bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dementia is strongly associated with medial temporal atrophy even after accounting for neuropathologies
Authors: Woodworth Davis C. , Sheikh-Bahaei Nasim , Scambray Kiana A. , Phelan Michael J. , Perez-Rosendahl Mari , Corrada María M. , Kawas Claudia H. , Sajjadi S. Ahmad ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: June 2021

ABSTRACTObjectiveBrain atrophy is associated with degenerative neuropathologies as well as clinical status of dementia. Whether dementia influences atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies.MethodsWe used data from National Alzheimer’s Coordinating Center (NACC, N=129) and Alzheimer’s Disease Neuroimaging Initiative (ADNI, N=47) participants with suitable in-vivo 3D-T1w MRI and autopsy data. We determined dementia status at visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer’s disease neuropathology, hippocampal sclerosis, Lewy Bodies, cerebral amyloid angiopathy, atherosclerosis. Voxel-based morphometry (VBM) identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analyzed. We used multiple linear regression models adjusted for neuropathologies and demographic variables.ResultsWe found strong associations for dementia with volumes of the hippocampus, amygdala, and parahippocampus (semi-partial correlations≥0.28, P<0.0001 for all regions in NACC; semi-partial correlations≥0.35, P≤0.01 for hippocampus and parahippocampus in ADNI). Dementia status accounted for more unique variance in atrophy in these structures (∼8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%).ConclusionEven after accounting for the most common neuropathologies, dementia still had among the strongest correlations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to clinical status of dementia as opposed to Alzheimer’s or other neuropathologies.
The importance of time post-vaccination in determining the decrease in vaccine efficacy against SARS-CoV-2 variants of concern
Authors: On Yinon Bar , Noor Elad , Gottlieb Noam , Sigal Alex , Milo Ron 
Published: June 2021

AbstractWith the development of high-efficacy vaccines against SARS-CoV-2, an urgent open question is whether currently available vaccines protect with similar efficacy against infection with SARS-CoV-2 variants of concern (VOC). Recent reports quantifying the extent by which VOC can evade vaccine immunity resulted in a range of estimates for the same VOC, which makes them difficult to interpret. One possible explanation for the discrepancies between different studies is an inconsistency in terms of the time post-vaccination of the sampled population. Here we present a model based on the observed correlation between antibody neutralization levels and vaccine efficacy, which demonstrates the impact of time post-vaccination on the comparison of the vaccine efficacy for VOC versus non-VOC infections. Our model predicts and exemplifies several possible consequences for vaccine efficacy in VOC infections: 1) a delay in the onset of vaccine efficacy against VOC; 2) a transient increase in susceptibility to breakthrough infection with VOC compared to non-VOC as a function of time after vaccination. We review preliminary data indicating that such phenomena are observed in studies of the B.1.1.7 and B.1.351 variants. We find that ignoring the strong dependence on the time post-vaccination can lead to contradictory reports of relative efficacy against VOC versus non-VOC, with implications on mitigation strategies against VOC and the design of vaccine efficacy studies.
CHA2DS2-VASc score on admission to predict mortality in COVID-19 patients: A meta-analysis
Authors: Sarkar Prattay Guha , Kumar Amit , Bandyopadhyay Debdutta 
Published: June 2021

AbstractBackgroundCHA2DS2-VASc score is used in non-valvular AF patients to predict thromboembolic risk. Recent studies have tried to evaluate CHA2DS2-VASc score on admission in COVID-19 patients to predict mortality.MethodsWe conducted a literature search on 14 April 2021 to retrieve all published studies, pre-prints and grey literature related to the predictive power of CHA2DS2-VASc score in COVID-19 patients of admission and mortality. Screening of studies and data extraction was done by two authors independently. We used the Quality in Prognosis Studies (QUIPS) tool for the methodological quality assessment of the included studies.ResultsFive studies involving 5,941 patients reported the predictive value of CHA2DS2-VASc score for mortality in COVID-19 patients. The pooled sensitivity (SEN), specificity (SPE) and area under curve were 0.72 (95% CI 0.63-0.79), 0.74 (95% CI 0.67-0.81) and 0.80 (95% CI 0.76-0.83).ConclusionsCHA2DS2-VASc score at admission has good predictive value for mortality in patients with COVID-19 infection and can help clinicians identify potentially severe cases early. Early initiation of effective management in these cases may help in reducing overall mortality due to COVID-19.Trial registryWe prospectively registered this meta-analysis on PROSPERO database (Reg number: CRD42021248398).
Brain atrophy progression in Parkinson’s disease is shaped by connectivity and local vulnerability
Authors: Tremblay Christina , Rahayel Shady , Vo Andrew , Morys Filip , Shafiei Golia , Markello Ross D. , Gan-Or Ziv , Misic Bratislav , Dagher Alain 
Published: June 2021

