bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary study on the pathogenesis of anal fistula
Authors: Zhu Jingyi , Wang Qingming , Mei Zubing 
Published: April 2021

ABSTRACTBACKGROUNDAnal gland infection is one of the main pathogenic factors of anal fistula. The anal gland is mainly consist of columnar epithelial cells and goblet cells. Goblet cells could secrete mucins which maintain the surface mucous gel layer of intestine to prevent columnar epithelial cells from the direct acting of bacteria. The absence or diminished secretion of goblet cells could lead to the exposure of columnar epithelial cells to bacteria. In recent years, studies have found that most of the microorganisms in perianal abscess and anal fistula are intestinal bacteria. So, it can be considered that the occurrence and development of anal fistula is closely related to gut microbiota. However, the molecular mechanism of gut microbiota acting on the epithelial cells of anal gland leading to the occurrence and development of anal fistula has not been explored.METHODSAnal fistula tissues were collected from 30 patients, and HE staining was employed to observe pathological changes of anal gland. Stool specimens were collected from normal group (14 normal subjects), preoperative group (21 subjects before surgery) and postoperative group (16 subjects after surgery). High-throughput 16S rRNA gene sequencing was performed to explore differences among different groups.RESULTSIt was found by HE staining that normal anal gland is composed of a large number of columnar epithelial cells as well as goblet cells, while the anal gland of patients with anal fistula is seriously lack of goblet cells. In the normal ones, a large number of vacuoles formed by the dye dissolution of mucin particles can be seen at the top of the goblet cells, and a large amount of mucin secretion can be seen in the center of the anal gland. The results of high-throughput 16S rRNA gene sequencing showed that there were significant statistical differences in species richness, species evenness and species composition between the preoperation group and the normal group (P1 =0.00004), and between the preoperative group and the postoperative group (P2 =0.00003). It also showed that PWY-6471 metabolic pathway was the most significant difference between the preoperative group and the postoperative group (P=0.0033).CONCLUSIONSThe occurrence of anal fistula may be related to the abnormal permeability of mucus layer and the change of intestinal flora composition. The absence or diminished secretion of goblet cells may cause exception of the permeability of mucus layer which makes the columnar epithelial cells of anal gland exposed to the direct contact of peptidoglycan. The metabolite of pathogenic microorganisms could activate the signal pathway (i.g. NLR/NF-κB) which leading to the overexpression of inflammatory factors and cause anal fistula.
Associations of genetic scores for birth weight with newborn size and later Anthropometric traits and cardiometabolic risk markers in South Asians
Authors: Nongmaithem Suraj S , Beaumont Robin N , Dedaniya Akshay , Wood Andrew R , Ogunkolade Babatunji-William , Hassan Zahid , Krishnaveni Ghattu V , Kumaran Kalyanaraman , Potdar Ramesh D , Sahariah Sirajul A , Krishna Murali , Di Gravio Chiara , Mali Inder D , Sankareswaran Alagu , Hussain Akhtar , Bhowmik Biswajit W , Khan Abdul Kalam A , Knight Bridget A , Frayling Timothy M , Finer Sarah , Fall Caroline HD , Yajnik Chittaranjan S , Freathy Rachel M , Hitman Graham A , Chandak Giriraj R 
Published: April 2021

AbstractWe recently reported genetic variants associated with birth weight and their effect on future cardiometabolic risk in Europeans. Despite a higher burden of low birth weight and cardiometabolic disorders, such studies are lacking in South Asians. We generated fetal and maternal genetic scores (fGS and mGS) from 196 birth weight-associated variants identified in Europeans and conducted association analysis with various birth measures and serially measured anthropometric and cardiometabolic traits from seven Indian and Bangladeshi cohorts. Although fGS and mGS were comparable to Europeans, birth weight was substantially smaller suggesting strong environmental constraints on fetal growth in South Asians. Birth weight increased by 50.7g and 33.6g per standard deviation fGS (P=9.1×10−11) and mGS (P=0.003) in South Asians. The fGS was further associated with childhood body size and head circumference, fasting glucose, and triglycerides in adults (P<0.01). Our study supports a common genetic mechanism partly explaining associations between early development and later cardiometabolic health in different populations, despite phenotypic and environmental differences.
Towards fast, routine blood sample quality evaluation by Probe Electrospray Ionization (PESI) metabolomics
Authors: Bordag Natalie , Zügner Elmar , López-García Pablo , Kofler Selina , Tomberger Martina , Al-Baghdadi Abdullah , Schweiger Jessica , Erdem Yasemin , Magnes Christoph , Hidekazu Saiki , Wadsak Wolfgang , Erxleben Björn-Thoralf , Prietl Barbara 
Published: April 2021

