bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness of BBV152 vaccine against SARS-CoV-2 infections, hospitalizations and deaths among healthcare workers in the setting of high delta variant transmission in New Delhi, India
Authors: Malhotra Sumit , Kalaivani Mani , Lodha Rakesh , Bakhshi Sameer , Mathur Vijay Prakash , Gupta Pooja , Kedia Saurabh , Sankar Jeeva , Kumar Parmeshwar , Kumar Arvind , Ahuja Vineet , Sinha Subrata , Guleria Randeep 
Published: January 2022

AbstractBackgroundDelta variant transmission resulted in surge of SARS CoV-2 cases in New Delhi, India during the early half of year 2021. Health Care Workers (HCWs) received vaccines on priority for prevention of infection. Real life effectiveness of BBV152 vaccine against severe disease including hospitalization and death was not known.ObjectiveTo estimate effectiveness of BBV152 vaccine among HCWs against SARS CoV-2 infection, hospitalization or deathDesignObservational studySettinga multi -speciality tertiary care public funded hospital in New Delhi, India.Participants12,237 HCWsInterventionsBBV152 vaccine (Covaxin, Bharat Biotech limited, Hyderabad, India); whole virion inactivated vaccine; two doses four weeks apartMeasurementsvaccine effectiveness after receipt of two doses of BBV152 protecting against any SARS CoV-2 infection, symptomatic infections or hospitalizations or deaths, and hospitalizations or deaths.ResultsThe mean age of HCWs was 36(±11) years, 66% were men and 16% had comorbidity. After adjusting for potential covariates viz age, sex, health worker type category, body mass index, and comorbidity, the vaccine effectiveness (95% Confidence Interval) in fully vaccinated HCWs and ≥14 days elapsed after the receipt of second dose was 44% (37 to 51, p<0.001) against symptomatic infection, hospitalization or death due to SARS CoV-2, and 61% (37 to 76, p<0.001) against hospitalization or death, respectively.ConclusionsBBV152 vaccine with complete two doses offer a modest response to SARS CoV-2 infection in real life situations against a backdrop of high delta variant community transmission. Efforts in maximizing receipt of full vaccines should be invested for HCWs, who are at higher occupational risk for infection.
Harringtonine has the effects of double blocking SARS-CoV-2 membrane fusion
Authors: Hu Shiling , Wang Nan , Chen Shaohong , Ding Qiang , Wang Cheng , Ma Weina , Zhang Xinghai , Wu Yan , Lv Yanni , Xue Zhuoyin , Bai Haoyun , Ge Shuai , He Huaizhen , Lu Wen , Zhang Tao , Ding Yuanyuan , Liu Rui , Han Shengli , Zhan Yingzhuan , Zhan Guanqun , Guo Zengjun , Zhang Yongjing , Lu Jiayu , Gao Jiapan , Jia Qianqian , Wang Yuejin , Wang Hongliang , Lu Shemin , Zhang Huajun , He Langchong 
Published: January 2022

AbstractFusion with host cell membrane is the main mechanism of infection of SARS-CoV-2. Here, we propose a new strategy to double block SARS-CoV-2 membrane fusion by using Harringtonine (HT), a small-molecule antagonist. By using cell membrane chromatography (CMC), we found that HT specifically targeted the SARS-CoV-2 S protein and host cell TMPRSS2, and then confirmed that HT can inhibit pseudotyped virus membrane fusion. Furthermore, HT successfully blocked SARS-CoV-2 infection, especially in the delta and Omicron mutant. Since HT is a small-molecule antagonist, it is minimally affected by the continuous variation of SARS-CoV-2. Our findings show that HT is a potential small-molecule antagonist with a new mechanism of action against SARS-CoV-2 infection, and thus HT mainly targets the S protein, and thus, greatly reduces the damage of the S protein’s autotoxicity to the organ system, has promising advantages in the clinical treatment of COVID-19.
A robust and fast two-sample test of equal correlations with an application to differential co-expression
Authors: He Liang , Philipp Ian , Webster Stephanie , Kulminski Alexander M. 
Published: January 2022

