bluuebunny/crossref_metadata_2025_split huggingface dataset:
Restoration of β-globin expression with optimally designed lentiviral vector for β-thalassemia treatment in Chinese patients
Authors: Ouyang Wenjie , Dong Guoyi , Zhao Weihua , Li Jing , Zhou Ziheng , Yang Gaohui , Liu Rongrong , Li Yue , Zhang Qiaoxia , Du Xin , Sun Haixi , Gu Ying , Lai Yongrong , Liu Sixi , Liu Chao 
Published: July 2020

Abstractβ-thalassemia is one of the most prevalent genetic diseases worldwide. The current treatment for β–thalassemia is allogeneic hematopoietic stem cell transplantation (HSCT), which is limited due to lack of matched donors. Gene therapy has been developed as an alternative therapeutic option for transfusion-ependent β-thalassemia (TDT). However, successful gene therapy for β-thalassemia patients in China has not been reported. Here we present the results of preclinical studies of an optimally designed LV named LentiHBBT87Q in hematopoietic stem cells (HSCs) derived from Chinese TDT patients. LentiHBBT87Q was selected from a series of LVs with optimized backbone and de novo cloning strategy. It contains an exogenous T87Q β-globin gene (HBBT87Q) driven by a specific reconstituted locus control region (rLCR) and efficiently express HBB mRNA and HBB protein in erythroblasts derived from cord blood (CB) HSCs. To facilitate clinical transformation, we manufactured clinical grade LentiHBBT87Q (cLentiHBBT87Q) and optimized its transduction procedure. Importantly, transduction of cLentiHBBT87Qrestored expression of HBB monomer and adult hemoglobin (HbA) tetramer to relatively normal level in erythroblasts from bone marrow (BM) HSCs of Chinese TDT patients, that carry the most common mutation types and cover various genotypes, including β0/β0. Furthermore, viral integration sites (VIS) of cLentiHBBT87Q were similar to other LVs safely used in previous clinical trials and the associated risk of tumorigenesis was not observed in cLentiHBBT87Q transduced HSCs through comprehensive analysis. Taken together, we have engineered the cLentiHBBT87Q that can restore β-globin expression in the HSCs-derived erythroblasts of Chinese TDT patients with minimal risk on tumorigenesis, providing a favorable starting point for future clinical application.
Clinical Characteristics and Outcomes for 7,995 Patients with SARS-CoV-2 Infection
Authors: McPadden Jacob , Warner Frederick , Young H. Patrick , Hurley Nathan C. , Pulk Rebecca A. , Singh Avinainder , Durant Thomas JS , Gong Guannan , Desai Nihar , Haimovich Adrian , Taylor Richard Andrew , Gunel Murat , Cruz Charles S. Dela , Farhadian Shelli F. , Siner Jonathan , Villanueva Merceditas , Churchwell Keith , Hsiao Allen , Torre Charles J. , Velazquez Eric J. , Herbst Roy S. , Iwasaki Akiko , Ko Albert I. , Mortazavi Bobak J. , Krumholz Harlan M. , Schulz Wade L. 
Published: July 2020

