bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathway-based integration of multi-omics data reveals lipidomics alterations validated in an Alzheimer’s Disease mouse model and risk loci carriers
Authors: Garcia-Segura Monica Emili , Durainayagam Brenan R. , Liggi Sonia , Graça Gonçalo , Jimenez Beatriz , Dehghan Abbas , Tzoulaki Ioanna , Karaman Ibrahim , Elliott Paul , Griffin Julian L. 
Published: May 2021

AbstractAlzheimer’s Disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of important metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these datasets using gene ontology, and transcription factor, pathway and cell-type enrichment analysis. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic dataset derived from cortical tissue of ABCA7-null mice, a mouse model of one of the genes associated with late onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and AD.We found 203 DE transcripts, 164 DE proteins and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetics metabolic pathways were significantly over-represented across the AD multi-omics datasets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modelled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms (SNP)-metabolite associations, of which 70% corresponded to lipid classes.These results support the importance of lipid metabolism dysregulation in AD and highlight the suitability of mapping AD multi-omics data into GSMNs to identify metabolic alterations.
Development of a parent-reported screening tool for avoidant/restrictive food intake disorder (ARFID): Initial validation and prevalence in 4-7-year-old Japanese children
Authors: Dinkler Lisa , Yasumitsu-Lovell Kahoko , Eitoku Masamitsu , Fujieda Mikiya , Suganuma Narufumi , Hatakenaka Yuhei , Hadjikhani Nouchine , Bryant-Waugh Rachel , Råstam Maria , Gillberg Christopher 
Published: May 2021

AbstractThe prevalence of avoidant/restrictive food intake disorder (ARFID) in the general child population is still largely unknown and validated screening instruments are lacking. The aims of this study were to investigate the prevalence of children screening positive for ARFID in a Japanese birth cohort using a newly developed parent-reported screening tool, to estimate the prevalence of children with ARFID experiencing physical versus psychosocial consequences of their eating pattern, and to provide preliminary evidence for the validity of the new screening tool. Data were collected from 3,728 4-7-year-old children born in Kochi prefecture (response rate was 56.5%), Japan, between 2011 and 2014; a sub-sample of the Japan Environment and Children’s Study (JECS). Parents completed a questionnaire including the ARFID screener and several other measures to assess convergent validity. The point prevalence of children screening positive for ARFID was 1.3%; half of them met criteria for ARFID based on psychosocial impairment alone, while the other half met diagnostic criteria relating to physical impairment (and additional psychosocial impairment in many cases). Sensory sensitivity to food characteristics (63%) and/or lack of interest in eating (51%) were the most prevalent drivers of food avoidance. Children screening positive for ARFID were lighter in weight and shorter in height, they showed more problem behaviors related to mealtimes and nutritional intake, and they were more often selective eaters and more responsive to satiety, providing preliminary support for the validity of the new screening tool. This is the largest screening study to date of ARFID in children up to 7 years. Future studies should examine the diagnostic validity of the new ARFID screener using clinically ascertained cases. Further research on ARFID prevalence in the general population is needed.
Detection of Antibody Responses against SARS-CoV-2 in Plasma and Saliva from Vaccinated and Infected Individuals
Authors: Klingler Jéromine , Lambert Gregory S. , Itri Vincenza , Liu Sean , Bandres Juan C. , Enyindah-Asonye Gospel , Liu Xiaomei , Simon Viviana , Gleason Charles R. , Kleiner Giulio , Chiu Hsin-Ping , Hung Chuan-Tien , Kowdle Shreyas , Amanat Fatima , Lee Benhur , Zolla-Pazner Susan , Upadhyay Chitra , Hioe Catarina E. 
Published: May 2021