AbstractAtrophy in multiple brain regions has been reported in the early stages of Parkinson’s Disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell type distribution and gene expression combine to determine the pattern of disease progression remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties.Here we used MRI data from the Parkinson Progression Markers Initiative to test this model by mapping the progression of brain atrophy over one, two and four years and relating it to brain structural and functional connectivity, cell type expression and gene ontology enrichment analyses. In this longitudinal study, we derived atrophy progression maps for the three time points using deformation-based morphometry applied to T1-weighted MRI from 74 de novo Parkinson’s Disease patients (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). After regressing out the expected age and sex effects associated with normal aging, we found that atrophy significantly progressed over two and four years in the caudate, nucleus accumbens, hippocampus, and the temporal, parietal, occipital and posterior cingulate cortex. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was related to the prevalence of oligodendrocytes and endothelial cells.In sum, we demonstrate that the progression of atrophy in Parkinson’s Disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson’s Disease.
High throughput sequencing based detection of SARS-CoV-2 prevailing in wastewater of Pune, West India
Authors: Dharmadhikari Tanmay , Rajput Vinay , Yadav Rakeshkumar , Boaragaonkar Radhika , Panse Dayanand , Kamble Sanjay , Dastager Syed , Dharne Mahesh 
Published: June 2021

AbstractGiven a large number of SARS-CoV-2 infected individuals, clinical detection has proved challenging. The wastewater-based epidemiological paradigm would cover the clinically escaped asymptomatic individuals owing to the faecal shedding of the virus. We hypothesised using wastewater as a valuable resource for analysing SARS-CoV-2 mutations circulating in the wastewater of Pune region (Maharashtra; India), one of the most affected during the covid-19 pandemic. We conducted a case study in open wastewater drains from December 2020-March 2021 to assess the presence of SARS-CoV-2 nucleic acid and further detect mutations using ARTIC protocol of MinION sequencing. The analysis revealed 108 mutations across six samples categorised into 40 types of mutations. We report the occurrence of mutations associated with B.1.617 lineage in March-2021 samples, simultaneously also reported as a Variant of Concern (VoC) responsible for the rapid increase in infections. The study also revealed four mutations; S:N801, S:C480R, NSP14:C279F and NSP3:L550del not currently reported from wastewater or clinical data in India but reported in the world. Further, a novel mutation NSP13:G206F mapping to NSP13 region was observed from wastewater. Notably, S:P1140del mutation was observed in December 2020 samples while it was reported in February 2021 from clinical data, indicating the instrumentality of wastewater data in early detection. This is the first study in India to conclude that wastewater-based epidemiology to identify mutations associated with SARS-CoV-2 virus from wastewater as an early warning indicator system.
The role of nature conservation and commercial farming in psychological distress among rural Ugandans
Authors: Pienkowski Thomas , Keane Aidan , Kinyanda Eugene , Knizek Birthe Loa , Asiimwe Caroline , Muhanguzi Geoffrey , Milner-Gulland E.J. 
Published: June 2021

