bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of the North Star Assessment for Limb-Girdle Type Muscular Dystrophies
Authors: James Meredith K , Alfano Lindsay N , Muni-Lofra Robert , Reash Natalie F , Sodhi Jassi , Iammarino Megan A , Moat Dionne , Shannon Kianna , McCallum Michelle , Richardson Mark , Eagle Michelle , Straub Volker , Marini-Bettolo Chiara , Lowes Linda P , Mayhew Anna G 
Published: August 2022

Abstract

Objective
The North Star Assessment for limb-girdle type muscular dystrophies (NSAD), a clinician-reported outcome measure (ClinRO) of motor performance, was initially developed and validated for use in dysferlinopathy, an autosomal recessive form of limb-girdle muscular dystrophy (LGMD R2/2B). Recent developments in treatments for limb-girdle muscular dystrophies (LGMD) have highlighted the urgent need for disease-specific ClinROs. The purpose of this study was to understand the ability of the NSAD to quantify motor function across the broad spectrum of LGMD phenotypes.

Methods
Assessments of 130 individuals with LGMD evaluated by the physical therapy teams at Nationwide Children’s Hospital and the John Walton Muscular Dystrophy Research Centre were included in the analysis. NSAD, 100-m timed test (100MTT), and Performance of Upper Limb 2.0 assessment data were collected. Psychometric analysis with Rasch measurement methods was used to examine the NSAD for suitability and robustness by determining the extent to which the observed data “fit” with predictions of those ratings from the Rasch model. The NSAD score was correlated with the 100MTT and Performance of Upper Limb 2.0 assessment scores for external construct validity.

Results
The NSAD demonstrated a good spread of items covering a continuum of abilities across both individuals who had LGMD and were ambulatory and individuals who had LGMD and were weaker and nonambulatory. Items fit well with the construct measured, validating a summed total score. The NSAD had excellent interrater reliability [intraclass correlation coefficient (ICC) = 0.986, 95% CI = 0.981–0.991] and was highly correlated with the 100MTT walk/run velocity (Spearman rho correlation coefficient of rs(134) = .92).

Conclusion
Although LGMD subtypes may differ in age of onset, rate of progression, and patterns of muscle weakness, the overall impact of progressive muscle weakness on motor function is similar. The NSAD is a reliable and valid ClinRO of motor performance for individuals with LGMD and is suitable for use in clinical practice and research settings.

Impact
Recent developments in potential pharmacological treatments for LGMD have highlighted the urgent need for disease-specific outcome measures. Validated and meaningful outcome measures are necessary to capture disease presentation, to inform expected rates of progression, and as endpoints for measuring the response to interventions in clinical trials. The NSAD, a scale of motor performance for both individuals who have LGMD and are ambulatory and those who are nonambulatory, is suitable for use in clinical and research settings.
Responding to a disease with resources from other diseases: Evidence from Zika vaccine research dynamics
Authors: Yaqub Ohid , Luna Javier A , Moore Duncan Aq , Yegros-Yegros Alfredo 
Published: August 2022

AbstractResponding to health needs in one disease area might rely on being able to draw on research and funding oriented towards other disease areas. However, the tendency of medical research to cross-disease areas has received limited empirical consideration. An outbreak, in a disease area with little prior research or funding, means that any research response will necessarily be rich with cross-disease flows. This affords a setting that allows us to identify and examine the phenomenon over time. We estimate the extent to which the vaccine research community’s response to Zika virus drew on research and funding from other diseases. We find that a persistently low share of funding into Zika vaccine research was Zika-oriented. In contrast, a much higher share of knowledge inputs was oriented to Zika. The exercise serves to illustrate some general themes in priority setting for health research systems alongside some core features of vaccine innovation.
Overexpression of PdeGATA3 results in a dwarf phenotype in poplar by promoting the expression of PdeSTM and altering the content of gibberellins
Authors: Liu Meifeng , Huang Liyu , Zhang Yan , Yan Zhaogui , Wang Nian 
Published: August 2022