AbstractPESI-MS enables with its greatly simplified handling and fast result delivery the application field for high-throughput use in routine settings. In health care and research, pre-analytical errors often remain undetected and disrupt diagnosis, treatment, clinical studies and biomarker validations incurring high costs. This proof-of-principle study investigates the suitability of PESI-MS for robust, routine sample quality evaluation.One of the most common pre-analytical quality issues in blood sampling are prolonged transportations times from bedside to laboratory promptly changing the metabolome. Here, human blood (n=50) was processed immediately or with a time delay of 3 h. The developed sample preparation method delivers ready-to-measure extracts in <8 min. PESI-MS spectra were measured in both ionization modes in 2 min from as little as 2 µl plasma allowing 3 replicate measurements. The mass spectra contained 1200 stable features covering a broad chemical space covering major metabolic classes (e.g. fatty acids, lysolipids, lipids). The time delay of 3 h was predictable by using 18 features with AUC > 0.95 with various machine learning and was robust against loss of single features.Our results serve as first proof of principle for the unique advantages of PESI-MS in sample quality assessments. The results pave the way towards a fully automated, cost-efficient, user-friendly, robust and fast quality assessment of human blood samples from minimal sample amounts.Graphical abstract
Tracking white and grey matter degeneration along the spinal cord axis in degenerative cervical myelopathy
Authors: Vallotton Kevin , David Gergely , Hupp Markus , Pfender Nikolai , Cohen-Adad Julien , Fehlings Michael , Samson Rebecca S. , Wheeler-Kingshott Claudia A. M. Gandini , Curt Armin , Freund Patrick , Seif Maryam 
Published: April 2021

AbstractObjectiveTo determine tissue-specific neurodegeneration across the spinal cord in patients with mild-moderate degenerative cervical myelopathy (DCM).MethodsTwenty-four mild-moderate DCM and 24 healthy subjects were recruited. In patients, a T2-weighted scan was acquired at the compression site, while in all participants a T2*-weighted and diffusion-weighted scan was acquired at the cervical level (C2-C3) and in the lumbar enlargement (i.e. rostral and caudal to the site of compression). We quantified intramedullary signal changes, maximal canal and cord compression, white (WM) and grey matter (GM) atrophy, and microstructural indices from diffusion-weighted scans. All patients underwent clinical (modified Japanese Orthopaedic Association (mJOA)) and electrophysiological assessments. Regression analysis assessed associations between MRI readouts and electrophysiological and clinical outcomes.ResultsTwenty patients were classified with mild and four with moderate DCM using the mJOA scale. The most frequent site of compression was at C5-C6 level with maximum cord compression of 4.68±0.83 mm. Ten patients showed imaging evidence of cervical myelopathy. In the cervical cord, WM and GM atrophy and WM microstructural changes were evident, while in the lumbar cord only WM showed atrophy and microstructural changes. Remote cervical cord WM microstructural changes were pronounced in patients with radiological myelopathy and associated with impaired electrophysiology. Lumbar cord WM atrophy was associated with lower limb sensory impairments.ConclusionTissue-specific neurodegeneration revealed by quantitative MRI, already apparent across the spinal cord in mild-moderate DCM prior to the onset of severe clinical impairments. WM microstructural changes are particularly sensitive to remote pathologically and clinically eloquent changes in DCM.
Brain lesion locations associated with secondary seizure generalization
Authors: Nordberg Janne , Schaper Frederic LWVJ. , Bucci Marco , Nummenmaa Lauri , Joutsa Juho 
Published: April 2021