AbstractMental illness is a leading contributor to the global burden of disease, but there is limited understanding of how it is influenced by socio-ecological context, particularly in the global south. We asked how interactions with ecological systems influence stressors associated with psychological distress in a rural Ugandan case study. We conducted and thematically analyzed 45 semi-structured interviews with residents of Nyabyeya Parish, Masindi District. Our results suggest that poverty and food insecurity were the primary reported causes of “thinking too much” and related idioms of psychological distress. The expansion of commercial agriculture may have been associated with the contraction of subsistence farming, reportedly exacerbating poverty and food insecurity among poorer households but contributing incomes to wealthier ones. Furthermore, households bordering a conservation area reported that crop losses from wildlife contributed to food insecurity. However, forest resources were important safety nets for those facing poverty and food insecurity. Our study suggests how two globally prevalent land uses – commercial agriculture and nature conservation – may influence social determinants of psychological distress in our study area. Psychological distress does not necessarily imply mental disorder. Nonetheless, exploring socially-mediated interactions with ecosystems may help explain the etiology of psychological distress. Furthermore, we suggest opportunities to manage socio-ecological systems to support mental health, such as promoting equitable access and control of livelihood resources. We also highlight co-benefits and trade-offs between global sustainability goals that could be managed for mental health, and why these should be recognized in the anticipated ‘New Deal for Nature.’HighlightsFood insecurity and poverty were major stressors reportedly causing psychological distress, characterized as “thinking too much.”Complex interactions between conservation, commercial agriculture, and poverty influenced psychological distress.Commercial agriculture displaced subsistence farming, exacerbating poverty and food security among poorer households.Conserved forests were both home to crop-raiding wildlife and sources of income and food, affecting poverty and food insecurity.Mental health needs to be included in assessments of the role of the ecosystems in public health.
The ChAdOx1 vectored vaccine, AZD2816, induces strong immunogenicity against SARS-CoV-2 Beta (B.1.351) and other variants of concern in preclinical studies
Authors: Spencer Alexandra J , Morris Susan , Ulaszewska Marta , Powers Claire , Kailath Reshma , Bissett Cameron , Truby Adam , Thakur Nazia , Newman Joseph , Allen Elizabeth R , Rudiansyah Indra , Liu Chang , Dejnirattisai Wanwisa , Mongkolsapaya Juthathip , Davies Hannah , Donnellan Francesca R , Pulido David , Peacock Thomas P. , Barclay Wendy S. , Bright Helen , Ren Kuishu , Screaton Gavin , McTamney Patrick , Bailey Dalan , Gilbert Sarah C , Lambe Teresa 
Published: June 2021

AbstractThere is an ongoing global effort to design, manufacture, and clinically assess vaccines against SARS-CoV-2. Over the course of the ongoing pandemic a number of new SARS-CoV-2 virus isolates or variants of concern (VoC) have been identified containing mutations in key proteins. In this study we describe the generation and preclinical assessment of a ChAdOx1-vectored vaccine (AZD2816) which expresses the spike protein of the Beta VoC (B.1.351). We demonstrate that AZD2816 is immunogenic after a single dose. When AZD2816 is used as a booster dose in animals primed with a vaccine encoding the original spike protein (ChAdOx1 nCoV-19/ [AZD1222]), high titre binding and neutralising antibodies against Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2) are induced. In addition, a strong and polyfunctional T cell response was measured in these booster regimens. These data support the ongoing clinical development and testing of this new variant vaccine.
The Lipid Droplet Knowledge Portal: A resource for systematic analyses of lipid droplet biology
Authors: Mejhert Niklas , Gabriel Katlyn R. , Krahmer Natalie , Kuruvilla Leena , Chitraju Chandramohan , Boland Sebastian , Jang Dong-Keun , von Grotthuss Marcin , Costanzo Maria C. , Flannick Jason , Burtt Noël P. , Farese Robert V. , Walther Tobias C. 
Published: June 2021

