combination therapy to inhibit cancer cells may have important clinical implications. Therefore, to assess the combination therapy of 2μM Arsenic trioxide, 100μM EGCG, and 100μM Resveratrol, we examined the metabolic activity, colony formation, media pH, cell proliferation, Caspase 3 activity, and gene expression analysis of BCL2, Caspase 3, MMP2, MMP9, CA9, u-PA, u-PAR, and Cathepsin B genes in apoptosis and invasion by both quantitative PCR experiments and Western blot assay. Systems biology tools also were used to obtain, the related network, involved pathways, and identifying the key genes in our selected criteria. The results of the study confirmed that the combined therapy prevents cell proliferation and induces of apoptosis in the Brain tumor cell lines including: U87-MG, A-172, and 1321N1. Furthermore, over-expression of caspase-3 and down-regulation of BCL-2, MMP-2, and MMP-9 confirmed that combination therapy leads to induces apoptosis and decreases invasion. Nevertheless, the lowering of pharmacological doses and improving therapeutic efficacy through combination therapy may provide advantages to treat resistance cancer cells with lower side effects. Finally, the results might suggest new modality for Glioblastoma treatment.
Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction
Authors: Tribble James R , Otmani Amin , Sun Shanshan , Ellis Sevannah A , Cimaglia Gloria , Vohra Rupali , Jöe Melissa , Lardner Emma , Venkataraman Abinaya P , Domínguez-Vicent Alberto , Kokkali Eirini , Rho Seungsoo , Jóhannesson Gauti , Burgess Robert W , Fuerst Peter G , Brautaset Rune , Kolko Miriam , Morgan James E , Crowston Jonathan G , Votruba Marcela , Williams Pete A 
Published: October 2020

AbstractNicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. Repleting NAD via dietary supplementation of nicotinamide (a precursor to NAD) is effective in preventing retinal ganglion cell neurodegeneration in mouse models. Supporting this, short-term oral nicotinamide treatment in human glaucoma patients provides a recovery of retinal ganglion cell function implying a protection of visual function. Despite this, the mechanism of neuroprotection and full effects of nicotinamide on retinal ganglion cells is unclear. Glaucoma is a complex neurodegenerative disease in which a mix of healthy, stressed, and degenerating retinal ganglion cells co-exist, and in which retinal ganglion cells display compartmentalized degeneration across their visual trajectory. Therefore, we assess the effects of nicotinamide on retinal ganglion cells in normal physiological conditions and across a range of glaucoma relevant insults. We confirm neuroprotection afforded by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We define a small molecular weight metabolome for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption that can be prevented by nicotinamide. Nicotinamide provides these neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term NAM treatment as a neuroprotective therapy for human glaucoma.One Sentence SummaryThe NAD precursor nicotinamide has a potent neuroprotective effect in the retina and optic nerve, targeting neuronal function, metabolism, and mitochondrial function.
A stacked ensemble method for forecasting influenza-like illness visit volumes at emergency departments
Authors: de Amorim Arthur Novaes , Deardon Rob , Saini Vineet 
Published: October 2020

AbstractAccurate and reliable short-term forecasts of influenza-like illness (ILI) visit volumes at the emergency departments can improve staffing and resource allocation decisions in each hospital. In this paper, we developed a stacked ensemble model that averages the predictions from various competing methodologies in the current frontier for ILI-related forecasts. We also constructed a back-of-the-envelope prediction interval for the stacked ensemble, which provides a conservative characterization of the uncertainty in the stacked ensemble predictions. We assessed the reliability and accuracy of our model’s 1 to 4 weeks ahead forecasts using real-time hospital-level data on weekly ILI visit volumes during the 2012-2018 flu seasons in the Alberta Children’s Hospital, located in Calgary, Alberta, Canada. Over this time period, our model’s prediction deviated from the realized ILI visit volume by an average of 12% for 1 week ahead forecasts, with a 90% prediction interval having coverage rates ranging from 90.7 to 97.7%.
PharmaNet: Pharmaceutical discovery with deep recurrent neural networks
Authors: Puentes Paola Ruiz , Valderrama Natalia , González Cristina , Daza Laura , Muñoz-Camargo Carolina , Cruz Juan C. , Arbeláez Pablo 
Published: October 2020