AbstractA robust and fast two-sample test for equal Pearson correlation coefficients (PCCs) is important in solving many biological problems, including, e.g., analysis of differential co-expression. However, few existing methods for this test can achieve robustness against deviation from normal distributions, accuracy under small sample sizes, and computational efficiency simultaneously. Here, we propose such a method for testing DIfferential COrrelation using a Saddlepoint Approximation of the Residual bootstrap (DICOSAR). To achieve robustness, accuracy, and efficiency, DICOSAR combines the ideas underlying the pooled residual bootstrap, the signed root of a likelihood ratio statistic, and a multivariate saddlepoint approximation. Through a comprehensive simulation study and a real data analysis of gene co-expression, we demonstrate that DICOSAR is accurate and robust in controlling the type I error rate for detecting differential correlation and provides a faster alternative to the permutation method. We further show that it can also be used for testing differential correlation matrices. These results suggest that DICOSAR provides an analytical approach to facilitate rapid testing for the equality of PCCs in a large-scale analysis.
Marine invertebrate diversity and distribution; the evidence of human activities in Rommel Bay
Authors: Ibrahim Marwa Abd El-Aziz M. , Zidan Islam Mohammad 
Published: January 2022

AbstractThe current note hypothesised that human/tourism beach activities in Rommel Bay, Marsa Matrouh, Egypt (31°21’39.9”N 27°15’12.3”E) affected the marine invertebrates in this area. The note resulted some new findings of arthropod, molluscan, and seagrasses species diversity and distribution. The hypothesised study concluded that human/tourism beach activities did not eliminate the invertebrate communities, but these animals have shifted and moved themselves to escape away from noise and pollution. Further investigations should be taken into consideration about aquatic insects, mites, crustaceans, seagrasses, and molluscans diversity and distribution, to figure out the actual structures and interactions between these animals within the Rommel Bay ecosystem, besides what are the stresses they have, and what are the consequences.
Chondroitin sulfates enhances the barrier function of basement membrane assembled by heparan sulfates
Authors: Tao Chenqi , Makrides Neoklis , Wu Yihua , Brooks Steven E , Esko Jeffrey D. , Zhang Xin 
Published: January 2022

AbstractGlycosaminoglycans (GAGs) are ubiquitously expressed polysaccharides attached to proteoglycans, but their functions in the retina are poorly understood. Here we generated conditional knockouts of biosynthetic enzymes for heparan sulfate (HS) and chondroitin sulfate (CS) in retinal progenitor cells. We showed that ablation of HS polymerase Ext1 did not affect initial progression of retinal angiogenesis, but it disrupted the pruning of blood vessels and establishment of arterioles and venules. In the absence of retinal HS, blood vessels were also vulnerable to high oxygen tension in early postnatal stages, which can be rescued by exogenous VEGF, consistent with the role of retinal HS in the fine-tuning of VEGF signaling. Furthermore, we observed that the retinal inner limiting membrane (ILM) was disrupted by deletion of Ext1 in a timing specific manner, suggesting that retinal HS is required for the assembly but not the maintenance of the ILM. Lastly, we showed that further deletion of C4st1, a CS sulfation enzyme, did not affect the assembly of the ILM, but aggravated the ILM permeability when combined with Ext1 deletion. These results demonstrated an important role of CS and HS in establishing the barrier function of basement membrane.
Global success in oyster reef restoration despite ongoing recovery debt
Authors: Hemraj Deevesh A. , Bishop Melanie J. , Hancock Boze , Minuti Jay J. , Thurstan Ruth H. , Zu Ermgassen Philine S.E. , Russell Bayden D. 
Published: January 2022

AbstractHabitat destruction and biodiversity loss from exploitation of ecosystems have led to increased restoration and conservation efforts worldwide. Disturbed ecosystems accumulate a recovery debt – the accumulated loss of ecosystem services - and quantifying this debt presents a valuable tool to develop better ecosystem restoration practices. Here, we quantified the ongoing recovery debt following structural restoration of oyster habitats, one of the most degraded marine ecosystems worldwide. We found that whilst restoration initiates a rapid increase in biodiversity and abundance of 2- to 5-fold relative to unrestored habitat, recovery rate decreases substantially within a few years post-restoration and accumulated global recovery debt persists at >35% per annum. Therefore, while efficient restoration methods will produce enhanced recovery success and minimise recovery debt, potential future coastal development should be weighed up against not just the instantaneous damage to ecosystem functions and services but also the potential for generational loss of services and long-term recovery.
Reversal of obesogenic feeding and hypometabolism by a bifurcating GABAergic neural circuit
Authors: Han Yong , He Yang , Harris Lauren , Xu Yong , Wu Qi 
Published: January 2022

