bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative single-dose mRNA and ChAdOx1 vaccine effectiveness against SARS-CoV-2, including early variants of concern: a test-negative design, British Columbia, Canada
Authors: Skowronski Danuta M , Setayeshgar Solmaz , Zou Macy , Prystajecky Natalie , Tyson John R , Sbihi Hind , Fjell Chris D , Galanis Eleni , Naus Monika , Patrick David M , Adam Shiraz El , Ahmed May , Kim Shinhye , Henry Bonnie , Hoang Linda M N , Sadarangani Manish , Jassem Agatha N , Krajden Mel 
Published: September 2021

ABSTRACTIntroductionIn randomized controlled trials, single-dose efficacy against SARS-CoV-2 illness exceeded 90% for mRNA vaccines (BNT162b2 and mRNA-1273), and 75% for ChAdOx1. In British Columbia (BC), Canada second doses were deferred up to 16 weeks and ChAdOx1 was only initially recommended for adults 55 years of age and older. We compared single-dose vaccine effectiveness (VE) during the spring 2021 wave in BC when Alpha and Gamma variants of concern (VOC) predominated.MethodsVE was estimated against infection and hospitalization by test-negative design: cases were RT-PCR test-positive for SARS-CoV-2 and controls were test-negative. Adults 50-69 years old with specimen collection between April 4 and May 22 (weeks 14-20) were included. Variant-specific VE was estimated between weeks 17-20 when genetic characterization of all case viruses was performed, primarily through whole genome sequencing.ResultsVE analyses included 7,116 (10%) cases and 60,958 controls. Three-quarters of vaccinated participants received mRNA vaccine (60% BNT162b2, 15% mRNA-1273) and 25% received ChAdOx1. Half of genetically characterized viruses were Alpha, with 38% Gamma, 4% Delta and 8% non-VOCs. Single-dose VE against any infection was 75% (95%CI: 72-78) for BNT162b2, 82% (95%CI: 76-87) for mRNA-1273 and 61% (95%CI: 54-66) for ChAdOx1. VE against hospitalization was 83% (95%CI: 76-89), 85% (95%CI: 63-94) and 96% (95%CI: 86-99), respectively. VE against Alpha vs. Gamma infections did not differ among mRNA (78%;95%CI: 73-82 and 80%;95%CI: 74-85) or ChAdOx1 (66%;95%CI: 57-74 and 60%;95%CI: 48-69) recipients.ConclusionsA single dose of mRNA vaccine reduced the SARS-CoV-2 infection risk by at least 75%, including infections due to early VOC. Although effectiveness of a single dose of ChAdOx1 was lower at 60% against infection, just one dose of any vaccine reduced the hospitalization risk by more than 80%. In the context of constrained vaccine supplies, these findings have implications for global vaccine deployment to reduce the overall burden of infections and hospitalizations due to SARS-CoV-2.
Polygenic signals of sexually antagonistic selection in contemporary human genomes
Authors: Ruzicka Filip , Holman Luke , Connallon Tim 
Published: September 2021

AbstractMutations that increase fitness in one sex may decrease fitness in the other. Such “sexually antagonistic” (SA) genetic variants can constrain adaptation and increase variability for fitness components (e.g., survival, fertility, and disease susceptibility). However, detecting SA selection in genomes is immensely challenging, as it requires prohibitively large datasets that combine genomic sequences with individual fitness measurements. Here, we use genotypic and reproductive success data from ∼250,000 UK Biobank individuals to comprehensively assess the extent of SA genetic variation in humans. We first develop new theoretical models for signals of SA selection spanning a full generational life cycle—including SA polymorphisms affecting survival, reproductive success and overall fitness. Comparing our models with UK Biobank data, we uncover multiple empirical signals of polygenic SA selection, including sex-differential effects of genetic variants on each fitness component, and positive correlations between sex-differential effects and minor allele frequencies. We show that these signals cannot be explained by simple models of sex differences in purifying selection, or by potential confounders such as population structure and sequence mapping errors. We further show that candidate SA sites disproportionately affect functional genomic regions, including polymorphisms associated with quantitative traits and disease. Finally, we examine historical evolutionary processes affecting candidate SA sites, which are consistent with the drift-dominated dynamics predicted by previous theory. Overall, our results support SA genomic variation in humans and highlight its broader functional and evolutionary consequences.
Imaging Sensitive and Drug-Resistant Bacterial Infection with [11C]-TMP: In Vitro and First-in-Human Evaluation
Authors: Lee Iris K. , Jacome Daniel A. , Cho Joshua K. , Tu Vincent , Young Anthony , Dominguez Tiffany , Northrup Justin D. , Etersque Jean M. , Lee Hsiaoju , Ruff Andrew , Aklilu Ouniol , Bittinger Kyle , Glaser Laurel , Dorgan Daniel , Hadjiliadis Denis , Kohli Rahul M. , Mach Robert H. , Mankoff David A. , Doot Robert , Sellmyer Mark A. 
Published: September 2021

