bluuebunny/crossref_metadata_2025_split huggingface dataset:
Homologous Recombination Inquiry Through Ovarian Malignancy Investigations: The Japanese Gynecologic Oncology Group study JGOG3025
Authors: Yoshihara Kosuke , Baba Tsukasa , Shimada Muneaki , Nishino Koji , Sekine Masayuki , Takamatsu Shiro , Matsumura Noriomi , Yoshida Hiroshi , Kajiyama Hiroaki , Kagimura Tatsuo , Oda Katsutoshi , Sasajima Yuko , Okamoto Aikou , Sugiyama Toru , Enomoto Takayuki 
Published: July 2022

AbstractThe Cancer Genome Atlas has clarified that about 50% of high-grade serous ovarian cancer shows homologous recombination deficiency (HRD). However, the frequency of HRD in Japanese patients with ovarian cancer remains unclear. The aim of JGOG3025 study (NCT03159572) is to identify the frequency of HRD in Japanese patients with ovarian cancer. The JGOG3025 study is a multicenter collaborative prospective observational study involving 65 study sites throughout Japan. We recruited 996 patients who were clinically diagnosed with ovarian cancer before surgery from March 2017 to March 2019, and 701 patients were eligible for JGOG3025 criteria. We used frozen tumor tissues to extract DNA and performed targeted sequencing for 51 genes most of which are HR-associated genes in 701 ovarian cancers (298 high-grade serous, 189 clear cell, 135 endometrioid, 12 mucinous, 3 low-grade serous, and 64 others). HRD was defined as positive when at least one HR-associated gene was mutated. The frequencies of HRD and tumor BRCA1/2 mutation were 45.2% (317/701) and 18.5% (130/701) in the full analysis set (FAS), respectively. Next, we performed multivariate Cox proportional hazards regression analysis for progression-free survival (PFS) and overall survival (OS). Advanced-stage ovarian cancer patients with HRD had an adjusted hazard ratio of 0.72 (95%CI, 0.55-0.93) and 0.58 (95%CI, 0.39-0.87) for PFS and OS compared to those without HRD (p = 0.013 and 0.009). Our study demonstrated that mutations in HR-associated genes might be associated with their prognosis. Further study will be needed to investigate prognostic impact of each HR-associated gene in ovarian cancer.
Non-linear Measures of Gait Adaptability in Multiple Sclerosis - Sensitivity and Neurological Correlates
Authors: Panisset MG , Lizama LE Cofré , Peng L , Galea MP 
Published: July 2022

ABSTRACTMultiple sclerosis (MS) is the leading cause of non-traumatic disability among young and middle-aged adults. People with MS (pwMS) rate walking and mobility as their highest priority for both research and symptom management. Given the importance of early initiation of disease-modifying therapeutics (DMTs) to minimize long-term disability, tools to identify early disease activity are needed. Traditional measures of disability, the Expanded Disability Status Scale (EDSS) and gait speed tests demonstrate poor reliability and responsiveness in cases with minimal disability. Nonlinear measures of gait, Local dynamic stability (LDS), Complexity (sample entropy) and Regularity (autocorrelation), measured in laboratory settings is sensitive to subclinical gait deterioration in people with MS (pwMS). These measures have not been tested in a clinical setting using wearable sensors.MethodsGait metrics were calculated in MatLab from inertial data collected from 59 pwMS (EDSS 0-4) and 23 age- and sex-matched healthy controls (HC) during a 5-minute walk. We aimed to provide known-groups validation of non-linear gait measures and compare sensitivity of LDS from sensors placed at sternum and sacrum in pwMS (ROC analysis). Associations of gait metrics with disability, Kurtzke Functional System scores and 3T MRI segmental brain volumes were examined.ResultsMost sternum-derived LDS measures detected significant differences between HC and pwMS (EDSS0-1) with moderate to large effect sizes (η2=.100-305), while the effect sizes for sacrum-derived LDS were lower (η2=.104-.166). Sternum3D best distinuished EDSS0-1 from HC whereas the effect size was lower for gait speed (η2=.104). Sternum Instability-3D showed strongest correlation with pyramidal dysfunction (rs=.455, p<.001). Sensory dysfunction correlated significantly with Regularity in the vertical plane from both sensors, while cerebellar dysfunction was significantly associatesd with sacrum Regularity in the saggital plance (r=-.343, p=.008) and brainstem dysfunction with Complexity in the frontal plane (r=-.343, p=.008).ConclusionSternum-derived LDS measures were more sensitive than Sacrum-derived measures. Correlations with clinical and morphological brain measures support the validity of walking deterioration as reflective of neurodegeneration in subcortical grey matter. The current findings of high sensitivity in non-disabled cases, as well as the clinical feasibility and relatively low costs, support the utility of these measures as a supplementary clinical assessment tool.
Profiling of circulating glial cells allows accurate blood-based diagnosis of glial malignancies
Authors: O’Neill Kevin , Syed Nelofer , Crook Timothy , Dubey Sudhir , Potharaju Mahadev , Limaye Sewanti , Ranade Anantbhushan , Anichini Giulio , Datta Vineet 
Published: July 2022

