bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroExonator enables systematic discovery and quantification of microexons across mouse embryonic development
Authors: Parada Guillermo E. , Munita Roberto , Georgakopoulos-Soares Ilias , Fernandes Hugo J. R. , Kedlian Veronika R. , Metzakopian Emmanouil , Andres Maria Estela , Miska Eric A. , Hemberg Martin 
Published: January 2021

Abstract
Background
Microexons, exons that are ≤ 30 nucleotides, are a highly conserved and dynamically regulated set of cassette exons. They have key roles in nervous system development and function, as evidenced by recent results demonstrating the impact of microexons on behaviour and cognition. However, microexons are often overlooked due to the difficulty of detecting them using standard RNA-seq aligners.

Results
Here, we present MicroExonator, a novel pipeline for reproducible de novo discovery and quantification of microexons. We process 289 RNA-seq datasets from eighteen mouse tissues corresponding to nine embryonic and postnatal stages, providing the most comprehensive survey of microexons available for mice. We detect 2984 microexons, 332 of which are differentially spliced throughout mouse embryonic brain development, including 29 that are not present in mouse transcript annotation databases. Unsupervised clustering of microexons based on their inclusion patterns segregates brain tissues by developmental time, and further analysis suggests a key function for microexons in axon growth and synapse formation. Finally, we analyse single-cell RNA-seq data from the mouse visual cortex, and for the first time, we report differential inclusion between neuronal subpopulations, suggesting that some microexons could be cell type-specific.

Conclusions
MicroExonator facilitates the investigation of microexons in transcriptome studies, particularly when analysing large volumes of data. As a proof of principle, we use MicroExonator to analyse a large collection of both mouse bulk and single-cell RNA-seq datasets. The analyses enabled the discovery of previously uncharacterized microexons, and our study provides a comprehensive microexon inclusion catalogue during mouse development.
Integrative analyses of TEDDY Omics data reveal lipid metabolism abnormalities, increased intracellular ROS and heightened inflammation prior to autoimmunity for type 1 diabetes
Authors: Balzano-Nogueira Leandro , Ramirez Ricardo , Zamkovaya Tatyana , Dailey Jordan , Ardissone Alexandria N. , Chamala Srikar , Serrano-Quílez Joan , Rubio Teresa , Haller Michael J. , Concannon Patrick , Atkinson Mark A. , Schatz Desmond A. , Triplett Eric W. , Conesa Ana 
Published: January 2021

Abstract
Background
The Environmental Determinants of Diabetes in the Young (TEDDY) is a prospective birth cohort designed to study type 1 diabetes (T1D) by following children with high genetic risk. An integrative multi-omics approach was used to evaluate islet autoimmunity etiology, identify disease biomarkers, and understand progression over time.

Results
We identify a multi-omics signature that was predictive of islet autoimmunity (IA) as early as 1 year before seroconversion. At this time, abnormalities in lipid metabolism, decreased capacity for nutrient absorption, and intracellular ROS accumulation are detected in children progressing towards IA. Additionally, extracellular matrix remodeling, inflammation, cytotoxicity, angiogenesis, and increased activity of antigen-presenting cells are observed, which may contribute to beta cell destruction. Our results indicate that altered molecular homeostasis is present in IA-developing children months before the actual detection of islet autoantibodies, which opens an interesting window of opportunity for therapeutic intervention.

Conclusions
The approach employed herein for assessment of the TEDDY cohort showcases the utilization of multi-omics data for the modeling of complex, multifactorial diseases, like T1D.
Effect of early sleep apnoea treatment with adaptive servo-ventilation in acute stroke patients on cerebral lesion evolution and neurological outcomes: study protocol for a multicentre, randomized controlled, rater-blinded, clinical trial (eSATIS: early Sleep Apnoea Treatment in Stroke)
Authors: Duss Simone B. , Brill Anne-Kathrin , Baillieul Sébastien , Horvath Thomas , Zubler Frédéric , Flügel Dominique , Kägi Georg , Benz Gabriel , Bernasconi Corrado , Ott Sebastian R. , Korostovtseva Lyudmila , Sviryaev Yurii , Salih Farid , Endres Matthias , Tamisier Renaud , Gouveris Haralampos , Winter Yaroslav , Denier Niklaus , Wiest Roland , Arnold Marcel , Schmidt Markus H. , Pépin Jean-Louis , Bassetti Claudio L. A. 
Published: January 2021

Abstract
Background
Sleep-disordered breathing (SDB) is highly prevalent in acute ischaemic stroke and is associated with worse functional outcome and increased risk of recurrence. Recent meta-analyses suggest the possibility of beneficial effects of nocturnal ventilatory treatments (continuous positive airway pressure (CPAP) or adaptive servo-ventilation (ASV)) in stroke patients with SDB. The evidence for a favourable effect of early SDB treatment in acute stroke patients remains, however, uncertain.