AbstractRecently, several molecular imaging strategies have developed to image bacterial infections in humans. Nuclear approaches, specifically positron emission tomography (PET), affords sensitive detection and the ability to non-invasively locate infections deep within the body. Two key radiotracer classes have arisen: metabolic approaches targeting bacterial specific biochemical transformations, and antibiotic-based approaches that have inherent selectivity for bacteria over mammalian cells. A critical question for clinical application of antibiotic radiotracers is whether resistance to the template antibiotic abrogates specific uptake, thus diminishing the predictive value of the diagnostic test. We recently developed small-molecule PET radiotracers based on the antibiotic trimethoprim (TMP), including [11C]-TMP, and have shown their selectivity for imaging bacteria in preclinical models. Here, we measure the in vitro uptake of [11C]-TMP in pathogenic susceptible and drug-resistant bacterial strains. Both resistant and susceptible bacteria showed similar in vitro uptake, which led us to perform whole genome sequencing of these isolates to identify the mechanisms of TMP resistance that permit retained radiotracer binding. By interrogating these isolate genomes and a broad panel of previously sequenced strains, we reveal mechanisms where uptake or binding of TMP radiotracers can potentially be maintained despite the annotation of genes conferring antimicrobial resistance. Finally, we present several examples of patients with both TMP-sensitive and drug-resistant infections in our first-in-human experience with [11C]-TMP. This work underscores the ability of an antibiotic radiotracer to image bacterial infection in patients, which may allow insights into human bacterial pathogenesis, infection diagnosis, and antimicrobial response monitoring.One Sentence SummaryThe PET radiotracer [11C]-trimethoprim shows high uptake in both TMP-sensitive and -resistant bacteria in vitro, the potential for imaging many different pathogenic strains, and uptake in patients with active infections.
Viral loads and profile of the patients infected with SARS-CoV-2 Delta, Alpha or R.1 variants in Tokyo
Authors: Tani-Sassa Chihiro , Iwasaki Yumi , Ichimura Naoya , Nagano Katsutoshi , Takatsuki Yuna , Yuasa Sonoka , Takahashi Yuta , Nakajima Jun , Sonobe Kazunari , Nukui Yoko , Takeuchi Hiroaki , Tanimoto Kousuke , Tanaka Yukie , Kimura Akinori , Tohda Shuji 
Published: September 2021

ABSTRACTThe rapid spread of the Delta variant of SARS-CoV-2 became a serious concern worldwide in summer 2021. We examined the copy number and variant types of all SARS-CoV-2-positive patients who visited our hospital from February to August 2021 using PCR tests. Whole genome sequencing was performed for some samples. The R.1 variant (B.1.1.316) was responsible for most infections in March, replacing the previous variant (B.1.1.214); the Alpha (B.1.1.7) variant caused most infections in April and May; and the Delta variant (B.1.617.2) was the most prevalent in July and August. There was no significant difference in copy numbers among the previous variant cases (n=29, median 3.0×104 copies/μL), R.1 variant cases (n=28, 2.1×105 copies/μL), Alpha variant cases (n=125, 4.1×105 copies/μL), and Delta variant cases (n=106, 2.4×105 copies/μL). Patients with Delta variant infection were significantly younger than those infected with R.1 and the previous variants, possibly because many elderly individuals in Tokyo were vaccinated between May and August. There was no significant difference in mortality among the four groups. Our results suggest that the increased infectivity of Delta variant may be caused by factors other than the higher viral loads. Clarifying these factors is important to control the spread of Delta variant infection.
Linking rattiness, geography and environmental degradation to spillover Leptospira infections in marginalised urban settings: an eco-epidemiological community-based cohort study in Brazil
Authors: Eyre Max T. , Souza Fábio N. , Carvalho-Pereira Ticiana S. A. , Nery Nivison , de Oliveira Daiana , Cruz Jaqueline S , Sacramento Gielson A. , Khalil Hussein , Wunder Elsio A. , Hacker Kathryn P. , Childs James E. , Reis Mitermayer G. , Begon Mike , Diggle Peter J. , Ko Albert I. , Giorgi Emanuele , Costa Federico 
Published: September 2021

