bluuebunny/crossref_metadata_2025_split huggingface dataset:
Knowledge syntheses in medical education: Examining author gender, geographic location, and institutional affiliation
Authors: Maggio Lauren A. , Ninkov Anton , Costello Joseph A. , Driessen Erik W. , Artino Anthony R. 
Published: March 2021

ABSTRACTPurposeAuthors of knowledge syntheses make many subjective decisions during their review process. Those decisions, which are guided in part by author characteristics, can impact the conduct and conclusions of knowledge syntheses, which assimilate much of the evidence base in medical education. Therefore, to better understand the evidence base, this study describes the characteristics of knowledge synthesis authors, focusing on gender, geography, and institution.MethodIn 2020, the authors conducted a case study of authors of 963 knowledge syntheses published between 1999 and 2019 in 14 core medical education journals using a publicly accessible dataset.ResultsThe authors of the present study identified 4,110 manuscript authors across all authorship positions. On average there were 4.3 authors per knowledge synthesis (SD=2.51, Median=4, Range=1-22); 79 knowledge syntheses (8%) were single-author publications. Over time, the average number of authors per synthesis increased (M=1.80 in 1999; M=5.34 in 2019). Knowledge syntheses were authored by slightly more females (n=2047; 50.5%) than males (n=2005; 49.5%) across all author positions (Pearson X2=22.02, p<.001). Authors listed affiliations in 58 countries, and 58 knowledge syntheses (6%) included authors from low- or middle-income countries (LMIC). Authors from the United States (n=366; 38%), Canada (n=233; 24%), and the United Kingdom (n=180; 19%) published the most knowledge syntheses. Authors listed affiliation at 617 unique institutions, and first authors represented 362 unique institutions with greatest representation from the University of Toronto (n=55, 6%) and the Mayo Clinic (n=31, 3%). Across all authorship positions, the large majority of knowledge syntheses (n=753; 78%) included authors at top 200 ranked institutions.ConclusionsKnowledge synthesis author teams have grown over the past 20 years, and while there is near gender parity across all author positions, authorship has been dominated by North American researchers located at highly ranked institutions. This suggests a potential overrepresentation of certain authors with particular characteristics, which may impact the conduct and conclusions of knowledge syntheses in medical education.
Accounting for health inequities in the design of contact tracing interventions: a rapid review
Authors: Mathevet Isadora , Ost Katarina , Traverson Lola , Zinszer Kate , Ridde Valéry 
Published: March 2021

AbstractContextContact tracing has been a central COVID-19 transmission control measure. However, without the consideration of the needs of specific populations, public health interventions can exacerbate health inequities.PurposeThe purpose of this rapid review was to determine if and how health inequities were included in the design of contact tracing interventions in epidemic settings.MethodWe conducted a search of the electronic databases MEDLINE and Web of Science. Our inclusion criteria included articles that: (i) described the design of contact tracing interventions, (ii) have been published between 2013 and 2020 in English, French, Spanish, Chinese, or Portuguese, (iii) and included at least 50% of empiricism, according to the Automated Classifier of Texts on Scientific Studies (ATCER) tool. We relied on various tools to extract data.ResultFollowing the titles and abstracts screening of 230 articles, 39 articles met the inclusion criteria. Only seven references were retained after full text review. None of the selected studies considered health inequities in the design of contact tracing interventions.ConclusionThe use of tools/concepts for incorporating health inequities, such as the REFLEX-ISS tool, and “proportionate universalism” when designing contact tracing interventions, would enable practitioners, decision makers, and researchers to better consider health inequities.
Targeted Next Generation Sequencing of environmental DNA improves detection and quantification of invasive European green crab (Carcinus maenas)
Authors: Westfall Kristen Marie , Therriault Thomas W. , Abbott Cathryn L. 
Published: March 2021