Abstract
In previous studies, GA20 oxidase (GA20ox) has been identified to be an important enzyme in the biosynthesis of GA, and SHOOTMERISTEMLESS (STM) can repress the expression of GA20ox. In this study, the GATA transcription factor PdeGATA3 was identified in the poplar line NL895, and its overexpression (OE) transgenic lines showed a dwarf phenotype. RNA sequencing (RNA-Seq) analysis suggested that OE PdeGATA3 could promote the expression of PdeSTM and repress the expression of PdeGA20ox. Therefore, we hypothesized that PdeGATA3 would directly promote the expression of PdeSTM and that PdeSTM would repress the expression of PdeGA20ox. Four experiments, a dual-luciferase reporter assay, GUS transient coexpression assay, yeast one-hybrid assay and electrophoretic mobility shift assay, were conducted and verified that PdeGATA3 could promote the expression of PdeSTM by binding GATA-Boxes in its promoter. OE PdeSTM in poplar resulted in a dwarf phenotype and repressed the expression of PdeGA20ox. GA measurement of the OE PdeSTM and PdeGATA3 lines showed that GA3 and GA4 contents were significantly lower than those in the wild type (WT). Accordingly, we put forward a regulation model involving plant height regulation by PdeGATA3, PdeSTM and PdeGA20ox.
covSampler: A subsampling method with balanced genetic diversity for large-scale SARS-CoV-2 genome data sets
Authors: Cheng Yexiao , Ji Chengyang , Han Na , Li Jiaying , Xu Lin , Chen Ziyi , Yang Rong , Zhou Hang-Yu , Wu Aiping 
Published: August 2022

AbstractPhylogenetic analysis has been widely used to describe, display, and infer the evolutionary patterns of viruses. The unprecedented accumulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes has provided valuable materials for the real-time study of SARS-CoV-2 evolution. However, the large number of SARS-CoV-2 genome sequences also poses great challenges for data analysis. Several methods for subsampling these large data sets have been introduced. However, current methods mainly focus on the spatiotemporal distribution of genomes without considering their genetic diversity, which might lead to post-subsampling bias. In this study, a subsampling method named covSampler was developed for the subsampling of SARS-CoV-2 genomes with consideration of both their spatiotemporal distribution and their genetic diversity. First, covSampler clusters all genomes according to their spatiotemporal distribution and genetic variation into groups that we call divergent pathways. Then, based on these divergent pathways, two kinds of subsampling strategies, representative subsampling and comprehensive subsampling, were provided with adjustable parameters to meet different users’ requirements. Our performance and validation tests indicate that covSampler is efficient and stable, with an abundance of options for user customization. Overall, our work has developed an easy-to-use tool and a webserver (https://www.covsampler.net) for the subsampling of SARS-CoV-2 genome sequences.
Activation of hTREK-1 by polyunsaturated fatty acids does not only involve membrane tension
Authors: Bechard Emilie , Arel Elodie , Bride Jamie , Louradour Julien , Bussy Xavier , Elloumi Anis , Vigor Claire , Soule Pierre , Oger Camille , Galano Jean-Marie , Durand Thierry , Le Guennec Jean-Yves , Moha-Ou-Maati Hamid , Demion Marie 
Published: August 2022