AbstractBackgroundZoonotic spillover from animal reservoirs is responsible for a significant global public health burden, but the processes that promote spillover events are poorly understood in complex urban settings. Endemic transmission of Leptospira, the agent of leptospirosis, in marginalised urban communities occurs through human exposure to an environment contaminated by bacteria shed in the urine of the rat reservoir. However, it is unclear to what extent transmission is driven by variation in the distribution of rats or by the dispersal of bacteria in rainwater runoff and overflow from open sewer systems.MethodsWe conducted an eco-epidemiological study in a high-risk community in Salvador, Brazil, by prospectively following a cohort of 1,401 residents to ascertain serological evidence for leptospiral infections. A concurrent rat ecology study was used to collect information on the fine-scale spatial distribution of ‘rattiness’, our proxy for rat abundance and exposure of interest. We developed and applied a novel geostatistical framework for joint spatial modelling of multiple indices of disease reservoir abundance and human infection risk.ResultsThe estimated infection rate was 51.4 (95%CI 40.4, 64.2) infections per 1,000 follow-up events. Infection risk increased with age until 30 years of age and was associated with male gender. Rattiness was positively associated with infection risk for residents across the entire study area, but this effect was stronger in higher elevation areas (OR 3.27 95%CI 1.68, 19.07) than in lower elevation areas (OR 1.14 95%CI 1.05, 1.53).ConclusionsThese findings suggest that, while frequent flooding events may disperse bacteria in regions of low elevation, environmental risk in higher elevation areas is more localised and directly driven by the distribution of local rat populations. The modelling framework developed may have broad applications in delineating complex animal-environment-human interactions during zoonotic spillover and identifying opportunities for public health intervention.FundingThis work was supported by the Oswaldo Cruz Foundation and Secretariat of Health Surveillance, Brazilian Ministry of Health, the National Institutes of Health of the United States (grant numbers F31 AI114245, R01 AI052473, U01 AI088752, R01 TW009504 and R25 TW009338); the Wellcome Trust (102330/Z/13/Z), and by the Fundacção de Amparo à Pesquisa do Estado da Bahia (FAPES-B/JCB0020/2016). M.T.E is supported by an MRC doctorate studentship. F.N.S. participated in this study under a FAPESB doctorate scholarship.
LM-GVP: A Generalizable Deep Learning Framework for Protein Property Prediction from Sequence and Structure
Authors: Wang Zichen , Combs Steven A. , Brand Ryan , Calvo Miguel Romero , Xu Panpan , Price George , Golovach Nataliya , Salawu Emmanuel O. , Wise Colby J. , Ponnapalli Sri Priya , Clark Peter M. 
Published: September 2021

AbstractProteins perform many essential functions in biological systems and can be successfully developed as bio-therapeutics. It is invaluable to be able to predict their properties based on a proposed sequence and structure. In this study, we developed a novel generalizable deep learning framework, LM-GVP, composed of a protein Language Model (LM) and Graph Neural Network (GNN) to leverage information from both 1D amino acid sequences and 3D structures of proteins. Our approach outperformed the state-of-the-art protein LMs on a variety of property prediction tasks including fluorescence, protease stability, and protein functions from Gene Ontology (GO). We also illustrated insights into how a GNN prediction head can guide the protein LM to better leverage structural information. We envision that our deep learning framework will be generalizable to many protein property prediction problems to greatly accelerate protein engineering and drug development.
Brain I3 Binding Protein regulates K-Ras4B membrane localization and signaling
Authors: McCabe Ian , Zhang Huanqing , Cooper Jonathan A. , Turner David L. , Vojtek Anne B. 
Published: September 2021

