bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a core outcome set on traditional Chinese medicine (COS-TCM) for rheumatic heart disease (RHD): study protocol
Authors: Sheng Xiaodi , Chen Chao , Ji Zhaochen , Hu Haiyin , Zhang Mingyan , Wang Hui , Pang Bo , Zhang Dong , Zhang Junhua , Guo Liping 
Published: January 2022

ABSTRACTIntroductionRheumatic heart disease (RHD) is an important cause of acquired heart disease in children and adolescents globally. Clinical trials on RHD treatment with traditional Chinese medicine (TCM) are gradually increasing in China. However, because clinical trials are heterogeneous and report outcomes selectively, similar studies cannot be merged and compared, complicating assessing the effectiveness and safety of TCM, diminishes the value of clinical trials, and results in a waste of research resources. Therefore, there is an urgent need to develop a core outcome set of traditional Chinese medicine for rheumatic heart disease (COS-TCM-RHD). This study will report the protocol development process for COS-TCM-RHD.Methods and analysisA multidisciplinary Steering Committee will lead the development of this protocol through four stages (1). Establishing a comprehensive and systematic outcomes checklist through a systematic review of previously published research, retrieval of clinical trial registration centers, patient’s semi-structured interviews, and clinician’s questionnaire surveys; (2). Screen stakeholder groups from various fields to participate in the Delphi survey; (3). Two rounds of e-Delphi surveys will be conducted to determine the outcomes of various concerned stakeholder groups; (4). Hold a face-to-face consensus meeting to develop the COS-TCM-RHD.Ethics and disseminationEthical approval has been granted by the Tianjin university of Traditional Chinese Medicine Ethics Committee. The findings will be published in peer-reviewed journals and the website of Chinese Clinical Trials for Core Outcome Set.Trial registrationThis study protocol has been prospectively registered with the Core Outcome Measures in Effectiveness Trials (COMET):http://www.comet-initiative.org/Studies/Details/1743.Strengths and limitations of this study▪This protocol is the first core outcomes set registered on the Core Outcome Measures in Effectiveness Trials (COMET) website for the treatment of rheumatic heart disease by Traditional Chinese medicine.▪This study is guided by the Core Outcome Set-STAndards for Development and Core Outcome Set-Standardized Protocol Items, with recommendations of the COMET.▪A multidisciplinary Steering Committee will supervise this research, and stakeholders from different fields including clinicians, patients, methodologists, and COS developers will be engaged.▪Systematic reviews, qualitative research (patient’s semi-structured interviews and clinician’s questionnaire surveys), Delphi surveys, and consensus meetings will be used for core outcome set development.▪Traditional Chinese medicine is mainly used in China. Thus, the geographical distribution of stakeholders will be a limitation.
One vaccine to counter many diseases? Modelling the economics of oral polio vaccine against child mortality and COVID-19
Authors: Chang Angela Y. , Aaby Peter , Avidan Michael S. , Benn Christine S. , Bertozzi Stefano M. , Blatt Lawrence , Chumakov Konstantin , Khader Shabaana A. , Kottilil Shyam , Nekkar Madhav , Netea Mihai G. , Sparrow Annie , Jamison Dean T. 
Published: January 2022

AbstractBackgroundRecent reviews summarize evidence that some vaccines have heterologous or non-specific effects (NSE), potentially offering protection against multiple pathogens. Numerous economic evaluations examine vaccines’ pathogen-specific effects, but we have found only two economic evaluations of NSE. This paper starts to fill this gap by reporting economic evaluations of the NSE of oral polio vaccine (OPV) against under-five mortality and COVID-19.MethodsWe studied two settings: (1) reducing child mortality in a high-mortality setting (Guinea-Bissau) and (2) preventing COVID-19 in India. In the former, the intervention involves three annual campaigns in which children receive OPV incremental to routine immunization. In the latter, a susceptible-exposed-infectious-recovered model was developed to estimate the population benefits of two scenarios, in which OPV would be co-administered alongside COVID-19 vaccines. Incremental cost-effectiveness and benefit-cost ratios were modelled for ranges of intervention effectiveness estimates to supplement the headline numbers and account for heterogeneity and uncertainty.ResultsFor child mortality, headline cost-effectiveness was $650 per child death averted. For COVID-19, assuming OPV had 20% effectiveness, incremental cost per death averted was $23,000-65,000 if it were administered simultaneously with a COVID-19 vaccine less than 200 days into a wave of the epidemic. If the COVID-19 vaccine availability were delayed, the cost per averted death would decrease to $2600-6100. Estimated benefit-to-cost ratios vary but are consistently high.ConclusionEconomic evaluation suggests the potential of OPV to efficiently reduce child mortality in high mortality environments. Likewise, within a broad range of assumed effect sizes OPV could play an economically attractive role against COVID-19.
Whole-exome Sequencing Study of Hypospadias
Authors: Chen Zhongzhong , Lei Yunping , Finnell Richard H. , Su Zhixi , Wang Yaping , Xie Hua , Chen Fang 
Published: January 2022