AbstractIn the northeast Pacific Ocean there is high interest in developing eDNA-based survey methods to aid management of invasive populations of European green crab (Carcinus maenas). Expected benefits are improved sensitivity for early detection of secondary spread and quantification of abundances to assess the outcome of eradication efforts. A new eDNA-based approach we term ‘Targeted Next Generation Sequencing (tNGS)’ is introduced here and shown to improve detection relative to qPCR at low eDNA concentrations, as is characteristic of founding or spreading populations. tNGS is based on the premise that the number of NGS reads from non-normalized (i.e. equal volumes) targeted PCR amplicons will approximate the starting DNA amount. Standard DNA concentrations that were 10-to 100-times lower than the qPCR limit of detection returned significant numbers of sequencing reads, which in our field assessments translated to a 7% - 10% increase in crab detection probability from tNGS relative to qPCR at low abundances. We also found that eDNA concentration was highly correlated with crab abundance, as measured from traditional trapping methods, for both assays; however, tNGS data had greater precision and less error than qPCR. When partitioning the sources of variation in each assay we identified greater between-site variability for tNGS relative to qPCR, suggesting the former may offer more power for detecting spatial variation in eDNA concentration. When applying this assay in management programs, we suggest including a panel of eDNA samples from sites with trapping data as standards to estimate relative abundance at sites with no a priori information. Results presented here indicate the tNGS approach has great promise for surveillance of green crab and could easily be adopted for surveillance of any species of high interest to management, including endangered species, new incursions of invasive species, and species with low eDNA shedding rates. Pros and cons of this approach compared to qPCR are discussed.
Pericentromeric heterochromatin impacts genome compartmentalization and sex chromosome evolution in a fish
Authors: Xue Lingzhan , Gao Yu , Wu Meiying , Fan Haiping , Huang Yongji , Huang Zhen , Li Dapeng , Xu Luohao 
Published: March 2021

AbstractCompartmentalization is one of the principles of chromosome 3D organization and has been suggested to be driven by the attraction of heterochromatin. The extent to which the pericentromeric heterochromatin (PCH) impacts chromosome compartmentalization is yet unclear. Here we produced a chromosome-level and fully phased diploid genome of an aquaculture fish, zig-zag eel (Mastacembelus armatus), and identified the centromeric and pericentromeric regions in the majority of chromosomes of both haploid genomes. The PCH is on average 4.2 Mb long, covering 17.7% of the chromosomes, and is the major target of histone 3 lysine 9 trimethylation (H3K9me3). In nearly half of the chromosomes, the PCH drives the chromosomes into two or three megascale chromatin domains with the PCH being a single one. We further demonstrate that PCH has a major impact in submetacentric, metacentric and small telocentric chromosomes in which the PCH drives the distribution of active and inactive compartments along the chromosomes. Additionally, we identified the young and homomorphic XY sex chromosomes that are submetacentric with the entire short-arm heterochromatinized. Interestingly, the sex-determining region seems to arise within the PCH that has been in place prior to the X-Y divergence and recombination suppression. Together, we demonstrate that the PCH can cover a considerably large portion of the chromosomes, and when it does so, it drives chromosome compartmentalization; and we propose a new model for the origin and evolution of homomorphic sex chromosomes in fish.
Strong and Significant Associations of Single Nucleotide Variants (SNVs) in the Promoter and 3’-Untranslated Region (3’-UTR) ofVascular Endothelial Growth Factor(VEGF) Gene with Head and Neck Cancers
Authors: Ajaz Sadia , Muneer Rabbia , Siddiqa Aisha , Memon Muhammad Ali , Firasat Sadaf , Abid Aiysha , Khaliq Shagufta 
Published: March 2021