AbstractThe discovery and development of novel pharmaceuticals is an area of active research mainly due to the large investments required and long payback times. As of 2016, the development of a novel drug candidate required up to $ USD 2.6 billion in investment for only 10% rate of approval by the FDA. To help decreasing the costs associated with the process, a number ofin silicoapproaches have been developed with relatively low success due to limited predicting performance. Here, we introduced a machine learning-based algorithm as an alternative for a more accurate search of new pharmacological candidates, which takes advantage of Recurrent Neural Networks (RNN) for active molecule prediction within large databases. Our approach, termed PharmaNet was implemented here to search for ligands against specific cell receptors within 102 targets of the DUD-E database, which contains 22886 active molecules. PharmaNet comprises three main phases. First, a SMILES representation of the molecule is converted into araw molecular image. Second, a convolutional encoder processes the data to obtain afingerprint molecular imagethat is finally analyzed by a Recurrent Neural Network (RNN). This approach enables precise predictions of the molecules’ target on the basis of the feature extraction, the sequence analysis and the relevant information filtered out throughout the process. Molecule Target prediction is a highly unbalanced detection problem and therefore, we propose that an adequate evaluation metric of performance is the area under the Normalized Average Precision (NAP) curve. PharmaNet largely surpasses the previous state-of-the-art method with 97.7% in the Receiver Operating Characteristic curve (ROC-AUC) and 65.5% in the NAP curve. We obtained a perfect performance for human farnesyl pyrophosphate synthase (FPPS), which is a potential target for antimicrobial and anticancer treatments. We decided to test PharmaNet for activity prediction against FPPS by searching in the CHEMBL data set. We obtained three (3) potential inhibitors that were further validated through both molecular docking andin silicotoxicity prediction. Most importantly, one of this candidates, CHEMBL2007613, was predicted as a potential antiviral due to its involvement on thePCDH17pathway, which has been reported to be related to viral infections.
Dorsal anterior cingulate cortex intrinsic functional connectivity linked to electrocortical measures of error-monitoring
Authors: Gilbertson Hayley , Fang Lin , Andrzejewski Jeremy A. , Carlson Joshua M. 
Published: October 2020

AbstractThe error-related negativity (ERN) is a response-locked event-related potential, occurring approximately 50 ms following an erroneous response at frontocentral electrode sites. Source localization and functional magnetic resonance imaging (fMRI) research indicate that the ERN is likely generated by activity in the dorsal anterior cingulate cortex (dACC). The dACC is thought to be a part of a broader network of brain regions that collectively comprise an error-monitoring network. However, little is known about how intrinsic connectivity within the dACC-based error-monitoring network contributes to variability in ERN amplitude. The purpose of this study was to assess the relationship between dACC functional connectivity and ERN amplitude. In a sample of 53 highly trait-anxious individuals, the ERN was elicited in a flanker task and functional connectivity was assessed in a 10-minute resting-state fMRI scan. Results suggest that the strength of dACC seeded functional connectivity with the supplementary motor area is correlated with the ΔERN (i.e., incorrect – correct responses) amplitude such that greater ΔERN amplitude was accompanied by greater functional coupling between these regions. In addition to the dACC, exploratory analyses found that functional connectivity in the caudate, cerebellum, and a number of regions in the error-monitoring network were linked to variability in ΔERN amplitude. In sum, ERN amplitude appears to be related to the strength of functional connectivity between error-monitoring and motor control regions of the brain.
The state of oligomerization of Rubisco controls the rate of LSU translation inChlamydomonas reinhardtii
Authors: Wietrzynski Wojciech , Traverso Eleonora , Wollman Francis-André , Wostrikoff Katia 
Published: October 2020