ABSTRACTWhile hypospadias is one of the most common male congenital disorders, the missing heritability contributed by rare variants with larger effects is poorly understood. To systematically explore the variant patterns in the developing of hypospadias, we performed whole exome sequencing (WES) in 191 severe hypospadias cohort and three trios. Subsequent RNA sequencing of 12 severe hypospadiac foreskins and 6 non-hypospadiac foreskins were conducted. Among previous reported hypospadias risk associated genes, we found thatNR5A1, SRD5A2andARgenes are mutational hotspots in the etiology of severe hypospadias. Additionally, rare damaging variants in novel identified outer dynein arm heavy chain (ODNAH) genes (DNAH5, DNAH8, DNAH9, DNAH11, andDNAH17) (p= 4.8×10−17) were significantly enriched in 191 sporadic severe hypospadias compared with 208 controls. The following transcriptomic analysis further demonstrated that the mutations in theDNAH8andDNAH17genes might affect the network regulation of testosterone (T)-dihydrotestosterone-androgen receptor (T-DHT-AR) signaling. We also identified a novel rare damaging variant ofDNAH8in a severe hypospadias case which was transmitted from the mother. Overall, a panel ofODNAHgenes with rare damaging variants were identified in 22.5% of severe hypospadias patients. This study provides unequivocal evidence for association ofODNAHgenes and hypospadias. This knowledge may guide the genetic counseling for hypospadias.One Sentence SummaryRare damaging variants in outer DNAH genes were identified in 22.5% of severe hypospadias patients, which may guide the genetic counseling of families facing familial hypospadias.
Joinpoint Regression to Determine the Impact of COVID-19 on Mortality in Europe: A Longitudinal Analysis From 2000 to 2020 in 27 Countries
Authors: Rovetta Alessandro 
Published: January 2022

AbstractThe novel coronavirus disease 2019 (COVID-19) represented the most extensive health emergency in human history. However, to date, there is still a lot of uncertainty about the exact death toll the pandemic has claimed. In particular, the number of official deaths could be vastly underestimated. Despite this, many conspirationists speculate that COVID-19 is not a dangerous disease. Therefore, in this manuscript, we use joinpoint regression analysis to estimate the impact of COVID-19 in 27 European countries by comparing annual mortality trends from 2000 to 2020. Furthermore, we provide accessible evidence even for a non-expert audience. Siegel (A1) and Holm-Bonferroni (A2) approaches were employed to assess the significance of the results separately. In conclusion, these results estimate that COVID-19 increased the overall mortality in Europe by 10% (A1: P < .001, A2: Adjusted P = .001). In 16 out of 27 countries (59.3%), the excess mortality ranged from 7.4% to 18.5% (A1: P < .003, A2: Adjusted P < .040). Comparison of the excess mortalities’ distribution to the null counterfactual showed that the mortality increase was highly significant across Europe (Adjusted P < .001).
High Hedgehog signaling is transduced by a multikinase-dependent switch controling the apico-basal distribution of the GPCR Smoothened
Authors: Gonçalves-Antunes Marina , Sanial Matthieu , Contremoulins Vincent , Carvalho Sandra , Plessis Anne , Bécam et Isabelle 
Published: January 2022