ABSTRACTWe describe an in vitro test for detection of glial malignancies (GLI-M) based on enrichment and immunostaining of Circulating Glial Cells (CGCs) from peripheral blood sample. Extensive analytical validation studies using U87MG reference cell lines spiked into blood established the analytical performance characteristics of the test. The ability of the test to detect and differentiate GLI-M from non-malignant brain tumors (NBT), non glial type central nervous system (CNS) malignancies (NGCM), brain metastases from primary epithelial malignancies in other organs and healthy individuals were evaluated in four studies. The cumulative performance metrics of the test across all 4 clinical studies were 99.35% Sensitivity (95%CI: 96.44% - 99.98%) and 100% Specificity (95%CI: 99.37% - 100%). The performance characteristics of this test support its clinical utility for diagnostic triaging of individuals presenting with ICSOL.
Subgroups of people with high Autism-Spectrum Quotient scores identified from a large set of personality traits and attributes
Authors: Fujiwara Mao , Numano Shotaro , Tanaka Toshiko , Nakamura Motoaki , Kato Nobumasa , Haruno Masahiko 
Published: July 2022

AbstractThe Autism-Spectrum Quotient (AQ) is a widely used index to quantify autistic traits. Previous studies using clustering analysis have indicated that people showing high AQ and other autism indices may comprise several subtypes. However, those studies mainly focused on Big5 personality traits and analyzed a limited number of samples (participants). The inclusion of a larger set of personality traits and attributes would contribute not only to understanding autism more deeply, but also to characterizing AQ more precisely. In addition, an analysis of larger general populations would give new perspectives on people with high AQ scores. To address these issues, here we conducted a personality traits-based clustering of 1364 subjects who had an AQ score of 33 or higher (high AQ group) collected online. We identified three subclasses (subtypes): Group 1, characterized by emotional instability, low self-esteem, high hostility, anxiety, depressive tendency and schizotypal traits; Group 2, characterized by high BIS for an inhibitory attitude towards novelty, and high Interpersonal Reactivity Index (IRI) and Group 3, characterized by personality traits and attributes consistent of the average of the general population. Thus, this study provides empirical results showing subtypes of the high AQ population.
Loss of regulation of complement C5 activation in HIV associated Preeclampsia
Authors: Govender Sumeshree , Mduluza Takafira , Nandlal Louansha , Naicker Thajasvarie 
Published: July 2022