SUMMARYLipid droplets (LDs) are organelles of cellular lipid storage with fundamental roles in energy metabolism and cell membrane homeostasis. There has been an explosion of research into the biology of LDs, in part due to their relevance in diseases of lipid storage, such as atherosclerosis, obesity, type 2 diabetes mellitus, and hepatic steatosis. Consequently, there is an increasing need for a resource that combines large datasets from systematic analyses of LD biology. Here we integrate high-confidence, systematically generated data on studies of LDs in the framework of an online platform named the Lipid Droplet Knowledge Portal. This scalable and interactive portal includes comprehensive datasets, across a variety of cell types, for LD biology, including transcriptional profiles of induced lipid storage, organellar proteomics, genome-wide screen phenotypes, and ties to human genetics. This new resource is a powerful platform that can be utilized to uncover new determinants of lipid storage.HIGHLIGHTS■ The LD-Portal is a resource combining datasets from systematic analyses in LD biology■ The LD-Portal allows users to query genetic, proteomic, and phenotypic aspects of LD biology■ The LD-Portal can be used to discover new facets of lipid storage and LD biology■ A crucial function of MSRB3 is uncovered in cholesterol ester storage in LDs
A novel immunopeptidomic-based pipeline for the generation of personalized oncolytic cancer vaccines
Authors: Feola Sara , Chiaro Jacopo , Martins Beatriz , Russo Salvatore , Fusciello Manlio , Ylösmäki Erkko , Hamdan Firas , Feodoroff Michaela , Antignani Gabriella , Viitala Tapani , Pesonen Sari , Grönholm Mikaela , Branca Rui M M , Lehtiö Janne , Cerullo Vincenzo 
Published: June 2021

ABSTRACTBeside the isolation and identification of MHC-I restricted peptides from the surface of cancer cells, one of the challenges is eliciting an effective anti-tumor CD8+ T cell mediated response as part of therapeutic cancer vaccine. Therefore, the establishment of a solid pipeline for the downstream selection of clinically relevant peptides and the subsequent creation of therapeutic cancer vaccines are of utmost importance. Indeed, the use of peptides for eliciting specific anti-tumor adaptive immunity is hindered by two main limitations: the efficient selection of the most optimal candidate peptides and the use of a highly immunogenic platform to combine with the peptides to induce effective tumor-specific adaptive immune responses. Here, we describe for the first time a streamlined pipeline for the generation of personalized cancer vaccines starting from the isolation and selection of the most immunogenic peptide candidates expressed on the tumor cells and ending in the generation of efficient therapeutic oncolytic cancer vaccines. This immunopeptidomics-based pipeline was carefully validated in a murine colon tumor model CT26. Specifically, we used state-of-the-art immunoprecipitation and mass spectrometric methodologies to isolate >8000 peptide targets from the CT26 tumor cell line. The selection of the target candidates was then based on two separate approaches: RNAseq analysis and the HEX software. The latter is a tool previously developed by Chiaro et al. (1), able to identify tumor antigens similar to pathogen antigens, in order to exploit molecular mimicry and tumor pathogen cross-reactive T-cells in cancer vaccine development. The generated list of candidates (twenty-six in total) was further tested in a functional characterization assay using interferon-γ ELISpot (Enzyme-Linked Immunospot), reducing the number of candidates to six. These peptides were then tested in our previously described oncolytic cancer vaccine platform PeptiCRAd, a vaccine platform that combines an immunogenic oncolytic adenovirus (OAd) coated with tumor antigen peptides. In our work, PeptiCRAd was successfully used for the treatment of mice bearing CT26, controlling the primary malignant lesion and most importantly a secondary, non-treated, cancer lesion. These results confirmed the feasibility of applying the described pipeline for the selection of peptide candidates and generation of therapeutic oncolytic cancer vaccine, filling a gap in the field of cancer immunotherapy, and paving the way to translate our pipeline into human therapeutic approach.
Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation
Authors: Orth Martin F. , Surdez Didier , Marchetto Aruna , Grossetête Sandrine , Gerke Julia S. , Zaidi Sakina , Alonso Javier , Sastre Ana , Baulande Sylvain , Sill Martin , Cidre-Aranaz Florencia , Ohmura Shunya , Kirchner Thomas , Hauck Stefanie M. , Reischl Eva , Gymrek Melissa , Pfister Stefan M. , Strauch Konstantin , Delattre Olivier , Grünewald Thomas G. P. 
Published: June 2021