Methods
eSATIS is an open-label, multicentre (6 centres in 4 countries), interventional, randomized controlled trial in patients with acute ischaemic stroke and significant SDB. Primary outcome of the study is the impact of immediate SDB treatment with non-invasive ASV on infarct progression measured with magnetic resonance imaging in the first 3 months after stroke. Secondary outcomes are the effects of immediate SDB treatment vs non-treatment on clinical outcome (independence in daily functioning, new cardio-/cerebrovascular events including death, cognition) and physiological parameters (blood pressure, endothelial functioning/arterial stiffness). After respiratory polygraphy in the first night after stroke, patients are classified as having significant SDB (apnoea-hypopnoea index (AHI) > 20/h) or no SDB (AHI < 5/h). Patients with significant SDB are randomized to treatment (ASV+ group) or no treatment (ASV− group) from the second night after stroke. In all patients, clinical, physiological and magnetic resonance imaging studies are performed between day 1 (visit 1) and days 4–7 (visit 4) and repeated at day 90 ± 7 (visit 6) after stroke.

Discussion
The trial will give information on the feasibility and efficacy of ASV treatment in patients with acute stroke and SDB and allows assessing the impact of SDB on stroke outcome. Diagnosing and treating SDB during the acute phase of stroke is not yet current medical practice. Evidence in favour of ASV treatment from a randomized multicentre trial may lead to a change in stroke care and to improved outcomes.

Trial registration
ClinicalTrials.gov NCT02554487, retrospectively registered on 16 September 2015 (actual study start date, 13 August 2015), and www.kofam.ch (SNCTP000001521).
Quantifying the advantages of conducting a prospective meta-analysis (PMA): a case study of early childhood obesity prevention
Authors:   on behalf of the EPOCH Collaboration, Seidler A. L. , Hunter K. E. , Espinoza D. , Mihrshahi S. , Askie L. M. 
Published: January 2021

AbstractBackgroundFor prospective meta-analyses (PMAs), eligible studies are identified, and the PMA hypotheses, selection criteria, and analysis methods are pre-specifiedbeforethe results of any of the studies are known. This reduces publication bias and selective outcome reporting and provides a unique opportunity for outcome standardisation/harmonisation. We conducted a world-first PMA of four trials investigating interventions to prevent early childhood obesity. The aims of this study were to quantitatively analyse the effects of prospective planning on variations across trials, outcome harmonisation, and the power to detect intervention effects, and to derive recommendations for future PMA.MethodsWe examined intervention design, participant characteristics, and outcomes collected across the four trials included in the EPOCH PMA using their registration records, protocol publications, and variable lists. The outcomes that trials planned to collect prior to inclusion in the PMA were compared to the outcomes that trials collected after PMA inclusion. We analysed the proportion of matching outcome definitions across trials, the number of outcomes per trial, and how collaboration increased the statistical power to detect intervention effects.ResultsThe included trials varied in intervention design and participants, this improved external validity and the ability to perform subgroup analyses for the meta-analysis. While individual trials had limited power to detect the main intervention effect (BMIz-score), synthesising data substantially increased statistical power. Prospective planning led to an increase in the number of collected outcome categories (e.g. weight, child’s diet, sleep), and greater outcome harmonisation. Prior to PMA inclusion, only 18% of outcome categories were included in all trials. After PMA inclusion, this increased to 91% of outcome categories. However, while trials mostly collected the same outcome categories after PMA inclusion, some inconsistencies in how the outcomes were measured remained (such as measuring physical activity by hours of outside play versus using an activity monitor).ConclusionProspective planning led to greater outcome harmonisation and greater power to detect intervention effects, while maintaining acceptable variation in trial designs and populations, which improved external validity. Recommendations for future PMA include more detailed harmonisation of outcome measures and careful pre-specification of analyses to avoid research waste by unnecessary over-collection of data.
The coArtHA trial—identifying the most effective treatment strategies to control arterial hypertension in sub-Saharan Africa: study protocol for a randomized controlled trial
Authors: Mapesi Herry , Gupta Ravi , Wilson Herieth Ismael , Lukau Blaise , Amstutz Alain , Lyimo Aza , Muhairwe Josephine , Senkoro Elizabeth , Byakuzana Theonestina , Mphunyane Madavida , Bresser Moniek , Glass Tracy Renée , Lambiris Mark , Fink Günther , Gingo Winfrid , Battegay Manuel , Paris Daniel Henry , Rohacek Martin , Vanobberghen Fiona , Labhardt Niklaus Daniel , Burkard Thilo , Weisser Maja 
Published: January 2021