AbstractObjectiveSevere acute respiratory syndrome virus (SARS-CoV-2) has infected millions of people worldwide. Our goal was to identify risk factors associated with admission and disease severity in patients with SARS-CoV-2.DesignThis was an observational, retrospective study based on real-world data for 7,995 patients with SARS-CoV-2 from a clinical data repository.SettingYale New Haven Health (YNHH) is a five-hospital academic health system serving a diverse patient population with community and teaching facilities in both urban and suburban areas.PopulationsThe study included adult patients who had SARS-CoV-2 testing at YNHH between March 1 and April 30, 2020.Main outcome and performance measuresPrimary outcomes were admission and in-hospital mortality for patients with SARS-CoV-2 infection as determined by RT-PCR testing. We also assessed features associated with the need for respiratory support.ResultsOf the 28605 patients tested for SARS-CoV-2, 7995 patients (27.9%) had an infection (median age 52.3 years) and 2154 (26.9%) of these had an associated admission (median age 66.2 years). Of admitted patients, 1633 (75.8%) had a discharge disposition at the end of the study period. Of these, 192 (11.8%) required invasive mechanical ventilation and 227 (13.5%) expired. Increased age and male sex were positively associated with admission and in-hospital mortality (median age 81.9 years), while comorbidities had a much weaker association with the risk of admission or mortality. Black race (OR 1.43, 95%CI 1.14-1.78) and Hispanic ethnicity (OR 1.81, 95%CI 1.50-2.18) were identified as risk factors for admission, but, among discharged patients, age-adjusted in-hospital mortality was not significantly different among racial and ethnic groups.ConclusionsThis observational study identified, among people testing positive for SARS-CoV-2 infection, older age and male sex as the most strongly associated risks for admission and in-hospital mortality in patients with SARS-CoV-2 infection. While minority racial and ethnic groups had increased burden of disease and risk of admission, age-adjusted in-hospital mortality for discharged patients was not significantly different among racial and ethnic groups. Ongoing studies will be needed to continue to evaluate these risks, particularly in the setting of evolving treatment guidelines.
Simulating drug effects on blood glucose laboratory test time series with a conditional WGAN
Authors: Yahi Alexandre , Tatonetti Nicholas P. 
Published: July 2020

AbstractThe unexpected effects of medications has led to more than 14 million drug adverse events reported to the Food and Drug Administration (FDA) over the past 10 years in the United States alone, with a little over 1.3 million of them linked to death, and represents a medical and financial burden on our healthcare. Laboratory tests have the potential to capture inter-individual variability in drug responses, but a significant portion of the patient population has unique treatment pathways that impedes forecasting and optimal decision making.Generative Adversarial Networks (GANs) are flexible implicit generative models that have demonstrated their ability to capture complex correlations in field like computer vision and natural language. Their latent representation capacity is an opportunity for drug effect simulation on laboratory test trajectories. In this paper, we developed and evaluated conditional GANs on glucose laboratory tests in patients exposed to drug combinations and showed a proof of concept for these models in the simulation of unseen drug combinations. By using conditional Wasserstein GANs (WGANs) to simulate drug effects in laboratory tests, we hope to pave the way for novel clinical decision support (CDM) systems and enable the development of better predictive models for rare cohorts of patients.
Plexin-B1 mutation drives prostate cancer metastasis
Authors: Shorning Boris , Trent Neil , Griffiths David , Worzfeld Thomas , Offermanns Stefan , Masters John , Clarke Alan R. , Smalley Matthew J. , Williamson Magali 
Published: July 2020

AbstractProstate cancer mortality is associated with the metastatic spread of tumour cells. A better understanding of the mechanisms which allow a locally advanced tumour to disseminate around the body will identify new therapeutic targets to block this process. One of set of genes implicated in metastasis are plexins, which can promote or suppress tumour progression depending on cancer type and cellular context. We have taken a mouse genetics approach to gain insight into the role of Plexin-B1 in prostate cancer progressionin vivo.We show here that genetic deletion of Plexin-B1 inPbCre+Ptenfl/flKrasG12VandPbCre+Ptenfl/flp53fl/flmouse prostate cancer models significantly decreased metastasis. High levels of prostate epithelial cell-specific expression of wild-type Plexin-B1 in knock-in mice with aPbCre+Ptenfl/flKrasG12Vbackground also significantly decreased metastasis. In contrast, expression of a Plexin-B1 mutant (P1597L; identified from metastatic deposits in prostate cancer patients) in prostate epithelial cells inPbCre+Ptenfl/flKrasG12VandPbCre+Ptenfl/flp53fl/flmice significantly increased metastasis, in particular metastasis to distant sites. In line with these findings, both deletion and overexpression of wild-type Plexin-B1 reduced invasion of tumour cells into the prostate stroma, while overexpression of mutant Plexin-B1 significantly increased invasion, suggesting that Plexin-B1 has a role in the initial stages of metastasis. Invasion and metastasis also correlated with phosphorylation of myosin light chain, suggesting that Plexin-B1 signals via the Rho/ROCK pathway to promote metastasis.Our results demonstrate that mutant Plexin-B1 promotes metastasis in prostate cancer and represents a new therapeutic target to suppress tumour spread.
CETSA®MS profiling for a comparative assessment of FDA approved antivirals repurposed for COVID-19 therapy identifies Trip13 as a Remdesivir off-target
Authors: Friman Tomas , Chernobrovkin Alexey , Molina Daniel Martinez , Arnold Laurence 
Published: July 2020