AbstractBackgroundStructural brain lesions are the most common cause of adult-onset epilepsy. The lesion location may contribute to the risk for epileptogenesis, but whether specific lesion locations are associated with a risk for secondary seizure generalization from focal to bilateral tonic-clonic seizures, is unknown.MethodsWe identified patients with a diagnosis of adult-onset epilepsy caused by an ischemic stroke or a tumor diagnosed at the Turku University Hospital in 2004-2017. Lesion locations were segmented on patient-specific MR imaging and transformed to a common brain atlas (MNI space). Both region-of-interest analyses (intersection with the cortex, hemisphere, and lobes) and voxel-wise analyses were conducted to identify the lesion locations associated with focal to bilateral tonic-clonic compared to focal seizures.ResultsWe included 170 patients with lesion-induced epilepsy (94 tumors, 76 strokes). Lesions predominantly localized in the cerebral cortex (OR 2.50, 95% C.I. 1.21-5.15, p = 0.01) and right hemisphere (OR 2.22, 95% C.I. 1.17-4.20, p = 0.01) were independently associated with focal to bilateral tonic-clonic seizures. At the lobar-level, focal to bilateral tonic-clonic seizures were associated with lesions in the right frontal cortex (OR 4.41, 95% C.I. 1.44-13.5, p = 0.009). No single voxels were significantly associated with seizure type. These effects were independent of lesion etiology.ConclusionsOur results demonstrate that lesion location is associated with the risk for secondary generalization of epileptic seizures independent of lesion etiology. These findings may contribute to identifying patients at risk for focal to bilateral tonic-clonic seizures.
Effects of BNT162b2 mRNA vaccine on Covid-19 infection and hospitalisation among older people: matched case control study for England
Authors: Mason Thomas , Whitston Matt , Hodgson Jack , Watkinson Ruth E , Lau Yiu-Shing , Abdulrazeg Omnia , Sutton Matt 
Published: April 2021

AbstractBackgroundThe BNT162b2 mRNA vaccine has been shown to be effective at preventing serious Covid-19 events in clinical trials. There is less evidence on effectiveness in real-world settings, especially for older people. The rapid roll-out of the NHS vaccination programme in England based on age thresholds offers an opportunity to make unbiased comparisons of outcomes between vaccinated and unvaccinated populations.Methods and FindingsWe matched older (aged 80-83 years) vaccine recipients with younger (aged 76-79 years) persons not yet eligible to receive the vaccine on gender, area of residence, area deprivation, health status, living arrangements, acute illness, and history of seasonal flu vaccination. We also adjusted for the over-representation of Covid-19 positive individuals in the control population because eligibility for vaccination required no Covid-19 symptoms in the previous two weeks. The study population included 170,226 individuals between the ages of 80 and 83 years from community settings outside care homes who received one dose of BNT162b2 mRNA between the 15th and 20th December 2020 and were scheduled a second dose 21 days later.We found emergency hospital admissions were 51.0% (95% confidence interval: 19.9% to 69.5%) lower and positive Covid-19 tests were 55.2% (40.8% to 66.8%) lower for vaccinated individuals compared to matched controls 21 to 27 days after first vaccination. Emergency admissions were 75.6% (52.8% to 87.6%) lower and positive Covid-19 tests were 70.1% (55.1% to 80.1%) lower 35 to 41 days after first vaccination when 79% of participants had received a second dose within 26 days of their first dose.ConclusionsReceipt of the BNT162b2 mRNA vaccine is effective at reducing Covid-19 hospitalisations and infections. The nationwide vaccination of older adults in England with the BNT162b2 mRNA vaccine reduced the burden of Covid-19.
Modelling to inform the COVID-19 response in Bangladesh
Authors: Ferguson Elaine A , Brum Eric , Chowdhury Anir , Chowdhury Shayan , Kundegorski Mikolaj , Mahmud Ayesha S , Purno Nabila , Sania Ayesha , Steenson Rachel , Tasneem Motahara , Hampson Katie 
Published: April 2021

AbstractBackgroundNon-pharmaceutical interventions (NPIs) used to limit SARS-CoV-2 transmission vary in their feasibility, appropriateness and effectiveness in different contexts. In Bangladesh a national lockdown implemented in March 2020 exacerbated poverty and was untenable long-term, and a resurgence in 2021 warranted renewed NPIs.MethodsWe developed an SEIR model for Dhaka District, parameterised from literature values and calibrated to data from Bangladesh. We discussed scenarios and parameterisations with policymakers with the aid of an interactive app. These discussions guided modelling of lockdown and two post-lockdown measures considered feasible to deliver; symptoms-based household quarantining and compulsory mask-wearing. We examined how testing capacity affects case detection, and compared NPI scenarios on deaths, hospitalisations relative to capacity, working days lost, and cost-effectiveness.ResultsLockdowns alone were predicted to delay the first epidemic peak but could not prevent overwhelming of the health service and were costly in lost working days. Impacts of post-lockdown interventions depended heavily on compliance. Assuming 80% compliance, symptoms-based household quarantining alone could not prevent hospitalisations exceeding capacity, whilst mask-wearing prevented overwhelming health services and was cost-effective given masks of high filtration efficiency. Combining masks with quarantine increased their impact. Even at maximum testing capacity, confirmed cases far underestimate total cases. Recalibration to surging cases in 2021 suggests potential for another wave later in 2021, dependent on uncertainties in case reporting and immunity.ConclusionsMasks and symptoms-based household quarantining synergistically prevent transmission, and are cost-effective in Bangladesh. Our interactive app was valuable in supporting decision-making, with mask-wearing being mandated early, and community teams being deployed to support quarantining across Dhaka. These measures likely contributed to averting the worst public health impacts, but delivering an effective response at scale has been challenging. Messaging to increase compliance with mask-wearing and quarantine is needed to reduce the risk and impacts from another wave.
The impact of education inequality on rheumatoid arthritis risk is mediated by smoking and body mass index: mendelian randomization study
Authors: Zhao Sizheng Steven , Holmes Michael V , Zheng Jie , Sanderson Eleanor , Carter Alice R 
Published: April 2021