Abstract
Background
Arterial hypertension is the most prevalent risk factor for cardiovascular disease in sub-Saharan Africa. Only a few and mostly small randomized trials have studied antihypertensive treatments in people of African descent living in sub-Saharan Africa.

Methods
In this open-label, three-arm, parallel randomized controlled trial conducted at two rural hospitals in Lesotho and Tanzania, we compare the efficacy and cost-effectiveness of three antihypertensive treatment strategies among participants aged ≥ 18 years. The study includes patients with untreated uncomplicated arterial hypertension diagnosed by a standardized office blood pressure ≥ 140/90 mmHg. The trial encompasses a superiority comparison between a triple low-dose antihypertensive drug combination versus the current standard of care (monotherapy followed by dual treatment), as well as a non-inferiority comparison for a dual drug combination versus standard of care with optional dose titration after 4 and 8 weeks for participants not reaching the target blood pressure. The sample size is 1268 participants with parallel allocation and a randomization ratio of 2:1:2 for the dual, triple and control arms, respectively. The primary endpoint is the proportion of participants reaching a target blood pressure at 12 weeks of ≤ 130/80 mmHg and ≤ 140/90 mmHg among those aged < 65 years and ≥ 65 years, respectively. Clinical manifestations of end-organ damage and cost-effectiveness at 6 months are secondary endpoints.

Discussion
This trial will help to identify the most effective and cost-effective treatment strategies for uncomplicated arterial hypertension among people of African descent living in rural sub-Saharan Africa and inform future clinical guidelines on antihypertensive management in the region.

Trial registration
Clinicaltrials.govNCT04129840. Registered on 17 October 2019 (https://www.clinicaltrials.gov/).
The acupoint herbal plaster for the prevention and treatment of postoperative nausea and vomiting after PLIF with general anesthesia: study protocol for a multicenter randomized controlled trial
Authors: Xu Huiqing , Wei Xu , Zhang Ranxing , Li Ling , Zhang Zhijun , Jia Ruo , Zhang Xiaofei , Gao Xiumei , Dong Xicheng , Pan Junjun 
Published: January 2021

Abstract
Background
Postoperative nausea and vomiting (PONV) are common in posterior lumbar intervertebral fusion (PLIF) patients undergoing general anesthesia. The previous clinical observation has shown that a traditional acupoint herbal plaster (AHP) is beneficial to patients with PONV. This trial aims to assess the effect of the AHP for the prevention and treatment of PONV after PLIF in patients with general anesthesia.

Methods
A multicenter, parallel, randomized controlled trial (RCT) will be conducted. A total of 166 participants will be randomized to either a treatment group receiving an AHP or a control groups receiving an acupoint placebo plaster (APP) in a 1:1 ratio. The primary outcomes are the first occurrence and frequency of nausea and vomiting. The secondary outcomes include the severity grading of nausea and vomiting using a visual analog scale (VAS) measurement system, quality of life, and serological indicators. The safety evaluation is mainly about adverse events and skin reactions’ observation. Assessments will be carried out at the baseline, day 1, and day 2 (the end of the intervention). The central randomization system in the clinical trial (http://124.205.181.142:8082/xwtf/) will be used to conduct random allocation.

Discussion
This scientific methodology design of the trial is expected to provide clinical evidence to support the AHP for the prevention and treatment of PONV.