AbstractThe reuse of pre-existing small molecules for a novel emerging disease threat is a rapid measure to discover unknown applications for previously validated therapies. A pertinent and recent example where such strategy could be employed is in the fight against COVID-19. Therapies designed or discovered to target viral proteins also have off-target effects on the host proteome when employed in a complex physiological environment. This study aims to assess these host cell targets for a panel of FDA approved antiviral compounds including Remdesivir, using the cellular thermal shift assay (CETSA®) coupled to mass spectrometry (CETSA MS) in non-infected cells. CETSA MS is a powerful method to delineate direct and indirect interactions between small molecules and protein targets in intact cells. Biologically active compounds can induce changes in thermal stability, in their primary binding partners as well as in proteins that in turn interact with the direct targets. Such engagement of host targets by antiviral drugs may contribute to the clinical effect against the virus but can also constitute a liability. We present here a comparative study of CETSA molecular target engagement fingerprints of antiviral drugs to better understand the link between off-targets and efficacy.
Protein Structure Refinement Guided by Atomic Packing Frustration Analysis
Authors: Chen Mingchen , Chen Xun , Jin Shikai , Lu Wei , Lin Xingcheng , Wolynes Peter G. 
Published: July 2020

1AbstractRecent advances in machine learning, bioinformatics and the understanding of the folding problem have enabled efficient predictions of protein structures with moderate accuracy, even for targets when there is little information from templates. All-atom molecular dynamics simulations provide a route to refine such predicted structures, but unguided atomistic simulations, even when lengthy in time, often fail to eliminate incorrect structural features that would allow the structure to become more energetically favorable owing to the necessity of making large scale motions and overcoming energy barriers for side chain repacking. In this study, we show that localizing packing frustration at atomic resolution by examining the statistics of the energetic changes that occur when the local environment of a site is changed allows one to identify the most likely locations of incorrect contacts. The global statistics of atomic resolution frustration in structures that have been predicted using various algorithms provide strong indicators of structural quality when tested over a database of 20 targets from previous CASP experiments. Residues that are more correctly located turn out to be more minimally frustrated than more poorly positioned sites. These observations provide a diagnosis of both global and local quality of predicted structures, and thus can be used as guidance in all-atom refinement simulations of the 20 targets. Refinement simulations guided by atomic packing frustration turn out to be quite efficient and significantly improve the quality of the structures.
Phylogenetic diversity analysis of shotgun metagenomic reads describes gut microbiome development and treatment effects in the post-weaned pig
Authors: Gaio Daniela , DeMaere Matthew Z. , Anantanawat Kay , Eamens Graeme J , Zingali Tiziana , Falconer Linda , Chapman Toni A. , Djordjevic Steven , Darling Aaron E. 
Published: July 2020