AbstractAntibodies (Abs) are essential for the host immune response against SARS-CoV-2, and all the vaccines developed so far have been designed to induce Abs targeting the SARS-CoV-2 spike. Many studies have examined Ab responses in the blood from vaccinated and infected individuals. However, since SARS-CoV-2 is a respiratory virus, it is also critical to understand the mucosal Ab responses at the sites of initial virus exposure. Here, we examined plasma versus saliva Ab responses in vaccinated and convalescent patients. Although saliva levels were significantly lower, a strong correlation was observed between plasma and saliva total Ig levels against all SARS-CoV-2 antigens tested. Virus-specific IgG1 responses predominated in both saliva and plasma, while a lower prevalence of IgM and IgA1 Abs was observed in saliva. Antiviral activities of plasma Abs were also studied. Neutralization titers against the initial WA1 (D614G), B.1.1.7 (alpha) and B.1.617.2 (delta) strains were similar but lower against the B.1.351 (beta) strain. Spike-specific antibody-dependent cellular phagocytosis (ADCP) activities were also detected and the levels correlated with spike-binding Ig titers. Interestingly, while neutralization and ADCP potencies of vaccinated and convalescent groups were comparable, enhanced complement deposition to spike-specific Abs was noted in vaccinated versus convalescent groups and corresponded with higher levels of IgG1 plus IgG3 among the vaccinated individuals. Altogether, this study demonstrates the detection of Ab responses after vaccination or infection in plasma and saliva that correlate significantly, although Ig isotypic differences were noted. The induced plasma Abs displayed Fab-mediated and Fc-dependent functions with comparable neutralization and ADCP potencies, but a greater capacity to activate complement was elicited upon vaccination.
SARS-CoV-2 R.1 lineage variants prevailed in Tokyo in March 2021
Authors: Nagano Katsutoshi , Tani-Sassa Chihiro , Iwasaki Yumi , Takatsuki Yuna , Yuasa Sonoka , Takahashi Yuta , Nakajima Jun , Sonobe Kazunari , Ichimura Naoya , Nukui Yoko , Takeuchi Hiroaki , Tanimoto Kousuke , Tanaka Yukie , Kimura Akinori , Tohda Shuji 
Published: May 2021

AbstractBackgroundThe spread of SARS-CoV-2 variants, such as B.1.1.7 and B.1.351, has become a crucial issue worldwide. Therefore, we began testing all patients with COVID-19 for the N501Y and E484K mutations by using polymerase chain reaction (PCR)-based methods.MethodsNasopharyngeal swab samples from 108 patients who visited our hospital between February and April 2021 were analyzed. The samples were analyzed using reverse transcription-PCR with melting curve analysis to detect the N501Y and E484K mutations. A part of the samples were also subjected to whole genome sequencing (WGS). Clinical parameters such as mortality and admission to the intensive care unit were analyzed to examine the association between increased disease severity and the E484K mutation.ResultsThe ratio of cases showing the 501N+484K mutation rapidly increased from 8% in February to 46% in March. WGS revealed that the viruses with 501N+484K mutation are R.1 lineage variants. Evidence of increased disease severity related to the R.1 variants were not found.ConclusionsWe found that the R.1 lineage variants rapidly prevailed in Tokyo in March 2021, which suggests the increased transmissibility of R.1 variants while they showed no increased severity.
Susceptibility and infectiousness of children and adults with SARS-CoV-2 variant B.1.1.7 deduced from three daycare centre outbreaks and related household situations; Germany, 2021
Authors: Loenenbach Anna , Markus Inessa , Lehfeld Ann-Sophie , der Heiden Matthias an , Haas Walter , Kiegele Maya , Ponzi André , Unger-Goldinger Barbara , Weidenauer Cornelius , Schlosser Helen , Beile Alexander , Buchholz Udo 
Published: May 2021

AbstractWe investigated three SARS-CoV-2 variant B.1.1.7 kindergarten outbreaks and related household situations. Despite group cohorting, cases occurred in almost all groups, i.e. also among persons without close contact. Secondary attack rates (SAR) of children were similar to adults (day care: 23% vs. 30%; p=0.15; households: 32% vs. 39%; p=0.27), and also child-induced household outbreaks led to similar SAR compared to adults. With the advent of B.1.1.7, susceptibility and infectiousness of children and adults seem to converge.
Morphological and Functional Assessment of Thyroid in Individuals with Down Syndrome
Authors: Mangabeira Célia Neder Kalil , Mangabeira Rafael Kalil , de Oliveira Andrade Luis Jesuino 
Published: May 2021

AbstractIndividuals with Down’s syndrome (DS) present increased risk for thyroid dysfunction, especially hypothyroidism, due in increased expression of the DYRK1A gene.ObjectiveThe aim of this study was to make a morphological-functional thyroid assessment in individuals with DS.Materials and MethodsThis is a descriptive cross-sectional study, consisting of 29 individuals with DS, with a mean age of 12,3 ± 9,5 (0.66 – 36.00) years, 16 women (55.2%) and 13 men (44.8%), with a morphological-functional thyroid assessment being made comprising hormonal dose (Free T4, TSH), antithyroid antibody (TPOAb and TgAb) and ultrasonography of the thyroid.ResultsTwenty-three (79.3%) individuals presented normal thyroid function while 6 (20.7%) presented with thyroid dysfunction, 4 with hypothyroidism and 2 with hyperthyroidism. Autoimmune thyroiditis and goiter were present in 27.6% of the individuals.ConclusionThyroid function should be assessed periodically in individuals with DS, in view of the high prevalence of thyroid dysfunction, especially autoimmune thyroiditis with consequent hypothyroidism.
Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19
Authors: Schmaier Alec A. , Hurtado Gabriel Pajares , Manickas-Hill Zachary J. , Sack Kelsey D. , Chen Siyu M , Bhambhani Victoria , Quadir Juweria , Nath Anjali K. , Collier Ai-ris Y. , Ngo Debby , Barouch Dan H. , Gerszten Robert E. , Yu Xu G. ,   MGH COVID-19 Collection and Processing Team, Peters Kevin , Flaumenhaft Robert , Parikh Samir M. 
Published: May 2021