AbstractDiet-induced obesity is characterized by unsatiated consumption of energy-dense diets and impaired metabolism, whereby anti-obesity effect of the high-level of circulating leptin is unknowingly blunted. Emerging evidence suggests that the leptin receptor (LepR) signaling system, residing within the agouti-related protein (AgRP) neurons of the hypothalamus, critically contributes to obesogenic feeding, nutrient partitioning, and energy metabolism. However, the neural circuit mechanism underlying the leptin-dependent control of obesogenic feeding and energy balance remains largely elusive. Here, we show that two distinct subgroups of LepR-expressing AgRP neurons send non-collateral, GABAergic projections to the dorsomedial hypothalamic nucleus (DMH) and to the medial part of the medial preoptic nucleus (MPO) for the differential control of metabolic homeostasis and obesogenic feeding, respectively. We found that the AgRPLepR-DMH neural circuit plays a significant role in leptin-dependent control of metabolic homeostasis through the α3-containing GABAA receptor signaling on the melanocortin 4 receptor neurons within the DMH (MC4RDMH). In contrast, the AgRPLepR-MPO neural circuit elicits dominant effects on the appetitive response to high-fat diet through the α2-containing GABAA receptors on the MC4RMPO neurons. Consistent with these behavioral results, the post-synaptic GABAA neurons located within the DMH and MPO displayed differentiated firing responses under various feeding and nutrient conditions. Our results demonstrate that these novel GABAergic neural circuits exert differentiated control of metabolic hemostasis and obesogenic feeding via distinct post-synaptic targets of leptin-responsive AgRP neurons. The findings of two genetically and anatomically distinct GABAA receptor signaling pathways within the DMH and MPO would undoubtedly accelerate the development of targeted, individualized, anti-obesity therapy.
USH2A gene mutations in rabbits lead to progressive retinal degeneration and hearing loss
Authors: Nguyen Van Phuc , Song Jun , Prieskorn Diane , Li Yanxiu , Dolan David , Xu Jie , Zhang Jifeng , Jayasundera K Thiran , Raphael Yehoash , Chen Y. Eugene , Paulus Yannis M. , Yang Dongshan 
Published: January 2022

AbstractMutations in USH2A gene are responsible for the greatest proportion of hearing and vision loss among individuals with Usher Syndrome (USH) and for autosomal recessive non-syndromic retinitis pigmentosa. Mutations on USH2A exon 13 account for more than 35% of the disease causing USH2A variants including the most prevalence point mutation, c.2299delG, a frameshift mutation. The lack of a clinically relevant animal model has been a bottleneck for the development of therapeutics for USH2A related vision loss. Using CRSPR/Cas9 technology, this study establishes a rabbit line carrying an USH2A frameshift mutation on exon12 (equivalent to human USH2A Exon 13) as a novel mammalian animal model of USH2A. The bi-allelic mutant rabbits exhibit hyper reflective signals in FAF indicating RPE damage and OCT changes indicating photoreceptor degeneration as early as 4 months of age. ERG signals of both rod and cone function were reduced in the USH2A mutant rabbits starting from 7 months old and further decreased at 15-22 months old, indicating progressive retinal photoreceptor degeneration, which is further confirmed by retinal histopathology examination. ABR examination showed moderate to server hearing loss in the USH2A mutant rabbits. These results indicated that disruption of USH2A gene in rabbits is sufficient to induce hearing loss and progressive photoreceptor degeneration. To our knowledge, this is the first mammalian animal model of USH2 which closely recapitulates the phenotype of retinitis pigmentosa in human patients. This study supports the use of rabbits as a clinically relevant animal model to understand the pathogenesis and to develop novel therapeutics for Usher Syndrome.
Transforming chemical proteomics enrichment into high-throughput method using SP2E workflow
Authors: Becker Tobias , Wiest Andreas , Telek András , Bejko Daniel , Hoffmann-Röder Anja , Kielkowski Pavel 
Published: January 2022