SUMMARYThe oncogenic GPCR Smoothened is a key transducer of the Hedgehog morphogen, which plays essential roles in the patterning of epithelial structures. Here, we examine how Hedgehog controls Smoothened subcellular localization and activity in a polarized epithelium using the Drosophila wing imaginal disc as a model. We provide evidence that Hedgehog promotes the stabilization of Smoothened by switching its fate after endocytosis toward recycling. This effect involves the sequential and additive action of Protein Kinase A, Casein Kinase I and the Fused kinase. Moreover, in the presence of very high levels of Hedgehog, a second effect of Fused leads to the local enrichment of Smoothened in the most basal domain of the cell membrane. Together, these results link the morphogenetic effects of Hedgehog to the apico-basal distribution of Smoothened and provide a novel mechanism for regulation of a GPCR by plasma membrane subcompartimentalisation.
Alternative splicing changes are associated with pre-birth adaptation during lung development
Authors: Fidalgo Marta F. , Fonseca Catarina G. , Caldas Paulo , Raposo Alexandre A. S. F. , Balboni Tania , Grosso Ana R. , Vasconcelos Francisca F. , Franco Cláudio A. 
Published: January 2022

AbstractGas exchanges are ensured by lung alveoli, which are mainly composed by epithelial alveolar type 1 (AT1), alveolar type 2 (AT2) and capillary endothelial cells (ECs). Alveologenesis starts during late embryonic development and continues after birth and relies on extensive biochemical crosstalk between these cell types. How this crosstalk is modulated to anticipate and accommodate the radical changes occurring at birth is still unclear.We investigated the alternative splicing (AS) changes occurring during lung development at the embryonic to postnatal transition by performing RNAseq of mouse lungs at distinct developmental stages. We found that most of the AS changes occur at the embryonic to postnatal transition. In addition, we identified hnRNP A1, Cpeb4 and Elavl2/HuB as putative splicing regulators of this transition. We show that the AS of a major pro- angiogenic chemokine, vascular endothelial growth factor A (VEGFA), is differentially regulated at this transition. Remarkably, we found that there is a switch from the predominance of Vegfa 164 to Vegfa 188 just before birth specifically in AT1 cells, whilst in other cell populations Vegfa does not undergo AS changes. Moreover, we identified a novel Vegfa isoform generated by the retention of intron 5, Vegfa i5.Our results reveal a cell type-specific regulation of Vegfa AS that may constitute a pre- birth adaptation mechanism of the epithelial-endothelial crosstalk, which may be fundamental for the adaptation to breathing and may have implications for pathological conditions.
Lysosomes are Required for Early Dorsal Signaling in theXenopusEmbryo
Authors: Tejeda-Muñoz Nydia , De Robertis Edward M. 
Published: January 2022

ABSTRACTLysosomes are the digestive center of the cell and play important roles in human disease, including cancer. Previous work has suggested that late endosomes, also known as multivesicular bodies (MVBs), and lysosomes are essential for canonical Wnt pathway signaling. Sequestration of Glycogen Synthase 3 (GSK3) and of β□catenin destruction complex components in MVBs is required for sustained canonical Wnt signaling. Little is known about the role of lysosomes during early development. In theXenopusegg, a Wnt-like cytoplasmic determinant signal initiates formation of the body axis following a cortical rotation triggered by sperm entry. Here we report that cathepsin D was activated in lysosomes specifically on the dorsal marginal zone of the embryo at 64-cell stage, long before zygotic transcription starts. Expansion of the multivesicular body (MVB) compartment with low-dose Hydroxychloroquine (HCQ) greatly potentiated the dorsalizing effects of the Wnt agonist Lithium chloride (LiCl) in embryos, and this effect required macropinocytosis. Formation of the dorsal axis required lysosomes, as indicated by brief treatments with the vacuolar ATPase (V-ATPase) Bafilomycin A1 inhibitor at the 32-cell stage. Inhibiting the MVB-forming machinery with a dominant-negative point mutation in Vacuolar Protein Sorting 4 (Vps4-EQ) also interfered with the endogenous dorsal axis. The Wnt-like activity of the dorsal cytoplasmic determinant Huluwa (Hwa), and that of microinjected xWnt8 mRNA, also required lysosome acidification and the MVB-forming machinery. We conclude that lysosome function is essential for early dorsal axis development inXenopus. The results highlight the intertwining between membrane trafficking, lysosomes, and vertebrate axis formation.SignificanceThe dorsal axis of the vertebrate Xenopus embryo is established by an early Wnt signal generated by a rotation of the cortex of the egg towards the opposite side of the sperm entry point. In this study, we report that lysosomal Cathepsin D becomes activated on the dorsal marginal zone of the embryo already at the 64-cell stage, and that this asymmetry is enhanced by increasing Wnt signaling levels. We present experiments showing that lysosome activity, macropinocytosis, and multivesicular body formation are required for the dorsal signal provided maternally in the egg, and for twinning by microinjectedhuluwaandWnt8mRNA. The results indicate that the cell biology of lysosomes plays a fundamental role in vertebrate development.
Overlapping transcriptional programs promote survival and axonal regeneration of injured retinal ganglion cells
Authors: Jacobi Anne , Tran Nicholas M , Yan Wenjun , Benhar Inbal , Tian Feng , Schaffer Rebecca , He Zhigang , Sanes Joshua 
Published: January 2022