AbstractBackgroundIntensive farming practices can increase exposure of animals to infectious agents against which antibiotics are used. Besides leading to antimicrobial resistance (AMR), orally administered antibiotics are well known to cause dysbiosis. To counteract dysbiotic effects, numerous studies in the past two decades sought to understand whether probiotics are a valid tool to help re-establish a healthy gut microbial community after antibiotic treatment. However, although dysbiotic effects of antibiotics are well investigated, little is known about the effects of intramuscular antibiotic treatment on the gut microbiome and a few studies attempted to study treatment effects using phylogenetic diversity analysis techniques. In this study we sought to determine the effects of two probiotic- and one intramuscularly administered antibiotic treatment on the developing gut microbiome of post-weaning piglets between their 3rdand 9thweek of life.MethodsShotgun metagenomic sequences from over 800 faecal time-series samples derived from 126 piglets and 42 sows were analysed in a phylogenetic framework to characterise the developing gut microbial community composition of post-weaning piglets. We assessed the effects of intramuscular antibiotic treatment and probiotic oral treatment on the diversity of these gut microbial communities using alpha and beta diversity measures.ResultsDifferences between individual hosts such as breed, litter, and age, were found to be important contributors to variation in the community composition. Host age was the dominant factor in shaping the gut microbiota of piglets after weaning. The post-weaning pig gut microbiome appeared to follow a highly structured developmental program with characteristic post-weaning changes that can distinguish hosts that were born as little as two days apart in the second month of life. Treatment effects of the antibiotic and probiotic treatments were found but were subtle and included a higher representation ofMollicutesassociated with intramuscular antibiotic treatment, and an increase ofLactobacillusassociated with probiotic treatment.DiscussionThe discovery of correlations between experimental factors and microbial community composition is more commonly addressed with OTU-based methods and rarely analysed via phylogenetic diversity measures. The latter method, although less intuitive than the former, suffers less from library size normalization biases, and it proved to be instrumental in this study for the discovery of correlations between microbiome composition and host-, and treatment factors.
Mapping specificity, entropy, allosteric changes and substrates in blood proteases by a high-throughput protease screen
Authors: Uliana Federico , Vizovišek Matej , Acquasaliente Laura , Ciuffa Rodolfo , Fossati Andrea , Frommelt Fabian , Gstaiger Matthias , De Filippis Vincenzo , auf dem Keller Ulrich , Aebersold Ruedi 
Published: July 2020

AbstractProteases are among the largest protein families in eukaryotic phylae with more than 500 genetically encoded proteases in humans. By cleaving a wide range of target proteins, proteases are critical regulators of a vast number of biochemical processes including apoptosis and blood coagulation. Over the last 20 years, knowledge of proteases has been drastically expanded by the development of proteomic approaches to identify and quantify proteases and their substrates. In spite of their merits, some of these methods are laborious, not scalable or incompatible with native environments. Consequentially, a large number of proteases remain poorly characterized. Here, we introduce a simple proteomic method to profile protease activity based on isolation of protease products from native lysates using a 96FASP filter and their analysis in a mass spectrometer. The method is significantly faster, cheaper, technically less demanding, easily multiplexed and produces accurate protease fingerprints in near-native conditions. By using the blood cascade proteases as a case study we obtained protease substrate profiles of unprecedented depth that can be reliably used to map specificity, entropy and allosteric changes of the protease and to design fluorescent probes and predict physiological substrates. The native protease characterization method is comparable in performance, but largely exceeds the throughput of current alternatives.
Hot, humid air decontamination of aircraft confirmed that high temperature and high humidity are critical for inactivation of infectious, enveloped ribonucleic acid (RNA) virus
Authors: Buhr Tony L. , Young Alice A. , Borgers-Klonkowski Erica , Kennihan Neil L. , Barnette Harold K. , Minter Zachary A. , Bohmke Matthew D. , Osborn Emily B. , Hamilton Shelia M. , Kimani Monique B. , Hammon Mark W. , Miller Charles T. , Mackie Ryan S. , Innocenti Jennifer M. , Bensman Misty D. , Gutting Bradford W. , Lilly Samuel D. , Hammer Emlyn E. , Yates Vanessa L. , Luck Brooke B. 
Published: July 2020