ABSTRACTTREK-1 is a mechanosensitive channel also activated by polyunsaturated fatty acids (PUFAs). In this study, we compared the effect of multiple fatty acids and ML402. First, we showed a variable TREK-1 activation by PUFAs related to the variable constitutive activity of TREK-1. Then, we observed no correlation between TREK-1 activation and acyl chain length or number of double bonds suggesting that the bilayer-couple hypothesis cannot explain by itself the activation of TREK-1 by PUFAs. The membrane fluidity measurement is not modified by PUFAs at 10 µM. The spectral shift analysis in TREK-1-enriched microsomes indicates a KD,TREK1at 44 µM of C22:6 n-3. PUFAs display the same activation and reversible kinetics than the direct activator ML402 and activate TREK-1 in both whole-cell and inside-out configurations of patch-clamp suggesting that the binding site of PUFAs is accessible from both sides of the membrane, as for ML402. Finally, we proposed a two steps mechanism for TREK-1 activation by PUFAs: first, insertion into the membrane, without fluidity or curvature modifications, and then interaction with TREK-1 channel to open it.
Resurrecting the Alternative Splicing Landscape of Archaic Hominins using Machine Learning
Authors: Brand Colin M. , Colbran Laura L. , Capra John A. 
Published: August 2022

AbstractAlternative splicing contributes to adaptation and divergence in many species. However, it has not been possible to directly compare splicing between modern and archaic hominins. Here, we unmask the recent evolution of this previously unobservable regulatory mechanism by applying SpliceAI, a machine-learning algorithm that identifies splice altering variants (SAVs), to high-coverage genomes from three Neanderthals and a Denisovan. We discover 5,950 putative archaic SAVs, of which 2,186 are archaic-specific and 3,607 also occur in modern humans via introgression (244) or shared ancestry (3,520). Archaic-specific SAVs are enriched in genes that contribute to many traits potentially relevant to hominin phenotypic divergence, such as the epidermis, respiration, and spinal rigidity. Compared to shared SAVs, archaic-specific SAVs occur in sites under weaker selection and are more common in genes with tissue-specific expression. Further underscoring the importance of negative selection on SAVs, Neanderthal lineages with low effective population sizes are enriched for SAVs compared to Denisovan and shared SAVs. Finally, we find that nearly all introgressed SAVs in humans were shared across Neanderthals, suggesting that older SAVs were more tolerated in modern human genomes. Our results reveal the splicing landscape of archaic hominins and identify potential contributions of splicing to phenotypic differences among hominins.
CaviDB: a database of cavities and their features in the structural and conformational space of proteins
Authors: Rueda Ana Julia Velez , Bulgarelli Franco Leonardo , Palopoli Nicolás , Parisi Gustavo 
Published: August 2022

AbstractProteins are the functional and evolutionary units of cells. On their surface, proteins are sculpted into numerous concavities and bulges, offering unique microenvironments for ligand binding or catalysis. The dynamics, size, and chemical features of these cavities are essential for the mechanistic understanding of protein function.Here we present CaviDB (https://www.cavidb.org), a novel database of cavities and their features in known protein structures, which integrates the results from commonly used software for cavities detection with protein features obtained from sequence, structure, and function analyses. Additionally, each protein in CaviDB is associated with its corresponding conformers which help to analyze conformational changes in cavities as well. We were able to characterize a total number of 16,533,339 cavities, 62,0431 of them predicted as druggable targets. CaviDB contains 276,432 different proteins, with information about all their conformers. It also offers the capability to compare cavities and their features from different conformational states of the protein. Furthermore, we have recently added the available models from the AlphaFold database versions 2 and 3, which allow further cavity explorations and comparisons.Each entry information is organized in sections, highlighting the general cavities descriptors, including the inter-cavities contacts, activated residues per cavity, the information about druggable cavities, and the global protein descriptors. The data retrieved by the user can be downloaded in a format that is easy to parse and integrate with custom pipelines for protein analysis.CaviDB aims to offer a comprehensive database for use not only in different aspects of drug design and discovery but also to better understand the basis of the protein structure-function relationship better. With its unique approach, CaviDB provides an essential resource for the wide community of bioinformaticians in particular and biologists in general.
Homeostatic regulation through strengthening of neuronal network-correlated synaptic inputs
Authors: Barnes Samuel J. , Keller Georg B. , Keck Tara 
Published: August 2022