Trial registration
This study is retrospectively registered with the Chinese Clinical Trial Registry (http://www.chictr.org.cn) on 19 April 2018. ID: ChiCTR1800015768.
Efficacy of silver needle therapy for the treatment of chronic nonspecific low back pain: a prospective, single-center, randomized, parallel-controlled clinical trial
Authors: Hu Xuesong , Dong Shaoxing , Zhang Bing , Wang Xuan , Yin Yanwei , Liu Chuansheng , Yu Junmin , Wu Xing , Xu Fenghu , Meng Chao 
Published: January 2021

AbstractBackgroundChronic nonspecific low back pain (CNSLBP) troubles approximately 30% of people worldwide. Silver needle therapy (SNT) is a treatment method to relieve soft tissue pain through heating. Therefore, this study aimed to observe the effects of SNT on CNSLBP.MethodsIn this study, 100 patients were randomly divided into 2 groups: silver needle (SN) group and control group (n = 50). In the SN group, patients received SNT and physiotherapy, while patients received physiotherapy alone in the control group. At the 6-month follow-up, the numerical rating scale (NRS), Oswestry Disability Index (ODI), Short-Form 12 of quality of life (SF-12), the natural logarithms of low-frequency measurement (InLF), and the natural logarithms of high-frequency measurement (InHF) of heart rate variability (HRV) were recorded.ResultsIn both groups, NRS, ODI, SF-12 scores, and HRV at 2 weeks after treatment were improved and maintained for 6 months. Compared with the control group, more significant improvements were observed in the NRS and SF-12 scores at 1, 2, 3, and 6 months and in the ODI scores at 1 and 2 months in the SN group (P <  0.05). However, there was no significant difference between the groups in the ODI scores at 3 and 6 months. InLF and InHF in the SN group were higher than those in the control group at 3 and 6 months (P <  0.05).ConclusionsSNT relieved pain and improved quality of life and autonomic nerve activity, especially parasympathetic nerve, in patients with CNSLBP, without serious complications.Trial registrationChinese Clinical Trial Registry No.ChiCTR-OOC-17013237. Registered on November 11, 2017.
Detection of bluetongue virus in Culicoides spp. in southern Yunnan Province, China
Authors: Duan Ying Liang , Li Le , Bellis Glenn , Yang Zhen Xing , Li Hua Chun 
Published: January 2021

Abstract
Background
Culicoides (Diptera: Ceratopogonidae) are vectors for many arboviruses. At least 20 species are considered as vectors or potential vectors of bluetongue virus (BTV) which cause bluetongue disease in ruminants. A BTV prevalence of 30–50% among cattle and goats in tropical southern Yunnan Province, China, prompted an investigation of the potential BTV vectors in this area.

Methods
Culicoides were collected by light trapping at three sites in the tropical region of Yunnan Province. Species were identified based on morphology and DNA sequences of cytochrome c oxidase subunit 1 (cox1). PCR and quantitative PCR following reverse transcription were used to test for the presence of BTV RNA in these specimens. Phylogenetic analysis was used to analyze the cox1 sequences of Culicoides specimens infected with BTV.

Results
Approximately 67,000 specimens of Culicoides were collected, of which 748 were tested for the presence of BTV. Five specimens, including two of Culicoides jacobsoni, one of C. tainanus and two of C. imicola, were identified as infected with BTV. No specimens of C. (subgenus Trithecoides) or C. oxystoma tested were positive for BTV infection.

Conclusions
To our knowledge this is the first report of C. jacobsoni as a potential BTV vector and the fourth report of an association between C. tainanus and BTV, as well as the first direct evidence of an association between BTV and C. imicola in Asia. A fourth potential cryptic species within C. tainanus was identified in this study. Further analysis is required to confirm the importance of C. jacobsoni and C. tainanus in BTV epidemiology in Asia.

Graphical Abstract
Detection of heartworm antigen without cross-reactivity to helminths and protozoa following heat treatment of canine serum
Authors: Gruntmeir Jeff M. , Thompson Nina M. , Long Maureen T. , Blagburn Byron L. , Walden Heather D. S. 
Published: January 2021