AbstractObjectiveMaternal mortality remains a global health concern in developing countries that are also affected by HIV infection. Complement components are anaphylatoxin that mediate several growth factors necessary during pregnancy. An extensive stimulation of the complement system contributes to the pathogenesis of preeclampsia; hence its inhibition facilitates a successful pregnancy. The study evaluated the expression of complement components C2 and C5a in HIV and the association with preeclampsia.Materials and MethodsSerum samples were collected from 76 pregnant women of which 38 were preeclamptic and 38 normotensive pregnant. The participants were further stratified according to HIV infection status. Bio-Plex multiplex immunoassay method was used to quantify serum concentration of C5a and C2 complement components.ResultsThe C2 complement concentration was not significantly different between preeclamptic and normotensive pregnant women, irrespective of HIV status as well as pregnancy type. However, based on preeclampticvsnormotensive pregnancy type, the expression of C5a was significantly different (p= 0.05). The C5a levels were downregulated in preeclampsia compared to normotensive women, irrespective of HIV status. Both C2 and C5a concentrations did not differ across all study groups.ConclusionThis novel study reports a loss of regulation of complement activation shown by the downregulation of C5a in preeclamptic compared to normotensive pregnant women, regardless of HIV status. Complement dysregulation affects the host innate defence, and as a consequence, intensifies placental and fetal injury. Moreover, HIV status did not influence the expression of both C5a and C2, irrespective of pregnancy type, this may be attributed to Highly Active Antiretroviral Therapy.
A dataset of multi-contrast unbiased average MRI templates of a Parkinson’s disease population
Authors: Madge Victoria , Fonov Vladimir S , Xiao Yiming , Zou Lucy , Jackson Courtney , Postuma Ronald B , Dagher Alain , Fon Edward A , Collins D Louis 
Published: July 2022

AbstractParkinson’s disease (PD) is a complex neurodegenerative disorder affecting regions such as the substantia nigra (SN), red nucleus (RN) and locus coeruleus (LC). Processing MRI data from patients with PD requires anatomical structural references for spatial normalization and structural segmentation. Extending our previous work [1][2], we present multi-contrast unbiased MRI templates using nine 3T MRI modalities: T1w, T2*w, T1-T2* fusion, R2*, T2w, PDw, fluid-attenuated inversion recovery (FLAIR), improved susceptibility-weighted imaging (CLEAR-SWI) [3], and neuromelanin-sensitive MRI (NM). Using our previous methods to build unbiased average templates [4], 1 mm isotropic voxel size templates were created, along with 0.5 mm isotropic whole brain templates and 0.3 mm isotropic templates of the midbrain. All templates were created from 126 PD patients (44 female; ages=40-87), and 17 healthy controls (13 female; ages=39-84), except the NM template, which was created from 85 PD patients and 13 controls, respectively. The dataset is available on the NIST MNI Repository via the following link: http://nist.mni.mcgill.ca/multi-contrast-pd126-and-ctrl17-templates/.
Large deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome
Authors: Breen Michael S. , Fan Xuanjia , Levy Tess , Pollak Rebecca , Collins Brett , Osman Aya , Tocheva Anna S. , Sahin Mustafa , Berry-Kravis Elizabeth , Soorya Latha , Thurm Audrey , Powell Craig M. , Bernstein Jonathan A. , Kolevzon Alexander , Buxbaum Joseph D. 
Published: July 2022

ABSTRACTPhelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused at least in part by haploinsufficiency of the SHANK3 gene, due to sequence variants in SHANK3 or subtelomeric 22q13.3 deletions. Phenotypic differences have been reported between PMS participants carrying small ‘Class I’ mutations and large ‘Class II’ mutations, however the molecular perturbations underlying these divergent phenotypes remain obscure. Using peripheral blood transcriptome and serum metabolome profiling, we examined the molecular perturbations in the peripheral circulation associated with a full spectrum of PMS genotypes spanning Class I (n=37) and Class II mutations (n=39). Transcriptomic data revealed 52 genes with blood expression profiles that tightly scale with 22q.13.3 deletion size. Further, we uncover 208 under-expressed genes in PMS participants with Class II mutations, which were unchanged in Class I mutations. These genes were not linked to 22q13.3 and were strongly enriched for glycosphingolipid metabolism, NCAM1 interactions and cytotoxic natural killer (NK) immune cell signatures.In silicopredictions estimated a reduction in CD56+ CD16-NK cell proportions in Class II mutations, which was validated by mass cytometry time of flight. Global metabolomics profiling identified 24 metabolites that were significantly altered with PMS participants with Class II mutations, and confirmed a general reduction in sphingolipid metabolism. Collectively, these results provide new evidence linking PMS participants carrying Class II mutations with decreased expression of cytotoxic cell signatures, reduced relative proportions of NK cells, and lower sphingolipid metabolism. These findings highlight alternative avenues for therapeutic development and offer new mechanistic insights supporting genotype-to-phenotype associations in PMS.
Multi-trait Analysis of GWAS (MTAG) of Substance Use Traits Identifies Novel Genetic Loci and Phenomic Associations
Authors: Xu Heng , Toikumo Sylvanus , Crist Richard C. , Glogowska Klaudia , Deak Joseph D. , Gelernter Joel , Johnson Emma C. , Kranzler Henry R. , Kember Rachel L. 
Published: July 2022