AbstractHomeostatic regulation is essential for neuronal function. Several synaptic mechanisms of homeostatic plasticity have been described, but the functional properties of synapses involved in homeostasis are unknown. We used longitudinal two-photon functional imaging of dendritic spine calcium signals in visual and retrosplenial cortices of awake mice to quantify the sensory deprivation-induced changes in the responses of functionally identified spines. We found that spines whose activity selectively correlated with intrinsic network activity underwent TNF-α dependent homeostatic increases in their response amplitudes, but spines identified as responsive to sensory stimulation did not. We observed an increase in the global sensory-evoked responses following sensory deprivation, despite the fact that the identified sensory inputs did not strengthen. Instead, global sensory-evoked responses correlated with the strength of network-correlated inputs. Our results suggest that homeostatic regulation of global responses is mediated through changes to intrinsic network-correlated inputs rather than changes to identified sensory inputs thought to drive sensory processing.
A Reagent and Virus Benchmarking Panel for a Uniform Analytical Performance Assessment of N Antigen–Based Diagnostic Tests for COVID-19
Authors: Golden Allison , Cantera Jason L. , Lillis Lorraine , Phan Thanh T. , Slater Hannah , Webb Edwin J. , Peck Roger B. , Domingo Gonzalo J. , Boyle David S. 
Published: August 2022

ABSTRACTRapid diagnostic tests (RDTs) that detect antigen indicative of SARS-CoV-2 infection can help in making quick health care decisions and regularly monitoring groups at risk of infection. With many RDT products entering the market, it is important to rapidly evaluate their relative performance. Comparison of clinical evaluation study results is challenged by protocol design variations and study populations. Laboratory assays were developed to quantify nucleocapsid (N) and spike (S) SARS-CoV-2 antigens. Quantification of the two antigens in nasal eluates confirmed higher abundance of N than S antigen. The median concentration of N antigen was 10 times greater than S per genome equivalent. The N antigen assay was used in combination with quantitative RT-PCR to qualify a panel composed of recombinant antigens, inactivated virus, and clinical specimen pools. This benchmarking panel was applied to evaluate the analytical performance of the SD Biosensor STANDARD Q COVID-19 Ag test, Abbott Panbio COVID-19 Ag Rapid Test, Abbott BinaxNOW COVID-19 Ag test, and the LumiraDx SARS-CoV-2 Ag Test. The four tests displayed different sensitivities toward the different panel members, but all performed best with the clinical specimen pool. The concentration for a 90% probability of detection across the four tests ranged from 21 pg/mL to 102 pg/mL of N antigen in the extracted sample. Benchmarking panels provide a quick way to verify the baseline performance of a diagnostic and enable direct comparison between diagnostic tests.
Human activities impact microbial communities of Amazon Mangroves
Authors: da Costa Gleyciane Machado , Costa Sávio Souza , Barauna Rafael Azevedo , Castilho Bruno Pureza , Pinheiro Izabel Cruz , Silva Artur , Schaan Ana Paula , Ribeiro-dos-Santos Ândrea Kely Campos , das Graças Diego Assis 
Published: August 2022

AbstractMangroves provide a unique ecological environment for complex microbial communities. They are particularly important in controlling the chemical environment of the ecosystem. Microbial diversity analyses of these ecosystems help us understand the environmental dynamics and the changes due to impacts. Amazonian mangroves are distributed across Amapá, Pará and Maranhão states occupying an area of 9,000 km2 and correspond to 70% of the mangroves in Brazil, in which studies on microbial biodiversity are extremely rare. The present study aimed to determine changes in microbial community structure along the PA-458 highway that divided the mangrove. Mangrove samples were collected from three zones, (i) under anthropogenic actions, (ii) in the process of recovery and (ii) preserved. Total DNA was extracted, submitted for 16S rDNA amplification and sequenced on the Illumina MiSeq platform. Reads were analyzed using USEARCH tools and packages available in R Platform. The most abundant phyla were Proteobacteria, followed by Firmicutes and Bacteroidetes in all three mangrove locations. Genera such as Desulfuromonas, Desulfatiglans, Collinsella, Dorea, Dialister were not found in the impacted mangrove. The impacted mangrove proved to be ecologically different from other mangroves. Our results show that human impact in the mangrove areas has resulted in loss of biodiversity, caused by the construction of the PA-458 highway, reducing the support and maintenance of habitat life and the ecosystem’s resilience to disturbance.
Combinatorial perturbation sequencing on single cells using microwell-based droplet random pairing
Authors: Xie Run , Liu Yang , Wang Shiyu , Shi Xuyang , Zhao Zhantao , Liu Longqi , Liu Ya , Li Zida 
Published: August 2022