AbstractObjectiveTo estimate the causal relationship between educational attainment – as a proxy for socioeconomic inequality – and risk of RA and quantify the roles of cigarette smoking and body mass index (BMI) as potential mediators.MethodsUsing the largest genome-wide association studies (GWAS), we performed a two-sample Mendelian randomization (MR) study of genetically predicted educational attainment (instrumented using 1265 variants from 766,345 individuals) and RA (14,361 cases, 43,923 controls). We used two-step MR to quantify the proportion of education’s effect on RA mediated by smoking exposure (as a composite index capturing duration, heaviness and cessation, using 124 variants from 462,690 individuals) and BMI (517 variants, 681,275 individuals), and multivariable MR to estimate proportion mediated by both factors combined.ResultsEach standard deviation (SD) increase in educational attainment (4.2 years of schooling) was protective of RA (OR 0.37; 95%CI 0.31, 0.44). Higher educational attainment was also protective for smoking exposure (β= -0.25 SD; 95%CI -0.26, -0.23) and BMI (β= -0.27 SD (∼1.3kg/m2); 95%CI -0.31, - 0.24). Smoking mediated 24% (95%CI 13%, 35%) and BMI 17% (95%CI 11%, 23%) of the total effect of education on RA. Combined, the two risk factors explained 47% (95%CI 11%, 82%) of the total effect.ConclusionHigher educational attainment has a protective effect on RA risk. Interventions to reduce smoking and excess adiposity at a population level may reduce this risk, but a large proportion of education’s effect on RA remains unexplained. Further research into other risk factors that act as potentially modifiable mediators are required.Key messagesGenetically predicted higher educational attainment – as a proxy for socioeconomic position – is protective for RA.24% of this effect was mediated by smoking behaviour and 17% by body mass index.Efforts to reduce smoking and excess adiposity would help mitigate against socioeconomic inequalities in RA
Multiplex SARS-CoV-2 Genotyping PCR for Population-Level Variant Screening and Epidemiologic Surveillance
Authors: Wang Hannah , Miller Jacob A. , Verghese Michelle , Sibai Mamdouh , Solis Daniel , Mfuh Kenji O. , Jiang Becky , Iwai Naomi , Mar Marilyn , Huang ChunHong , Yamamoto Fumiko , Sahoo Malaya K. , Zehnder James , Pinsky Benjamin A. 
Published: April 2021