AbstractBackgroundVascular Endothelial Growth Factor (VEGF) has a potent role in tumorigenesis and metastasis. However, data for the role of common single nucleotide variants (SNVs) in the highly polymorphicVEGFgene in head and neck cancers (HNCs) is limited in general and unavailable in South Asian populations.The present study addresses this shortfall. It investigates the association of twoVEGFSNVs, −2578 C/A (rs699947) in the promoter region and +936 C/T (rs3025039) in 3’-UTR, with the risk of HNCs and tumour characteristics.MethodsThe study comprised 323 participants with 121 HNC patients and 202 controls. Germline DNA was isolated from peripheral blood samples. PCR-RFLP methods were optimized and validated by Sanger sequencing. After Hardy-Weinberg evaluation, the independent associations were analyzed by applying genetic models. The χ2test of independence or Fisher’s Exact test (significant p-values at <0.05) were performed and ORs (odds ratios) with 95% confidence interval were tabulated.ResultsVEGF−2578 A-allele, A-carrier and AA genotypes had significant protective association against HNCs. The respective ORs were: 0.651 (0.469 – 0.904), 0.613 (0.381 – 0.985), and 0.393 (0.193 – 0.804).VEGF+936 T-allele, CT and T-carrier genotypes had significantly increased susceptibility for HNCs. The respective ORs were 1.882 (1.001 – 3.536), 2.060 (1.035 – 4.102), and 2.023 (1.032 – 3.966). Additionally,VEGF+936 CT and T-carrier genotypes showed significant associations with higher tumour grade (p-value <0.029, and <0.037, respectively).ConclusionThe present study is the foremost report of independent and unique associations of the investigatedVEGFSNVs with HNCs.
Searching for prognostic biomarkers of Parkinson’s Disease development in the Spanish EPIC cohort through a multiplatform metabolomics approach
Authors: Gonzalez-Riano Carolina , Saiz Jorge , Barbas Coral , Bergareche Alberto , Huerta José Ma , Ardanaz Eva , Konjevod Marcela , Mondragon Elisabet , Erro ME , Chirlaque M. Dolores , Abilleira Eunate , Goñi-Irigoyen Fernando , Amiano Pilar 
Published: March 2021

ABSTRACTObjectiveThe lack of knowledge about the onset and progression of Parkinson’s disease (PD) hampers its early diagnosis and treatment. Our aim was to determine the biochemical remodeling induced by PD in a really early and pre-symptomatic stage and unveiling early potential diagnostic biomarkers adopting a multiplatform (LC-MS, GC-MS, CE-MS) untargeted metabolomics approach.Methods41,437 healthy volunteers from the European Prospective Study on Nutrition and Cancer (EPIC)-Spain cohort were followed for around 15 years to ascertain incident PD. For this study, baseline pre-clinical plasma samples of 39 randomly selected individuals (46% females, 41– 69 years old) that developed PD (Pre-PD group) and the corresponding control group (n=39, 46% females, 41–69 years old) were analyzed. The metabolic differences were investigated by univariate and multivariate data analyses, followed by pathway-based metabolite analyses to obtain possible clues on biological functions.ResultsOur results exposed significantly lower levels of seven free fatty acids in the pre-PD subjects, together with alterations in other metabolite classes. Our finding revealed alterations in fatty acids metabolism, mitochondrial dysfunction, oxidative stress, and gut-brain axis dysregulation.ConclusionsAlthough the biological purpose of these events is still unknown, the mechanisms involved in the remodelling of the suggested metabolic pathways seem to appear long before the development of PD hallmarks. These findings might be considered as worthy potential markers whose alteration might lead to the development of PD hallmarks in the future. Consequently, this study is of inestimable value since this is the first study conducted with samples collected many years before the disease development.
Meeting experiments at the diffraction barrier: anin-silicowidefield fluorescence microscopy
Authors: Mahajan Subhamoy , Tang Tian 
Published: March 2021