ABSTRACTAimsTo develop infectious (live/dead) enveloped virus test indicators and Response Surface Methodology (RSM) models that evaluate survival of an enveloped ribonucleic acid (RNA) virus on contaminated aircraft materials after exposure to hot, humid air (HHA).Methods and ResultsEnveloped RNA bacteriophage Phi6 (Φ6) was dried on wiring insulation, aircraft performance coating (APC), polypropylene, and nylon at ≥ 8 log10plaque-forming units (PFU) test coupon-1. Only 2.4 log10inactivation was measured on APC at 70°Celsius (°C), 5% relative humidity (RH) after 24 h. In contrast, HHA RSM models showed a 90% probability of a 7-log10inactivation at ≥63°C, 90% RH after 1 h, and decontamination kinetics were similar across different materials. HHA decontamination of C-130 and C-17 aircraft showed >7 log10and ≥5.9 log10inactivation of enveloped virus on 100 and 110 test indicators, respectively, with a 1-h treatment, excluding ramp-up and ramp-down times.ConclusionsEnveloped RNA virus test indicators were successfully developed, lab tested for HHA decontamination, analyzed for RSM, and field-tested in aircraft demonstrations.Significance and Impact of the StudyThe utility of HHA decontamination was demonstrated after inactivating enveloped RNA virus on aircraft with a 1-h HHA treatment within aircraft temperature and RH limits.
Multiscale interactions between plant part and a steep environmental gradient determine plant microbial composition in a tropical watershed
Authors: Bernard Jared , Wall Christopher B. , Costantini Maria S. , Rollins Randi L. , Atkins Melissa L. , Cabrera Feresa P. , Cetraro Nicolas D. , Feliciano Christian K. J. , Greene Austin L. , Kitamura Philip K. , Olmedo-Velarde Alejandro , Sirimalwatta Vithanage N. S. , Sung Helen W. , Thompson Leah P. M. , Vu Huong T. , Wilhite Chad J. , Amend Anthony S. 
Published: July 2020

AbstractPlant microbiomes are shaped by forces working at different spatial scales. Environmental factors determine a pool of potential symbionts while host physiochemical factors influence how those microbes associate with distinct plant tissues. Interactions between these scales, however, are seldom considered. Here we analyze epiphytic microbes from nineHibiscus tiliaceustrees across a steep environmental gradient within a single Hawaiian watershed. At each location we sampled eight microhabitats: leaves, petioles, axils, stems, roots, and litter from the plant, as well as surrounding air and soil. While the composition of microbial communities is driven primarily by microhabitat, this variable predicted more than twice the compositional variance for bacteria compared to fungi. Fungal community compositional dissimilarity increased more rapidly along the gradient than did bacteria. Additionally, the spatial dynamics of fungal communities differed among plant parts, and these differences influenced the distribution patterns and range size of individual taxa. Within plants, microbes were compositionally nested such that aboveground communities contained a subset of the diversity found belowground. Our findings identify potential differences underlying the mechanisms shaping communities of fungi and bacteria associated with plants, and indicate an interaction between assembly mechanisms working simultaneously on different spatial scales.
Evaluation of a novel multiplexed assay for determining IgG levels and functional activity to SARS-CoV-2
Authors: Johnson Marina , Wagstaffe Helen R. , Gilmour Kimberly C. , Mai Annabelle Lea , Lewis Joanna , Hunt Adam , Sirr Jake , Bengt Christopher , Grandjean Louis , Goldblatt David 
Published: July 2020

AbstractBackgroundThe emergence of SARS-CoV-2 has led to the development of new serological assays that could aid in diagnosis and evaluation of seroprevalence to inform an understanding of the burden of COVID-19 disease. Many available tests lack rigorous evaluation and therefore results may be misleading.ObjectivesThe aim of this study was to assess the performance of a novel multiplexed immunoassay for the simultaneous detection of antibodies against SARS-CoV-2 trimeric spike (S), spike receptor binding domain (RBD), spike N terminal domain and nucleocapsid antigen and a novel pseudo-neutralisation assay.MethodsA multiplexed solid-phase chemiluminescence assay (Meso Scale Discovery) was evaluated for the simultaneous detection of IgG binding to four SARS-CoV-2 antigens and the quantification of antibody-induced ACE-2 binding inhibition (pseudo-neutralisation assay). Sensitivity was evaluated with a total of 196 COVID-19 serum samples (169 confirmed PCR positive and 27 anti-nucleocapsid IgG positive) from individuals with mild symptomatic or asymptomatic disease. Specificity was evaluated with 194 control serum samples collected from adults prior to December 2019.ResultsThe specificity and sensitivity of the binding IgG assay was highest for S protein with a specificity of 97.4% and sensitivity of 96.2% for samples taken 14 days and 97.9% for samples taken 21 days following the onset of symptoms. IgG concentration to S and RBD correlated strongly with percentage inhibition measured by the pseudo-neutralisation assay.ConclusionExcellent sensitivity for IgG detection was obtained over 14 days since onset of symptoms for three SARS-CoV-2 antigens (S, RBD and N) in this multiplexed assay which can also measure antibody functionality.