AbstractRibulose 1,5-bisphosphate Carboxylase/Oxygenase (Rubisco) is a key enzyme for photosynthesis-driven life on Earth. While present in all photosynthetic organisms, its most prominent form is a hetero-oligomer in which a Small Subunit (SSU) stabilizes the core of the enzyme built from Large Subunits (LSU), yielding, after a chaperone-assisted multistep assembly, a LSU8SSU8hexadecameric holoenzyme. Here we useChlamydomonas reinhardtii, and a combination of site-directed mutants, to dissect the multistep biogenesis pathway of Rubiscoin vivo. We identify assembly intermediates, in two of which LSU is associated with the RAF1 chaperone. Using genetic and biochemical approaches we further unravel a major regulation process during Rubisco biogenesis which places translation of its large subunit under the control of its ability to assemble with the small subunit, by a mechanism of Control by Epistasy of Synthesis (CES). Altogether this leads us to propose a model where the last assembly intermediate, an octameric LSU8-RAF1 complex which delivers LSU to SSU to form the Rubisco enzyme, converts to a key regulator form able to exert a negative feed-back on the initiation of translation of LSU, when SSU is not available.
Ultrasound neuromodulation through nanobubble-actuated sonogenetics
Authors: Hou Xuandi , Qiu Zhihai , Kala Shashwati , Guo Jinghui , Wong Kin Fung , Zhu Ting , Zhu Jiejun , Xian Quanxiang , Yang Minyi , Sun Lei 
Published: October 2020

AbstractUltrasound neuromodulation is a promising new method to manipulate brain activity noninvasively. Here, we detail a neurostimulation scheme using gas-filled nanostructures, gas vesicles (GVs), as actuators for improving the efficacy and precision of ultrasound stimuli. Sonicated primary neurons displayed dose-dependent, repeatable Ca2+responses, closely synced to stimuli, and increased nuclear expression of the activation marker c-Fos only in the presence of GVs but not without. We identified mechanosensitive ion channels as important mediators of this effect, and neurons heterologously expressing the mechanosensitive MscL-G22S channel showed greater activation at lower acoustic pressure. This treatment scheme was also found not to induce significant cytotoxicity, apoptosis or membrane poration in treated cells. Altogether, we demonstrate a simple and effective method to achieve enhanced and more selective ultrasound neurostimulation.Graphical abstract
Genetic effects on brain traits impact cell-type specific gene regulation during neurogenesis
Authors: Aygün Nil , Elwell Angela L. , Liang Dan , Lafferty Michael J. , Cheek Kerry E. , Courtney Kenan P. , Mory Jessica , Hadden-Ford Ellie , Krupa Oleh , de la Torre-Ubieta Luis , Geschwind Daniel H. , Love Michael I. , Stein Jason L. 
Published: October 2020

AbstractInterpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map expression quantitative trait loci (eQTLs), splicing QTLs (sQTLs), and allele specific expression in primary human neural progenitors (n=85) and their sorted neuronal progeny (n=74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome wide association, we uncover cell-type specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL forCENPWco-localized with common variant associations of cortical area and educational attainment.
Restriction of SARS-CoV-2 Replication by Targeting Programmed −1 Ribosomal Frameshifting In Vitro
Authors: Sun Yu , Abriola Laura , Surovtseva Yulia V. , Lindenbach Brett D. , Guo Junjie U. 
Published: October 2020

SUMMARYTranslation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires programmed −1 ribosomal frameshifting (−1 PRF) promoted by an RNA pseudoknot. The extent to which SARS-CoV-2 replication may be sensitive to changes in −1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a −1 PRF inhibitor of SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on −1 PRF of other beta coronaviruses. Importantly, frameshift inhibition by merafloxacin substantially impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing the proof of principle of targeting −1 PRF as an effective antiviral strategy for SARS-CoV-2.