AbstractProtein post-translational modifications (PTMs) play a critical role in the regulation of protein catalytic activity, localization and protein-protein interactions. Attachment of PTMs onto proteins significantly diversifies their structure and function resulting in so-called proteoforms. However, the sole identification of post-translationally modified proteins, which are often cell type and disease specific, is still a highly challenging task. Sub-stoichiometric amounts and modification of low abundant proteins necessitate purification or enrichment of the modified proteins. Although the introduction of the mass spectrometry-based chemical proteomic strategies have enabled to screen protein PTMs with increased throughput, sample preparation has remained highly time consuming and tedious. Here, we report an optimized workflow for enrichment of PTM proteins in 96-well plate format which can be possible extended to robotic automatization. This platform allows to significantly lower the input of total protein, which opens up the opportunity to screen specialized and difficult to culture cell lines in high-throughput manner. The presented SP2E protocol is robust, time- and cost-effective as well as suitable for large-scale screening of proteoforms. Application of the SP2E protocol will thus enable the characterization of proteoforms in various processes such as neurodevelopment, neurodegeneration and cancer and may contribute to an overall acceleration of the recently launched Human Proteoform Project.
Genomic instability caused by Arp2/3 complex inactivation results in micronucleus biogenesis and cellular senescence
Authors: Haarer Elena L. , Guo Shirley , Campellone Kenneth G. 
Published: January 2022

AbstractThe Arp2/3 complex is a ubiquitous actin nucleator with well-characterized activities in cell organization and movement, but its roles in chromatin-associated and cell cycle-related processes are relatively understudied. We investigated how the Arp2/3 complex affects genomic integrity, mitosis, and cell proliferation using mouse fibroblasts containing an inducible knockout (iKO) of the ArpC2 subunit. We show that permanent Arp2/3 ablation results in DNA damage, the formation of cytosolic micronuclei, and cellular senescence. Upon Arp2/3 depletion, cells undergo an abrupt proliferation arrest that is accompanied by activation of the tumor suppressor p53, upregulation of its downstream cell cycle inhibitorCdkn1a/p21, and recognition of micronuclei by the cytosolic DNA sensor cGAS. Micronuclei arise in ArpC2 iKO cells due to chromosome segregation defects during mitosis and premature mitotic exits. Such phenotypes are explained by the presence of damaged chromatin fragments that fail to attach to the mitotic spindle, abnormalities in actin assembly during metaphase, and asymmetric microtubule architecture during anaphase. These studies establish functional requirements for the mammalian Arp2/3 complex in genome stability and mitotic spindle organization. They further expand our understanding of the intracellular mechanisms that lead to senescence and suggest that cytoskeletal dysfunction is an underlying factor in biological aging.Author SummaryThe actin cytoskeleton consists of protein polymers that assemble and disassemble to control the organization, shape, and movement of cells. However, relatively little is understood about how the actin cytoskeleton affects genome maintenance, cell multiplication, and biological aging. In this study, we show that knocking out the Arp2/3 complex, a core component of the actin assembly machinery, causes DNA damage, genomic instability, defects in chromosome partitioning during mitosis, and a permanent cell proliferation arrest called senescence. Since senescent cells are major contributors to both age-associated diseases and tumor suppression, our findings open new avenues of investigation into how natural or experimental alterations of cytoskeletal proteins impact the process of aging and the regulation of cancer.
Type IV pili is a critical virulence factor in clinical isolates ofPaenibacillus thiaminolyticus
Authors: Hehnly Christine , Shi Aiqin , Ssentongo Paddy , Zhang Lijun , Isaacs Albert , Morton Sarah U. , Streck Nicholas , Erdmann-Gilmore Petra , Tolstoy Igor , Reid Townsend R. , Limbrick David D. , Paulson Joseph N. , Ericson Jessica E. , Galperin Michael Y. , Schiff Steven J. , Broach James R. 
Published: January 2022