AbstractIntroductionA large majority of genome-wide significant (GWS) loci identified for substance use traits (SUTs) in genome-wide association studies (GWAS) have been for alcohol and smoking-related phenotypes. GWAS of opioid use disorder (OUD) and cannabis use disorder (CUD) have lagged those of the two historically legal substances.MethodsWe applied multi-trait analysis of GWAS (MTAG) to 2,888,727 single nucleotide polymorphisms (SNPs) common to GWAS of four SUTs (OUD, CUD, alcohol use disorder [AUD], and smoking initiation [SMK]) in European-ancestry (EUR) subjects. We calculated polygenic risk scores (PRS) for the four traits in an independent sample (i.e., the Yale-Penn sample; N=5,692 EUR) and examined the power increment for each set of MTAG-GWAS summary statistics relative to those of the input GWAS.ResultsMTAG increased the effective sample size for all four SUTs, which showed high pairwise genetic correlations. After clumping, MTAG identified independent GWS SNPs for all 4 traits: 41 SNPs in 36 loci (including 5 novel loci not previously associated with any SUT) for OUD; 74 SNPs in 60 loci (including 4 novel loci) for CUD; 63 SNPs in 52 loci (including 10 novel loci) for AUD; and 183 SNPs in 144 loci (including 8 novel loci) for SMK. In PRS analyses in the Yale-Penn sample, the MTAG-derived PRS consistently yielded more significant associations with both the corresponding substance use disorder diagnosis and multiple related phenotypes than each of the 4 GWAS-derived PRS.ConclusionsMTAG boosted the number of GWS loci for the 4 SUTs, including identifying genes not previously linked to any SUT. MTAG-derived PRS also showed stronger associations with expected phenotypes than PRS for the input GWAS. MTAG can be used to identify novel associations for SUTs, especially those with sample sizes smaller than for historically legal substances.
Following the evolution of Homo sapiens across Africa using a uniparental genetic guide
Authors: Cabrera Vicente M. 
Published: July 2022

AbstractThe origin and evolution of modern humans in Africa has reached a multidisciplinary consensus but the age and regions where it originated and evolved are current topics of discussion. In this study I put forward an integrative model guided by the phylogeny and phylogeography of mitochondrial DNA (and Y-chromosome) haplogroups. I propose an early origin of modern humans in northwest Africa in a temporal window of 257-345 thousand years ago. A first population split in central Africa around 175-288 thousand years ago. A subsequent northward spread with additional population subdivisions during a long statistical interval that culminated in a first successful out of Africa migration around 130 thousand years ago. A population constriction in southwest Asia motivated an early return to Africa between 79 and 107 thousand years ago. This ample Eurasian-ebb to Africa, detected by mitochondrial haplogroup L3 and Y-chromosome haplogroup E preceded other later and geographically more limited Eurasian backflows. The archaeological and fossil finds that could be coetaneous to this molecular journey have been integrated into this interdisciplinary model.
Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection
Authors: Lamarthée Baptiste , Callemeyn Jasper , Herck Yannick Van , Antoranz Asier , Anglicheau Dany , Becker Jan Ulrich , Debyser Tim , Smet Frederik De , Vusser Katrien De , Eloudzeri Maëva , Franken Amelie , Gwinner Wilfried , Koshy Priyanka , Kuypers Dirk , Lambrechts Diether , Marquet Pierre , Rabant Marion , Sprangers Ben , Tinel Claire , Brussel Thomas Van , Craenenbroeck Amaryllis Van , Loon Elisabet Van , Vaulet Thibaut , Bosisio Francesca , Naesens Maarten 
Published: July 2022

AbstractRejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the interactions of the alloreactive inflammatory infiltrate. We performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies and generated cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derivedFCGR3A+monocytes,FCGR3A+NK cells and the severity of intragraft inflammation. ActivatedFCGR3A+monocytes overexpressedCD47andLILRgenes and increased paracrine signaling pathways promoting T cell infiltration.FCGR3A+NK cells overexpressedFCRL3, suggesting that antibody-dependent cytotoxic activity is a central mechanism of NK cell mediated graft injury. Multiplexed immunohistochemistry using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results uncovered the central involvement of innate immune cells in the pathogenesis of allograft rejection and indicate several potential therapeutic targets to improve allograft longevity.
SHEAR Saliva Collection Device Augments Sample Properties for Improved Analytical Performance
Authors: Song Shang Wei , Gupta Rashi , Niharika Jothilingam , Qian Xinlei , Gu Yue , Lee V Vien , Sapanel Yoann , Allen David Michael , Wong John Eu Li , MacAry Paul A , Ho Dean , Blasiak Agata 
Published: July 2022

AbstractDespite human saliva representing a convenient and non-invasive clinical substrate for disease diagnosis and biomonitoring, its widespread utilization has been hampered by technical challenges. The non-Newtonian, heterogenous and highly viscous nature of clinical saliva samples complicate the development of automated fluid handling processes that are vital for accurate diagnoses. Furthermore, conventional saliva processing methods are either resource and/or time intensive precluding certain testing capabilities in low- and middle-income countries, with these challenges aggravated during a pandemic outbreak. The conventional approaches can also potentially alter analyte structure, reducing application opportunities in Point-of-Care diagnostics. To overcome these challenges, we introduce the SHEAR saliva collection device that preprocesses saliva for enhanced interfacing with downstream assays. We demonstrate the device’s impact on reducing saliva’s viscosity, improving sample uniformity and, increasing diagnostic performance of COVID-19 Rapid Antigen Tests. Importantly, in addition to reporting technical advances and to address downstream implementation factors, we conducted a formal user experience study, which resulted in generally positive comments. Effective implementation of this device could be of support to realize the potential of saliva, particularly in large-scale and/or resource-limited settings for global and community health diagnostics.
Genome-wide determinants of mortality and motor progression in Parkinson’s disease
Authors: Tan Manuela MX , Lawton Michael A , Pollard Miriam I , Brown Emmeline , Real Raquel , Martinez Carrasco Alejandro , Bekadar Samir , Jabbari Edwin , Reynolds Regina H , Iwaki Hirotaka , Blauwendraat Cornelis , Kanavou Sofia , Hubbard Leon , Malek Naveed , Grosset Katherine A , Bajaj Nin , Barker Roger A , Burn David J , Bresner Catherine , Foltynie Thomas , Wood Nicholas W , Williams-Gray Caroline H , Andreassen Ole A , Toft Mathias , Elbaz Alexis , Artaud Fanny , Brice Alexis , Corvol Jean-Christophe , Aasly Jan , Farrer Matthew J , Nalls Michael A , Singleton Andrew B , Williams Nigel M , Ben-Shlomo Yoav , Hardy John , Hu Michele TM , Grosset Donald G , Shoai Maryam , Pihlstrøm Lasse , Morris Huw R 
Published: July 2022

ABSTRACTBackgroundThere are 90 genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments.MethodsWe studied 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality).FindingsThere was a robust effect of theAPOEε4 allele on mortality in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity and/or expression quantitative trait loci data. One locus within theTBXAS1gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10-10). Another locus near theSYT10gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], p-value=5.31×10-8). We also report 4 independent loci associated with motor progression: the top locus withinMORN1(HR=2.76 [95% CI 1.97 to 3.87], p-value=3.1×10-9), the second most significant locus nearASNS, the third most significant locus nearPDE5A, and a fourth locus withinXPO1. We have nominated causal genes based on physical position, however we also discuss other possible causal genes based on expression quantitative trait loci, colocalization analysis, and tagging of rare variants. Only the non-Gaucher disease causingGBA1PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD.InterpretationWe report six novel loci associated with PD motor progression or mortality. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, thromboxane synthesis, vesicular peptidergic neurotransmitter release, and phosphodiesterase inhibition may represent new candidates for disease modification in PD.Funding sourcesParkinson’s UK, Aligning Science Across Parkinson’s through the Michael J Fox Foundation for Parkinson’s Research, Southern and Eastern Norway Regional Health Authority