SUMMARYInjured neurons in the adult mammalian central nervous system often die and seldom regenerate axons. To uncover transcriptional pathways that could ameliorate these disappointing responses we analyzed three interventions that increase survival and regeneration of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC) injury, albeit not to a clinically useful extent. We assessed gene expression in each of 46 RGC types by single cell transcriptomics following ONC and treatment. We also compared RGCs that regenerated to those that survived but did not regenerate. Each intervention enhanced survival of most RGC types, but type-independent axon regeneration required manipulation of multiple pathways. Distinct computational methods converged on separate sets of genes selectively expressed by RGCs likely to be dying, surviving, or regenerating. Overexpression of genes associated with the regeneration program enhanced axon regeneration in vivo, indicating that mechanistic analysis can be used to identify novel methods for promoting regeneration of injured neurons.
Cell atlas of the human ocular anterior segment: Tissue-specific and shared cell types
Authors: van Zyl Tavé , Yan Wenjun , McAdams Alexi , Monavarfeshani Aboozar , Hageman Gregory S. , Sanes Joshua R. 
Published: January 2022

ABSTRACTThe anterior segment of the eye consists of the cornea, iris, ciliary body, crystalline lens and aqueous humor outflow pathways. Together, these tissues are essential for the proper functioning of the eye. Disorders of vision have been ascribed to defects in all of them; some, including glaucoma and cataract, are among the most prevalent causes of blindness in the world. To characterize the cell types that comprise these tissues, we generated an anterior segment cell atlas of the human eye using high throughput single-nucleus RNA sequencing (snRNAseq). We profiled 191,992 nuclei from non-diseased anterior segment tissues from 6 human donors, identifying >60 cell types. Many of these cell types were discrete, whereas others, especially in lens and cornea, formed continua corresponding to known developmental transitions that persist in adulthood. Having profiled each tissue separately, we performed an integrated analysis of the entire anterior segment revealing that some cell types are unique to single structure whereas others are shared across tissues. The integrated cell atlas was then used to investigate cell type-specific expression patterns of more than 900 human ocular disease genes identified either through Mendelian inheritance patterns or genome-wide association studies (GWAS).SIGNIFICANCE STATEMENTSeveral of the most prevalent blinding ocular conditions worldwide, including glaucoma, cataract and uncorrected refractive error, involve structures of the anterior segment of the human eye, which consists of the cornea, iris, ciliary body, crystalline lens and aqueous humor outflow pathways. In addition to providing transcriptomic profiles of the cell types within individual tissues, this work contributes to our understanding of the relatedness and diversity of these cell types across contiguous tissues by generating an integrated anterior segment cell atlas and documenting the expression of over 900 disease-associated genes in each cell type. By allowing simultaneous interrogation of cell-type specific expression of genes across multiple tissues, the atlas may yield broad insight into normal and disease-associated anterior segment functions.
Computation of Antigenicity Predicts SARS-CoV-2 Vaccine Breakthrough Variants
Authors: Hu Ye-fan , Hu Jing-chu , Gong Hua-rui , Danchin Antoine , Sun Ren , Chu Hin , Hung Ivan Fan-Ngai , Yuen Kwok Yung , To Kelvin Kai-Wang , Zhang Bao-zhong , Yau Thomas , Huang Jian-Dong 
Published: January 2022