AbstractProfound endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. In the quiescent state, the endothelial surface is anticoagulant, a property maintained at least in part via constitutive signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from activated endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant dysfunction of the endothelium and alterations in the Tie2-angiopoietin axis. Primary human endothelial cells treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. On lung autopsy specimens from COVID-19 patients, we found a prothrombotic endothelial signature as evidenced by increased von Willebrand Factor and loss of anticoagulant proteins. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed profound endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity and highest levels were associated with worse survival. These data highlight the disruption of Tie2-angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Moreover, our findings provide novel rationale for current trials of Tie2 activating therapy with AKB-9778 in severe COVID-19 disease.
Multiparametric MRI of Early Tumor Response to Immune Checkpoint Blockade in Metastatic Melanoma
Authors: Lau Doreen , McLean Mary A. , Priest Andrew N. , Gill Andrew B. , Scott Francis , Patterson Ilse , Carmo Bruno , Riemer Frank , Kaggie Joshua D. , Frary Amy , Milne Doreen , Booth Catherine , Lewis Arthur , Sulikowski Michal , Brown Lee , Lapointe Jean-Martin , Aloj Luigi , Graves Martin J. , Brindle Kevin M. , Corrie Pippa G. , Gallagher Ferdia A. 
Published: May 2021

AbstractBackgroundImmune checkpoint inhibitors are now standard of care treatment for many cancers. Treatment failure in metastatic melanoma is often due to tumor heterogeneity not easily captured by conventional CT or tumor biopsy. The aim of this prospective study was to investigate early microstructural and functional changes within melanoma metastases following immune checkpoint blockade using multiparametric MRI.MethodsFifteen treatment-naïve metastatic melanoma patients (total 27 measurable target lesions) were imaged at baseline, and following three weeks and twelve weeks of treatment on immune checkpoint inhibitors using T2-weighted imaging, diffusion kurtosis imaging and dynamic contrast-enhanced MRI. Treatment timepoint changes in tumor cellularity, vascularity and heterogeneity within individual metastases were evaluated and correlated to the clinical outcome within each patient.ResultsDifferential tumor growth kinetics in response to immune checkpoint blockade were measured in individual metastases within the same patient. Early detection of tumor cell death or cell loss measured by a significant increase in the apparent diffusivity Dapp (p < 0.05) was observed in both responding and pseudoprogressive lesions after three week of treatment. Tumor heterogeneity (apparent kurtosis Kapp) was consistently higher in the pseudoprogressive and true progressive lesions, compared to the responding lesions throughout the first twelve weeks of treatment. These preceded tumor regression and significant tumor vascularity changes (Ktrans, ve and vp) detected after twelve weeks of immunotherapy (p < 0.05).ConclusionsMultiparametric MRI demonstrated potential for early detection of successful response to immunotherapy in metastatic melanoma.
Olfactory training and visual stimulation assisted by web-application in patients with persistent olfactory dysfunction after SARS-CoV-2 infection: observational study
Authors: Denis Fabrice , Septans Anne-Lise , Périers Léa , Maillard Jean-Michel , Legoff Florian , Gurden Hirac , Morinière Sylvain 
Published: May 2021