AbstractMembrane localization of Ras proteins is necessary for their biological functions and oncogenic activity. We report here on the identification of Brain I3 Binding Protein (BRI3BP) as a novel binding partner for Ras. We show that K-Ras4B plasma membrane localization and biological function are reduced in the absence of BRI3BP. BRI3BP interacts with K-Ras4B and K-Ras4A and our data suggest that BRI3BP operates within the recycling endosomal compartment to regulate K-Ras localization to the plasma membrane. This study uncovers a new regulatory protein for Ras membrane localization.
Ligand binding remodels protein side chain conformational heterogeneity
Authors: Wankowicz Stephanie A. , de Oliveira Saulo H.P. , Hogan Daniel W. , van den Bedem Henry , Fraser James S. 
Published: September 2021

ABSTRACTWhile protein conformational heterogeneity plays an important role in many aspects of biological function, including ligand binding, its impact has been difficult to quantify. Macromolecular X-ray diffraction is commonly interpreted with a static structure, but it can provide information on both the anharmonic and harmonic contributions to conformational heterogeneity. Here, through multiconformer modeling of time- and space-averaged electron density, we measure conformational heterogeneity of 743 stringently matched pairs of crystallographic datasets that reflect unbound/apo and ligand-bound/holo states. When comparing the conformational heterogeneity of side chains, we observe that when binding site residues become more rigid upon ligand binding, distant residues tend to become more flexible, especially in non-solvent exposed regions. Among ligand properties, we observe increased protein flexibility as the number of hydrogen bonds decrease and relative hydrophobicity increases. Across a series of 13 inhibitor bound structures of CDK2, we find that conformational heterogeneity is correlated with inhibitor features and identify how conformational changes propagate differences in conformational heterogeneity away from the binding site. Collectively, our findings agree with models emerging from NMR studies suggesting that residual side chain entropy can modulate affinity and point to the need to integrate both static conformational changes and conformational heterogeneity in models of ligand binding.
Mechanical stimulation promotes enthesis injury repair by mobilizing Prx1+cells via ciliary TGF-β signaling
Authors: Xiao Han , Zhang Tao , Li Changjun , Cao Yong , Wang Linfeng , Chen Huabin , Li Shengcan , Guan Changbiao , Hu Jianzhong , Chen Di , Chen Can , Lu Hongbin 
Published: September 2021

AbstractProper mechanical stimulation can improve rotator cuff enthsis injury repair. However, the underlying mechanism of mechanical stimulation promoting injury repair is still unknown. In this study, we found that Prx1+cell was essential for murine rotator cuff enthesis development identified by single-cell RNA sequence and involved in the injury repair. Proper mechanical stimulation could promote the migration of Prx1+cells to enhance enthesis injury repair. Meantime, TGF-β signaling and primary cilia played an essential role in mediating mechanical stimulation signaling transmission. Proper mechanical stimulation enhanced the release of active TGF-β1 to promote migration of Prx1+cells. Inhibition of TGF-β signaling eliminated the stimulatory effect of mechanical stimulation on Prx1+cell migration and enthesis injury repair. In addition, knockdown ofPallidinto inhibit TGF-βR2 translocation to the primary cilia or deletion ofIFT88in Prx1+cells also restrained the mechanics-induced Prx1+cells migration. These findings suggested that mechanical stimulation could increase the release of active TGF-β1 and enhance the mobilization of Prx1+cells to promote enthesis injury repair via ciliary TGF-β signaling.
Cell-surface tethered promiscuous biotinylators enable small-scale surface proteomics of human exosomes
Authors: Kirkemo Lisa L. , Elledge Susanna K. , Yang Jiuling , Byrnes James , Glasgow Jeff , Blelloch Robert , Wells James A. 
Published: September 2021