AbstractCombinatorial drug therapy reduces drug resistance and disease relapse, but informed drug combinations are lacking due to the high scale of possible combinations and the relatively simple phenotyping strategies. Here we report combinatorial perturbation sequencing (CP-seq) on single cells using microwell-base droplet random pairing. CP-seq uses oligonucleotides to barcode drugs, encapsulates drugs and cells in separate droplets, and pairs cell droplets with two drug droplets randomly on a microwell array chip to complete combinatorial drug treatment and barcode-tagging on cells. The subsequent single-cell RNA sequencing simultaneously detects the single-cell transcriptomes and drug barcodes to demultiplex the corresponding drug treatment. The microfluidic droplet operations had robust performance, with overall success rate among the microwells being up to 83%. We then progressively validated the CP-seq by performing single drug treatment and then combinatorial drug treatment. Leveraging the advantage of droplet microfluidics in massive multiplexing, the CP-seq can test thousands of drug combinations in a single experiment and represents a great technology for combinatorial perturbation screening with high throughput and comprehensive profiling.
Visualizing proteins by expansion microscopy
Authors: Shaib Ali H. , Chouaib Abed Alrahman , Chowdhury Rajdeep , Mihaylov Daniel , Zhang Chi , Imani Vanessa , Georgiev Svilen Veselinov , Mougios Nikolaos , Monga Mehar , Reshetniak Sofiia , Mimoso Tiago , Chen Han , Fatehbasharzad Parisa , Crzan Dagmar , Saal Kim-Ann , Alawar Nadia , Eilts Janna , Kang Jinyoung , Alvarez Luis , Trenkwalder Claudia , Mollenhauer Brit , Outeiro Tiago F. , Köster Sarah , Preobraschenski Julia , Becherer Ute , Moser Tobias , Boyden Edward S. , Aricescu A Radu , Sauer Markus , Opazo Felipe , Rizzoli Silvio O. 
Published: August 2022

AbstractFluorescence imaging is one of the most versatile and widely-used tools in biology1. Although techniques to overcome the diffraction barrier were introduced more than two decades ago, and the nominal attainable resolution kept improving2, 3, fluorescence microscopy still fails to image the morphology of single proteins or small molecular complexes, either purified or in a cellular context4, 5. Here we report a solution to this problem, in the form ofone-stepnanoscaleexpansion (ONE) microscopy. We combined the 10-fold axial expansion of the specimen (1000-fold by volume) with a fluorescence fluctuation analysis6, 7to enable the description of cultured cells, tissues, viral particles, molecular complexes and single proteins. At the cellular level, using immunostaining, our technology revealed detailed nanoscale arrangements of synaptic proteins, including a quasi-regular organisation of PSD95 clusters. At the single molecule level, upon main chain fluorescent labelling, we could visualise the shape of individual membrane and soluble proteins. Moreover, conformational changes undergone by the ∼17 kDa protein calmodulin upon Ca2+binding were readily observable. We also imaged and classified molecular aggregates in cerebrospinal fluid samples from Parkinson’s Disease (PD) patients, which represents a promising new development towards improved PD diagnosis. ONE microscopy is compatible with conventional microscopes and can be performed with the software we provide here as a free, open-source package. This technology bridges the gap between high-resolution structural biology techniques and light microscopy, and provides a new avenue for discoveries in biology and medicine.