ABSTRACTCell lines have been essential for major discoveries in cancer including Ewing sarcoma (EwS). EwS is a highly aggressive pediatric bone or soft-tissue cancer characterized by oncogenic EWSR1-ETS fusion transcription factors converting polymorphic GGAA-microsatellites (mSats) into neo-enhancers. However, further detailed mechanistic evaluation of gene regulation in EwS have been hindered by the limited number of well-characterized cell line models. Here, we present the Ewing Sarcoma Cell Line Atlas (ESCLA) comprising 18 EwS cell lines with inducible EWSR1-ETS knockdown that were profiled by whole-genome-sequencing, DNA methylation arrays, gene expression and splicing arrays, mass spectrometry-based proteomics, and ChIP-seq for EWSR1-ETS and histone marks. Systematic analysis of these multi-dimensional data illuminated hundreds of new potential EWSR1-ETS target genes, the nature of EWSR1-ETS-preferred GGAA-mSats, and potential indirect modes of EWSR1-ETS-mediated gene regulation. Moreover, we identified putative co-regulatory transcription factors and heterogeneously regulated EWSR1-ETS target genes that may have implications for the clinical heterogeneity of EwS. Collectively, our freely available ESCLA constitutes an extremely rich resource for EwS research and highlights the power of leveraging multidimensional and comprehensive datasets to unravel principles of heterogeneous gene regulation by dominant fusion oncogenes.
Locally secreted BiTEs complement CAR T cells by enhancing solid tumor killing
Authors: Yin Yibo , Rodriguez Jesse L. , Li Nannan , Thokala Radhika , Nasrallah MacLean P. , Hu Li , Zhang Logan , Zhang Jiasi Vicky , Kainth Devneet , Haddad Leila , Johns Emily X. , Long Yu , Liang Hongsheng , Qi Jiping , Zhang Xiangtong , Binder Zev A. , Lin Zhiguo , O’Rourke Donald M. 
Published: June 2021

ABSTRACTBispecific T-cell engagers (BiTEs) are bispecific antibodies that redirect T cells to target antigen-expressing tumors. BiTEs can be secreted by T cells through genetic engineering and perform anti-tumor activity. We hypothesized that BiTE-secreting T cells could be a valuable T cell-directed therapy in solid tumors, with distinct properties in mono- or multi-valent strategies incorporating chimeric antigen receptor (CAR) T cells. Glioblastomas represent a good model for solid tumor heterogeneity and represent a significant therapeutic challenge. We detected expression of tumor-associated epidermal growth factor receptor (EGFR), EGFR variant III (EGFRvIII), and interleukin-13 receptor alpha 2 (IL13Rα2) on glioma tissues and glioma cancer stem cells. These antigens formed the basis of a multivalent approach, using a conformation-specific tumor-related EGFR targeting antibody (806) and Hu08, an IL13Rα2-targeting antibody, as the scFvs to generate new BiTE molecules. Compared with 806CAR T cells and Hu08CAR T cells, BiTE T cells demonstrated prominent activation, cytokine production, and cytotoxicity in response to target-positive gliomas. Superior response activity was also demonstrated in BiTE secreting bivalent targeting T cells compared with bivalent targeting CAR T cells, which significantly delayed tumor growth in a glioma mouse model. In summary, BiTEs secreted by mono- or multi- valent targeting T cells have potent anti-tumor activity in vitro and in vivo with significant sensitivity and specificity, demonstrating a promising strategy in solid tumor therapy.
An Efficient and Cost-effective Purification Methodology for SaCas9 Nuclease
Authors: Teng Allen C.T. , Tavassoli Marjan , Shrestha Suja , Lindsay Kyle , Ivakine Evgueni , Cohn Ronald , Santerre J. Paul , Gramolini Anthony O. 
Published: June 2021

AbstractWith an ever-increasing demand for laboratory-grade Cas9 proteins by many groups advancing the use of CRISPR technology, a more efficient and scalable process for generating the proteins, coupled with rapid purification methods is in urgent demand. Here, we introduce a modified methodology for rapid purification of active SaCas9 protein within 24 hours. The product has over 90% protein purity. The simplicity and cost-effectiveness of such methodology will enable general labs to produce a sizable amount of Cas9 proteins, further accelerating the advancement of CRISPR/Cas9-based research.