AbstractCharacterization of cell surface proteome differences between cancer and healthy cells is a valuable approach for the identification of novel diagnostic and therapeutic targets. However, selective sampling of surface proteins for proteomics requires large samples (>10e7 cells) and long labeling times. These limitations preclude analysis of material-limited biological samples or the capture of rapid surface proteomic changes. Here, we present two labeling approaches to tether exogenous peroxidases (APEX2 and HRP) directly to cells, enabling rapid, small-scale cell surface biotinylation without the need to engineer cells. We used a novel lipidated DNA-tethered APEX2 (DNA-APEX2), which upon addition to cells promoted cell agnostic membrane-proximal labeling. Alternatively, we employed horseradish peroxidase (HRP) fused to the glycan binding domain of wheat germ agglutinin (WGA-HRP). This approach yielded a rapid and commercially inexpensive means to directly label cells containing common N-Acetylglucosamine (GlcNAc) and sialic acid glycans on their surface. The facile WGA-HRP method permitted high surface coverage of cellular samples and enabled the first comparative surface proteome characterization of cells and cell-derived exosomes, leading to the robust quantification of 1,020 cell and exosome surface proteins. We identified a newly-recognized subset of exosome-enriched markers, as well as proteins that are uniquely upregulated on Myc oncogene-transformed prostate cancer exosomes. These two cell-tethered enzyme surface biotinylation approaches are highly advantageous for rapidly and directly labeling surface proteins across a range of material-limited sample types.
Fault-tolerant control of spacecraft attitude regulation: a concise adaptive dual-mode scheme
Authors: Lu Yu , Ye Pengpeng , Dai Ming-Zhe , Wu Jin , Zhang Chengxi 
Published: September 2021

Purpose
This paper aims to address the spacecraft attitude regulation problem in the presence of extrinsic disturbances and actuator faults.

Design/methodology/approach
Based on adaptive backstepping design technique, a new concise adaptive dual-mode control scheme is proposed, which can either use the fault information detected by fault diagnosis mechanisms or switch to the fault-unknown mode when the fault diagnosis information is non-existent for control signal generation. These two modes share an adaptive mechanism that reduces the complexity of the algorithm.

Findings
The new fault-tolerant attitude control algorithm can accommodate both modes with and without fault diagnosis mechanisms.

Originality/value
The proposed algorithm in this paper can be applied to both cases when the attitude control system is equipped with or without fault diagnosis capability. This also enhances the robustness of attitude control algorithm. This study performs numerical simulations and verifies that the algorithm could effectively adapt to both modes.
Embracing advanced manufacturing technologies for performance improvement: an empirical study
Authors: Singh Rajesh Kumar , Gurtu Amulya 
Published: September 2021

PurposeThis study has analyzed strategic issues in implementing advanced manufacturing technologies (AMTs) in manufacturing organizations in India and their relative importance.Design/methodology/approachA survey of manufacturing organizations was conducted, and the data were analyzed using statistical tools (one-sample t-tests, correlation and regression analyses).FindingsImprovement in product quality and flexibility of operations are the motivation for AMTs implementation. Top management support and sound financial conditions are essential for implementing AMTs. Successful implementation of AMTs helps in reducing the lead time and improving overall business performance.Research limitations/implicationsThe findings of this study will help organizations in the implementation of AMTs for improving productivity and business performance. The study is limited to manufacturing organizations in India.Practical implicationsOrganizations should allocate sufficient funds for AMT applications. Organizational culture should be made conducive to the adoption of new technologies. Employees should be provided adequate training for its successful implementation.Originality/valueThe main contribution of this paper is that it provides a detailed analysis of strategic issues for implementing AMTs in manufacturing organizations.
Design of a small disc-type coreless permanent magnet brushed DC actuator
Authors: Alizadeh Pahlavani Mohammad Reza , Tahanian Hamed 
Published: September 2021

Purpose
Design of small disc-type permanent magnet (PM) brushed DC motors for servomechanisms is challenging. The purpose of this paper is to propose a special coreless double-sided structure. This easy to manufacture motor has two set of shifted concentrated windings on both sides of the rotor. All of the coils in each winding are simply connected in series. A simple arcless commutator, which shares the features of both the usual commutators and slip rings, is connected to each winding at only two points.

Design/methodology/approach
By replacing the PMs with an equivalent current density, main design equations of the motor have been derived through the solving of scalar Poisson equation. A radial division technique has been used to take the radial variations into account. This provides the ability of considering various shapes of coils and PMs. A novel iterative algorithm has been proposed to design a motor with high torque capability, compared to other coreless counterparts. Some design variables are obtained based on an independent optimization problem, which maximizes the active portion of windings. The other variables are calculated in such a way that the design requirements are satisfied.

Findings
The feasibility and capability of the new structure have been proved by prototyping a sample motor. Comparing the design outputs with the results of the 3D finite element analysis and experimental tests shows a good agreement. This verifies the accuracy of the proposed design method.

Originality/value
A new structure for PM brushed DC motors and a novel algorithm for its design has been developed.