AbstractIt has been reported that multiple SARS-CoV-2 variants of concerns (VOCs) including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) can reduce neutralisation by antibodies, resulting in vaccine breakthrough infections. Virus-antiserum neutralisation assays are typically performed to monitor potential vaccine breakthrough strains. However, such experimental-based methods are slow and cannot instantly validate whether newly emerging variants can break through current vaccines or therapeutic antibodies. To address this, we sought to establish a computational model to predict the antigenicity of SARS-CoV-2 variants by sequence alone and in real time. In this study, we firstly identified the relationship between the antigenic difference transformed from the amino acid sequence and the antigenic distance from the neutralisation titres. Based on this correlation, we obtained a computational model for the receptor binding domain (RBD) of the spike protein to predict the fold decrease in virus-antiserum neutralisation titres with high accuracy (~0.79). Our predicted results were comparable with experimental neutralisation titres of variants, including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), B.1.429 (Epsilon), P.1 (Gamma), B.1.526 (Iota), B.1.617.1 (Kappa), and C.37 (Lambda), as well as SARS-CoV. Here, we firstly predicted the fold of decrease of B.1.1.529 (Omicron) as 17.4-fold less susceptible to neutralisation. We visualised all 1521 SARS-CoV-2 lineages to indicate variants including B.1.621 (Mu), B.1.630, B.1.633, B.1.649, and C.1.2, which can induce vaccine breakthrough infections in addition to reported VOCs B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Our study offers a quick approach to predict the antigenicity of SARS-CoV-2 variants as soon as they emerge. Furthermore, this approach can facilitate future vaccine updates to cover all major variants. An online version can be accessed athttp://jdlab.online.
Pathogenicity of SARS-CoV-2 Omicron in Syrian hamsters and its neutralization with different Variants of Concern
Authors: Mohandas Sreelekshmy , Yadav Pragya D. , Sapkal Gajanan , Shete Anita M. , Deshpande Gururaj , Nyayanit Dimpal A. , Patil Deepak , Kadam Manoj , Kumar Abhimanyu , Mote Chandrashekhar , Jain Rajlaxmi 
Published: January 2022

AbstractSARS-CoV-2 Omicron variant is rampantly spreading across the globe. Animal models are useful in understanding the disease characteristics as well as properties of emerging SARS-CoV-2 variants. We assessed the pathogenicity and immune response generated by BA.1 sub-lineage of SARS-CoV-2 Omicron variant with R346K mutation in 5 to 6-week old Syrian hamsters. Virus shedding, organ viral load, lung disease and immune response generated were sequentially assessed. The disease characteristics of Omicron were found to be similar to that of other SARS-CoV-2 variants of concerns in hamsters like high viral replication in the respiratory tract and interstitial pneumonia. The infected hamsters demonstrated lesser body weight gain in comparison to the uninfected control hamsters. Viral RNA could be detected in nasal washes and respiratory organs (nasal turbinate, trachea, bronchi and lungs) till 10 and 14 days respectively. The clearance of the virus was observed from nasal washes and lungs by day 7. Neutralizing antibody response against Omicron variant was detected from day 5 with rising antibody titers till 14 days. However, the cross-neutralization titre of the sera against other variants showed severe reduction ie., 7 fold reduction against Alpha and no titers against B.1, Beta and Delta. This preliminary data shows that Omicron variant infection can produce moderate to severe lung disease and the neutralizing antibodies produced in response to Omicron variant infection shows poor neutralizing ability against other co-circulating SARS-CoV-2 variants like Delta which necessitates caution as it may lead to increased cases of reinfection.
Neurodevelopmental oscillatory basis of speech processing in noise
Authors: Bertels Julie , Niesen Maxime , Destoky Florian , Coolen Tim , Ghinst Marc Vander , Wens Vincent , Rovai Antonin , Trotta Nicola , Baart Martijn , Molinaro Nicola , Tiège Xavier De , Bourguignon Mathieu 
Published: January 2022

AbstractHumans’ extraordinary ability to understand speech in noise relies on multiple processes that develop with age. Using magnetoencephalography (MEG), we characterize the underlying neuromaturational basis by quantifying how cortical oscillations in 144 participants (aged 5 to 27 years) track phrasal and syllabic structures in connected speech mixed with different types of noise. While the extraction of prosodic cues from clear speech was stable during development, its maintenance in a multi-talker background matured rapidly up to age 9 and was associated with speech comprehension. Furthermore, while the extraction of subtler information provided by syllables matured at age 9, its maintenance in noisy backgrounds progressively matured until adulthood. Altogether, these results highlight distinct behaviorally relevant maturational trajectories for the neuronal signatures of speech perception. In accordance with grain-size proposals, neuromaturational milestones are reached increasingly late for linguistic units of decreasing size, with further delays incurred by noise.TeaserThe neural signature of speech processing in silence and noise features multiple behaviorally relevant developmental milestones