AbstractHydrocephalus, the leading indication for childhood neurosurgery worldwide, is particularly prevalent in low-and-middle-income countries (LMICs). Hydrocephalus preceded by an infection, or postinfectious hydrocephalus (PIH), accounts for up to 60% of hydrocephalus in LMICs. Since many children with hydrocephalus suffer poor long-term outcomes despite surgical intervention, prevention of hydrocephalus remains paramount. Our previous studies implicated a novel bacterial pathogen,Paenibacillus thiaminolyticus,as a contributor to PIH in Uganda. Here we report the isolation of threeP. thiaminolyticusstrains, Mbale, Mbale2, and Mbale3, from patients with PIH and the demonstration that the three clinical isolates exhibit virulence in mice whileP. thiaminolyticustype strain, B-4156, does not. We constructed complete genome assemblies of the clinical isolates as well as the reference strain and performed comparative genomics and proteomics analyses to identify potential virulence factors. One candidate virulence factor is a cluster of genes carried on a mobile genetic element that encodes a type IV pilus and is present in all three PIH patient strains but absent in the type strain. Proteomic and transcriptomic data confirmed the expression of this cluster of genes in the Mbale strain, while CRISPR-mediated deletion of the gene cluster substantially reduced the virulence of this strain. Our comparative proteogenomic analysis also identified various antibiotic resistance loci in the virulent strains. These results provide insight into the mechanism of virulence ofPaenibacillus thiaminolyticusand suggest avenues for the diagnosis and treatment of this novel bacterial pathogen.Author SummaryPostinfectious hydrocephalus (PIH), a devastating sequela of neonatal infection, is associated with increased childhood mortality and morbidity.Paenibacillus thiaminolyticuswas recently identified as the dominant organism highly associated with PIH in an African cohort. Our whole-genome sequencing, RNA sequencing and proteomics of three clinical isolates and a type strain in combination with CRISPR editing has revealed the type IV pili (T4P), encoded in a mobile genetic element, as a critical virulence factor forP. thiaminolyticusinfection. Given the widespread presence of T4P in pathogens, the presence of T4P operon could serve as an important diagnostic and therapeutic target inP. thiaminolyticusand related bacteria.
Differences in durability of PARP inhibition by clinically approved PARP inhibitors: implications for combinations and scheduling
Authors: Smith Hannah L , Willmore Elaine , Mukhopadhyay Asima , Drew Yvette , Curtin Nicola J 
Published: January 2022

AbstractFive PARP inhibitors (PARPi) are approved for cancer treatment, they exploit cancer-specific defects in homologous recombination repair (HRR) to selectively kill tumour cells. Continuous PARP inhibition is required for single-agent anticancer activity. PARPi are also being investigated with ATR inhibitors clinically. We previously showed rucaparib caused prolonged PARP inhibition. Here we aimed to determine if this property was unique to rucaparib or common to other PARPis and the implications for scheduling with an ATR inhibitor (VE-821). Durability of PARP inhibition was determined at 0, 1, 24, 48 and 72 h after a 1 h pulse of 1μM of rucaparib, olaparib, niraparib, talazoparib or pamiparib in IGROV-1 (human ovarian cancer) cells. Inhibition of PARP was sustained to a variable degree with all inhibitors, but reduced with time. Rucaparib caused the most persistent inhibition of PARP activity, which was maintained at ≥75% for 72 h after drug withdrawal. In contrast, only 12% inhibition remained at this time with talazoparib and pamiparib and no detectable inhibition with olaparib and niraparib. Rucaparib enhanced VE-821 cytotoxicity to a similar extent in a sequential schedule as in co-exposure studies (PF50: 2.6 vs. 2.7) and there was even an approx. 2-fold enhancement after a 24 h delay between rucaparib and VE-821. Olaparib and niraparib produced similar enhancement of VE-821 cytotoxicity if co-exposed but were ineffective in sequential exposures. These data have clinical implications for both schedules of current PARPi monotherapy and the scheduling of PARPi in combination with ATRi and other cytotoxic drugs.Novelty and ImpactPARPi are a new class of anticancer agent. We demonstrate for the first time that 5 PARPi continue to suppress cellular PARP activity after drug removal to a variable extent. Rucaparib caused the most durable PARP inhibition, olaparib and niraparib the least. Rucaparib enhanced ATR inhibitor cytotoxicity in sequential and co-exposures, olaparib and niraparib were only active in co-exposure settings. These data have implications for the clinical use of PARPi, particularly in combination with other drugs.