AbstractFluorescence microscopy allows the visualization of live cells and their components, but even with advances in super- resolution microscopy, atomic resolution remains unattainable. On the other hand, molecular simulations (MS) can easily access atomic resolution, but comparison with experimental microscopy images has not been possible. In this work, a novelin-silicowidefield fluorescence microscopy is proposed, which reduces the resolution of MS to generate images comparable to experiments. This technique will allow cross-validation and compound the knowledge gained from experiments and MS. We demonstrate thatin-silicoimages can be produced with different optical axis, object focal planes, exposure time, color combinations, resolution, brightness and amount of out-of-focus fluorescence. This allows the generation of images that resemble those obtained from widefield, confocal, light-sheet, two-photon and super-resolution microscopy. This technique not only can be used as a standalone visualization tool for MS, but also lays the foundation for otherin-silicomicroscopy methods.
Role of BRCA2 DNA-binding and C-terminal domain on its mobility and conformation in DNA repair
Authors: Paul Maarten W. , Sidhu Arshdeep , Liang Yongxin , van Rossum-Fikkert Sarah E. , Odijk Hanny , Zelensky Alex N. , Kanaar Roland , Wyman Claire 
Published: March 2021

AbstractBRCA2 is an essential protein in genome maintenance, homologous recombination and replication fork protection. Its function includes multiple interaction partners and requires timely localization to relevant sites in the nucleus. We investigated the importance of the highly conserved DNA binding domain (DBD) and C-terminal domain (CTD) of BRCA2. We generated BRCA2 variants missing one or both domains in mouse ES cells and defined their contribution in HR function and dynamic localization in the nucleus, by single particle tracking of BRCA2 mobility. Changes in molecular architecture of BRCA2 induced by binding partners of purified BRCA2 was determined by scanning force microscopy. BRCA2 mobility and DNA damage-induced increase in the immobile fraction was largely unaffected by C- terminal deletions. The purified proteins missing CTD and/or DBD were defective in architectural changes correlating with reduced homologous recombination function in cells. These results emphasize BRCA2 activity at sites of damage beyond promoting RAD51 delivery.
PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107
Authors: Fowle Holly , Zhao Ziran , Xu Qifang , Wang Xinru , Adeyemi Mary , Feiser Felicity , Kurimchak Alison , Kettenbach Arminja N. , Page Rebecca , Peti Wolfgang , Dunbrack Roland L. , Graña Xavier 
Published: March 2021

AbstractProtein phosphorylation is a reversible post-translation modification essential in cell signaling. This study addresses a long-standing question as to how the most abundant serine/threonine Protein Phosphatase 2 (PP2A) holoenzyme, PP2A/B55α, specifically recognizes substrates and presents them to the enzyme active site. Here, we show how the PP2A regulatory subunit B55α recruits p107, a pRB-related tumor suppressor and B55α substrate. Using molecular and cellular approaches, we identified a conserved region 1 (R1, residues 615-626) encompassing the strongest p107 binding site. This enabled us to identify an “HxRVxxV619-625” short linear motif (SLiM) in p107 as necessary for B55α binding and dephosphorylation of the proximal pSer-615in vitroand in cells. Numerous B55α/PP2A substrates, including TAU, contain a related SLiM C-terminal from a proximal phosphosite, “p[ST]-P-x(5-10)-[RK]-V-x-x-[VI]-R”. Mutation of conserved SLiM residues in TAU dramatically inhibits dephosphorylation by PP2A/B55α, validating its generality. A data-guided computational model details the interaction of residues from the conserved p107 SLiM, the B55α groove, and phosphosite presentation. Altogether these data provide key insights into PP2A/B55α mechanisms of substrate recruitment and active site engagement, and also facilitate identification and validation of new substrates, a key step towards understanding PP2A/B55〈 role in multiple cellular processes.
State-Transition Analysis of Time-Sequential microRNA Expression Predicts Development of Acute Myeloid Leukemia
Authors: Frankhouser D. E. , O’Meally D. , Branciamore S. , Uechi L. , Qin H. , Wu X. , Carlesso N. , Marcucci G. , Rockne R. C. , Kuo Ya-Huei 
Published: March 2021