AbstractBackgroundDetection ofDirofilaria immitis, or heartworm, through antigen in sera is the primary means of diagnosing infections in dogs. In recent years, the practice of heat-treating serum prior to antigen testing has demonstrated improved detection of heartworm infection. While the practice of heat-treating serum has resulted in earlier detection and improved sensitivity for heartworm infections, it has been suggested that heat treatment may cause cross reactivity withA. reconditumand intestinal helminth infections of dogs. No studies have assessed the potential cross-reactivity of these parasites with heartworm tests before and after heat treatment using blood products and an appropriate gold standard reference.MethodsCanine sera (n=163) was used to evaluate a heartworm antigen-ELISA (DiroCHEK®) and potential cross-reactivity with common parasitic infections. The heartworm status and additional parasite infections were confirmed by necropsy and adult helminth species verified morphologically or by PCR, and feces evaluated by centrifugal fecal flotation.ResultsIntestinal parasites were confirmed in 140 of the dogs by necropsy, and 130 by fecal flotation.Acanthocheilonema reconditummicrofilariae were confirmed in 22 dogs. Prevalence of heartworm infection confirmed by necropsy was 35.6% (58/163). In the 105 dogs without heartworms, specificity remained unchanged at 100% both before and after heat treatment despite confirmed infections withA. reconditum,Ancylostoma caninum,Ancylostoma brasiliense,Trichuris vulpis,Toxocara canis,Dipylidium caninum,Spirometra mansonoides,Macracanthorynchus ingens,Cystoisosporasp.,Giardiasp., andSarcocystissp.ConclusionsThese findings suggest that the use of heat treatment improves sensitivity of heartworm tests and is unlikely to cause false positive antigen results due toAcanthocheilonema reconditum, intestinal helminths, and protozoal parasites in dogs.Graphical Abstract
Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis
Authors: Wu Cuiyan , Tan Sijian , Liu Li , Cheng Shiqiang , Li Peilin , Li Wenyu , Liu Huan , Zhang Feng’e , Wang Sen , Ning Yujie , Wen Yan , Zhang Feng 
Published: January 2021

Abstract
Objective
To identify rheumatoid arthritis (RA)-associated susceptibility genes and pathways through integrating genome-wide association study (GWAS) and gene expression profile data.

Methods
A transcriptome-wide association study (TWAS) was conducted by the FUSION software for RA considering EBV-transformed lymphocytes (EL), transformed fibroblasts (TF), peripheral blood (NBL), and whole blood (YBL). GWAS summary data was driven from a large-scale GWAS, involving 5539 autoantibody-positive RA patients and 20,169 controls. The TWAS-identified genes were further validated using the mRNA expression profiles and made a functional exploration.

Results
TWAS identified 692 genes with PTWAS values < 0.05 for RA. CRIPAK (PEL = 0.01293, PTF = 0.00038, PNBL = 0.02839, PYBL = 0.0978), MUT (PEL = 0.00377, PTF = 0.00076, PNBL = 0.00778, PYBL = 0.00096), FOXRED1 (PEL = 0.03834, PTF = 0.01120, PNBL = 0.01280, PYBL = 0.00583), and EBPL (PEL = 0.00806, PTF = 0.03761, PNBL = 0.03540, PYBL = 0.04254) were collectively expressed in all the four tissues/cells. Eighteen genes, including ANXA5, AP4B1, ATIC (PTWAS = 0.0113, downregulated expression), C12orf65, CMAH, PDHB, RUNX3 (PTWAS = 0.0346, downregulated expression), SBF1, SH2B3, STK38, TMEM43, XPNPEP1, KIAA1530, NUFIP2, PPP2R3C, RAB24, STX6, and TLR5 (PTWAS = 0.04665, upregulated expression), were validated with integrative analysis of TWAS and mRNA expression profiles. TWAS-identified genes functionally involved in endoplasmic reticulum organization, regulation of cytokine production, TNF signaling pathway, immune response-regulating signaling pathway, regulation of autophagy, etc.

Conclusion
We identified multiple candidate genes and pathways, providing novel clues for the genetic mechanism of RA.
Obesity, leptin, and deregulation of microRNA in lipid metabolisms: their contribution to breast cancer prognosis
Authors: Taroeno-Hariadi Kartika W. , Hardianti Mardiah S. , Sinorita Hemi , Aryandono Teguh 
Published: January 2021

AbstractObesity and Metabolic Syndrome have been associated with cardiovascular, diabetes and cancer incidence. Obesity is a state of inflammation. There are cross-talks between adipocyte, adipokines, pro-inflammatory cytokines, insulin, leptin, and other growth factors to initiate signals for proliferation, anti-apoptosis, and angiogenesis. Those networks lead to cancer initiation, promotion, progression, and metastasis. Post menopause women with breast cancer commonly have overweight, obesity, and metabolic syndrome, which are previously reported as conditions to be associated with breast cancer prognosis. MicroRNAs (miRNAs), small non-coding RNA that regulate gene expression, are known to play important roles either in metabolic or carcinogenesis process in patients with breast cancer. Some miRNAs expressions are deregulated in persons either with obesity, breast cancer, or breast cancer with co-morbid obesity. This literature review aimed at reviewing recent publications on the role of obesity, leptin, and microRNA deregulation in adverse prognosis of breast cancer. Understanding the influence of deregulated miRNAs and their target genes in patients with breast cancer and obesity will direct more studies to explore the potential prognostic role of obesity in breast cancer from epigenetic points of view.