AbstractBackgroundPersistent olfactory dysfunction (OD) is a significant complication of SARS-CoV-2 infection. Olfactory training (OT) using aromatic oils are recommended to improve olfactory recovery, but quantitative data are missing.ObjectiveWe aimed to quantify the benefit of OT associated with visual stimulation assisted by a dedicated web-application on patients with 1-month or more OD.MethodsWe performed an observational real-life data-based study on a cohort of patients with at least 1-month persistent OD included between 1/30/21 and 3/26/2021. Analysis was performed after a 4-weeks mean time of OT and at least 500 patients assessable for primary outcome. Participants exposed themselves twice daily to odors from four high concentration oils and visual stimulation assisted by a dedicated web-application. Improvement was defined as a 2/10 points increase on self-assessed olfactory visual analogue scale.Results548 were assessable for primary outcome assessment. The mean baseline self-assessed olfactory score was 1.9/10 (SD 1.7) and increase to 4.6 (SD 2.8) beyond a mean time of olfactory training of 27.7 days (SD 17.2). Olfactory training was associated with at least 2-points increase in 64.2% (n=352). The rate of patients with improvement was higher in patients having trained for more than 28 days versus patients having trained for less than 28 days (72.2% vs 59.0% respectively, p=.002). The kinetic of improvement was 8 days faster in hyposmic than in anosmic patients (p<.001). The benefit was observed regardless of the duration of the OD.ConclusionsOT associated with visual stimulation assisted by a dedicated web-application was associated with significant improvement in olfaction, especially if OT duration was superior to 28 days.
Sensitive period-regulating genetic pathways and exposure to adversity shape risk for depression
Authors: Zhu Yiwen , Wang Min-Jung , Crawford Katherine M. , Ramírez-Tapia Juan Carlos , Lussier Alexandre A. , Davis Kathryn A. , de Leeuw Christiaan , Takesian Anne E. ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Hensch Takao K. , Smoller Jordan W. , Dunn Erin C. 
Published: May 2021

AbstractAnimal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects in shaping brain structure or function, behavior, and disease risk. Sensitive periods for depression likely arise through a complex interplay of genes and experience, though this possibility has not been explored. We examined the effect of sensitive period-regulating genetic pathways identified in preclinical animal studies, alone and in interaction with socioeconomic disadvantage, a common childhood adversity, on depression risk. Using a translational approach, we: (1) performed gene-set association analyses using summary data from a genome-wide association study of depression (n=807,553) to assess the effects of three gene sets (60 genes) shown in animal studies to regulate sensitive periods; (2) evaluated the developmental expression patterns of these sensitive period-regulating genes using data from BrainSpan (n=31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay by analyzing the combined effect of common variants in sensitive period genes and timing of exposure to socioeconomic disadvantage within a population-based birth cohort (n=6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, six of the 15 genes in this set showed developmentally regulated gene-level expression. A genome-wide polygenic risk score-by-environment analysis showed socioeconomic disadvantage during ages 1-5 years were independently associated with depression risk, but no gene-by-development interactions were found. Genes involved in regulating sensitive periods may be implicated in depression vulnerability and differentially expressed across the life course, though larger studies are needed to identify developmental interplays.
Real-time genomics to track COVID-19 post-elimination border incursions in Aotearoa New Zealand
Authors: Douglas Jordan , Geoghegan Jemma L. , Hadfield James , Bouckaert Remco , Storey Matthew , Ren Xiaoyun , de Ligt Joep , French Nigel , Welch David 
Published: May 2021

AbstractThere have been thirteen known COVID-19 community outbreaks in Aotearoa New Zealand since the virus was first eliminated in May 2020, two of which led to stay-at-home orders being issued by health officials. These outbreaks originated at the border; via isolating returnees, airline workers, and cargo vessels. With a public health system informed by real-time viral genomic sequencing which typically had complete genomes within 12 hours after a community-based positive COVID-19 test, every outbreak was well-contained with a total of 225 community cases, resulting in three deaths. Real-time genomics were essential for establishing links between cases when epidemiological data could not, and for identifying when concurrent outbreaks had different origins. By reconstructing the viral transmission history from genomic sequences, here we recount all thirteen community outbreaks and demonstrate how genomics played a vital role in containing them.SummaryThe authors recount the role of real-time viral genomics in containing the COVID-19 community outbreaks of Aotearoa New Zealand.
BK polyomavirus (BKPyV) is a risk factor for bladder cancer through induction of APOBEC3-mediated genomic damage
Authors: Baker Simon C. , Mason Andrew S. , Slip Raphael G. , Skinner Katie T. , Macdonald Andrew , Masood Omar , Harris Reuben S. , Fenton Tim R. , Periyasamy Manikandan , Ali Simak , Southgate Jennifer 
Published: May 2021

AbstractLimited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. BK polyomavirus (BKPyV) is a common childhood infection that can be reactivated in the adult kidney leading to viruria. Here we used a mitotically-quiescent, differentiated, normal human urothelial in vitro model to study BKPyV infection. BKPyV infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry into the cell cycle via inhibition of Retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, which combined to push urothelial cells from G0 into an arrested G2 cell cycle state. The single-stranded DNA displacement loops formed during BKPyV-infection, provide a substrate for APOBEC3 enzymes where they interacted with LT-Ag. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations, including transplant patients and the elderly.