AbstractMicroRNAs (miRNAs) are small non-coding RNA molecules involved in post-transcriptional regulation of gene expression and have been shown to hold prognostic value in a variety of settings, including acute myeloid leukemia (AML). However, the temporal dynamics of miRNA expression profiles as it relates to AML initiation and progression is poorly understood. Using serial samples from a mouse model of AML, we show that the miRNA transcriptome undergoes state-transition during AML initiation and progression. The AML state-transition was visualized and modeled by constructing an AML state-space from singular value decomposition of the time-series miRNA sequencing data. Within the AML state-space, we identified critical points of AML development characterized by unique differentially expressed miRNAs compared to healthy controls at critical points of leukemogenesis (early, transition, and late). Interestingly, we observed that changes in miRNA expression during leukemogenesis followed two patterns: 1) a monotonic pattern with continuously increasing or decreasing expression; and 2) a non-monotonic pattern with a local maximum or minimum at the transition critical point which was the “point of no-return” from health to AML. We validated the AML state-space and dynamics in an independent cohort of mice and demonstrated the state-transition model accurately predicted time to AML. Of note, we show that the miRNA-derived state-transition model produced a state-space and critical points that were strikingly similar, but not identical to that produced by the coding (i.e., messenger [m]RNA-based) transcriptome. This indicates that while both miRNA and mRNA expression may provide similar information, they also capture independent features of AML state-transition.SignificanceWe show that the microRNA transcriptome undergoes a global state transition during the initiation and progression of acute myeloid leukemia, and accurately predicts time to disease development.
Compositional analysis of ALS-linked stress granule-like structures reveals factors and cellular pathways dysregulated by mutant FUS under stress
Authors: An Haiyan , Litscher Gioana , Wei Wenbin , Watanabe Naruaki , Hashimoto Tadafumi , Iwatsubo Takeshi , Buchman Vladimir L. , Shelkovnikova Tatyana A. 
Published: March 2021

AbstractFormation of cytoplasmic RNA-protein structures called stress granules (SGs) is a highly conserved cellular response to stress. Abnormal metabolism of SGs may contribute to the pathogenesis of (neuro)degenerative diseases such as amyotrophic lateral sclerosis (ALS). Many SG proteins are affected by mutations causative of these conditions, including fused in sarcoma (FUS). Mutant FUS variants have high affinity to SGs and also spontaneously formde novocytoplasmic RNA granules. Mutant FUS-containing assemblies (mFAs), often called “pathological SGs”, are proposed to play a role in ALS-FUS pathogenesis. However, global structural differences between mFAs and physiological SGs remain largely unknown, therefore it is unclear whether and how mFAs may affect cellular stress responses. Here we used affinity purification to characterise the protein and RNA composition of normal SGs and mFAs purified from stressed cells. Comparison of the SG and mFA proteomes revealed that proteasome subunits and certain nucleocytoplasmic transport factors are depleted from mFAs, whereas translation elongation, mRNA surveillance and splicing factors as well as mitochondrial proteins are enriched in mFAs, as compared to SGs. Validation experiments for a hit from our analysis, a splicing factor hnRNPA3, confirmed its RNA-dependent sequestration into mFAs in cells and into pathological FUS inclusions in a FUS transgenic mouse model. Furthermore, silencing of theDrosophilahnRNPA3 ortholog dramatically enhanced FUS toxicity in transgenic flies. Comparative transcriptomic analysis of SGs and mFAs revealed that mFAs recruit a significantly less diverse spectrum of RNAs, including reduced recruitment of transcripts encoding proteins involved in protein translation, DNA damage response, and apoptotic signalling. However mFAs abnormally sequester certain mRNAs encoding proteins involved in stress signalling cascades. Overall, our study establishes molecular differences between physiological SGs and mFAs and identifies the spectrum of proteins, RNAs and respective cellular pathways affected by mFAs in stressed cells. In conclusion, we show that mFAs are compositionally distinct from SGs and that they cannot fully substitute for SG functions while gaining novel, potentially toxic functions in cellular stress response. Results of our study support a pathogenic role for stress-induced cytoplasmic FUS assemblies in ALS-FUS.