ABSTRACTBackgroundEmergence of SARS-CoV-2 variants with concerning phenotypic mutations is of public health interest. Genomic surveillance is an important tool for pandemic response, but many laboratories do not have the resources to support population-level sequencing. We hypothesized that a spike genotyping nucleic acid amplification test (NAAT) could facilitate high-throughput variant surveillance.MethodsWe designed and analytically validated a one-step multiplex allele-specific reverse transcriptase polymerase chain reaction (RT-qPCR) to detect three non-synonymous spike protein mutations (L452R, E484K, N501Y). Assay specificity was validated with next-generation whole-genome sequencing. We then screened a large cohort of SARS-CoV-2 positive specimens from our San Francisco Bay Area population.ResultsBetween December 1, 2020 and March 1, 2021, we screened 4,049 unique infections by genotyping RT-qPCR, with an assay failure rate of 2.8%. We detected 1,567 L452R mutations (38.7%), 34 N501Y mutations (0.84%), 22 E484K mutations (0.54%), and 3 (0.07%) E484K+N501Y mutations. The assay had near-perfect (98-100%) concordance with whole-genome sequencing in a validation subset of 229 specimens, and detected B.1.1.7, B.1.351, B.1.427, B.1.429, B.1.526, and P.2 variants, among others. The assay revealed rapid emergence of L452R in our population, with a prevalence of 24.8% in December 2020 that increased to 62.5% in March 2021.ConclusionsWe developed and clinically implemented a genotyping RT-qPCR to conduct high-throughput SARS-CoV-2 variant screening. This approach can be adapted for emerging mutations and immediately implemented in laboratories already performing NAAT worldwide using existing equipment, personnel, and extracted nucleic acid.Summary / Key PointsEmergence of SARS-CoV-2 variants with concerning phenotypes is of public health interest. We developed a multiplex genotyping RT-qPCR to rapidly detect L452R, E484K, and N501Y with high sequencing concordance. This high-throughput alternative to resource-intensive sequencing enabled surveillance of L452R emergence.
MYCdosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer
Authors: Acón ManSai , Geiß Carsten , Torres-Calvo Jorge , Bravo-Estupiñan Diana , Oviedo Guillermo , Arias-Arias Jorge L , Rojas-Matey Luis A , Baez Edwin , Vásquez-Vargas Gloriana , Oses-Vargas Yendry , Guevara-Coto José , Segura-Castillo Andrés , Siles-Canales Francisco , Quirós-Barrantes Steve , Régnier-Vigouroux Anne , Mendes Pedro , Mora-Rodríguez Rodrigo 
Published: April 2021

SummaryWe hypothesize that dosage compensation of critical genes arises from systems-level properties for cancer cells to withstand the negative effects of aneuploidy. We identified several candidate genes in cancer multi-omics data and developed a biocomputational platform to construct a mathematical model of their interaction network with miRNAs and transcription factors, where the property of dosage compensation emerged forMYCand was dependent on the kinetic parameters of its feedback interactions with three micro-RNAs. These circuits were experimentally validated with a novel genetic tug-of-war technique by overexpressing an exogenousMYCleading to over-expression of the three microRNAs involved and down-regulation of endogenousMYC.In addition,MYCoverexpression or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity inMYC-amplified colon cancer cells. Finally, we identified negative correlation ofMYCdosage compensation with patient survival in TCGA breast cancer patients, highlighting the potential of this mechanism to prevent aneuploid cancer progression.HighlightsThe systems-level property of gene dosage-compensation emergesin silicoin miRNA-transcription factor networks depending on the kinetic parameters of its interactions.We established a criterion to identify compensated candidate genes with low variation in expression despite high copy number variation.BioNetUCR is a novel biocomputational platform to model miRNA-transcription factor interactionsWe present a novel genetic tug-of-war technique to experimentally validate gene dosage compensation at the transcriptional level.Abstract Figure
METTL9 regulates N1-histidine methylation of zinc transporters to promote tumor growth
Authors: Lv Mengyue , Cao Dan , Zhang Liwen , Hu Chi , Li Shukai , Zhang Panrui , Zhu Lianbang , Yi Xiao , Li Chaoliang , Yang Alin , Yang Zhentao , Zhu Yi , Zhang Kaiguang , Pan Wen 
Published: April 2021

AbstractMethyltransferase like 9 (Mettl9) is a member of the methyltransferase like protein family which is characterized by the presence of binding domains for S-adenosyl methionine, (SAM), a co-substrate for methylation reactions. Despite METTL9 is predicted to be a methyltransferase, its enzymatic activity, substrate specificities and biological functions are still poorly characterized. In this study, we revealed a tumor-promoting role for METTL9. We found that deletion ofMettl9in tumor cells suppresses tumor growth and elicits potent anti-tumor immunity. Mechanistically, METTL9 is a N1-histidine methyltransferase which methylates the histidine residues of a x-His-x-His (xHxH) motif on the substrates. This motif is found extensively in zinc transporter families SLC39s and SLC30s, particularly in SLC39A7. Deletion ofMettl9impairs cytoplasmic zinc homeostasis, resulting in an altered gene expression program with increased endoplasmic reticulum (ER) stress and reduced cell cycle. Mutation of key METTL9 catalyzed methylhistidine residues of SLC39A7 impairs cytoplasmic zinc homeostasis and affects cell growth as well. Notably,METTL9expression is increased in some cancer types and its higher expression is associated with worse clinical outcomes, particularly in liver and pancreatic cancer. In summary, our work identifiedMETTL9as a potential new oncogene and its mediated methylation is of regulatory importance. Identifying selective and potent small-molecule inhibitors of METTL9 could thus represent novel therapeutic strategy for anti-proliferative cancer drugs.