bluuebunny/crossref_metadata_2025_split huggingface dataset:
Guiding principles for accelerating change through health inequities research and practice: A modified Delphi consensus process
Authors: Ahmed F. , Woodhead C. , Hossaini A. , Stanley N. , Ensum L. , Rhead R. , Onwumere J. , Mir G. , Dyer J. ,   HSE Collective, Hatch S.L. 
Published: April 2024

AbstractDespite a preponderance of evidence, and considerable resources, health & social inequities persist and there is evidence of widening unfair differences in markers of health and care. While power imbalances created by broader structural and economic systems are major influencing factors, reform within health inequities research, policy and health and social care practice is key to both bottom-up and top-down change. We aimed to develop agreement for an iterative set of guiding principles underpinning ways of working for a newly formed Health and Social Equity Collective comprising researchers, community leaders, policymakers, and health and care professionals, seeking to address inequity by identifying and engaging the levers of change within and across institutions. The principles aim to inform a more inclusive and translational knowledge base through research practices, tackling entrenched inequalities in education, training, and capacity-building; and centring communities affected by health inequities through engagement and advocacy. We carried out a modified Delphi consensus process between March and September 2022 with Collective members and networks through online workshops and surveys. Out of 24 consensus statements developed and refined over a workshop and three successive survey rounds, we identified eleven key principles agreed upon by a majority of respondents. Two of these were rated high priority by over 75% of respondents, four by over 60% and five by over 50%. These could be grouped into three main topics detailing ways of working and change needed within: ‘Knowledge and framing of health and social inequities, and incorporation into practice’, ‘Community engagement, involvement and peer research’, and ‘Organisational culture change’. Given the pressing need to address inequities, these principles offer a grounding for future consensus building initiatives which also incorporate a wider diversity of perspectives, and which should be iteratively updated with ongoing learning from health equity initiatives nationally and internationally.
AI-based model for T1-weighted brain MRI diagnoses Amyotrophic Lateral Sclerosis
Authors: Turrisi Rosanna , Forzanini Federica , Stanziano Mario , Nigri Anna , Fedeli Davide , Giovanna Carrara , Laura Lequio , Manera Umberto , Moglia Cristina , Valentini Maria Consuelo , Calvo Andrea , Chiò Adriano , Barla Annalisa 
Published: April 2024

AbstractAmyotrophic Lateral Sclerosis (ALS) is an incurable deadly motor neuron disease that causes the gradual deterioration of nerve cells in the spinal cord and brain. It impacts voluntary limb control and can result in breathing impairment. ALS diagnosis is often challenging due to its symptoms overlapping with other medical conditions and many tests must be performed to rule out other conditions, as easily identifiable biomarkers are still lacking. In this study, we explore T1-weighted (T1w) brain Magnetic Resonance Imaging (MRI), a non-invasive neuroimaging approach which has shown to be a reliable biomarker in many medical fields. Nonetheless, current literature on ALS diagnosis fails to retrieve evidence on how to identify biomarkers from T1w MRI.In this paper, we leverage Artificial Intelligence (AI) methods to unveil the unexplored potential of T1w brain MRI for distinguishing ALS patients from those who have similar symptoms but different diseases (mimicking). We consider a retrospective single-center dataset of brain T1-weighted MRIs collected from 2010 to 2018 recruited from the Piemonte and Valle d’Aosta ALS register (PARALS). The collection includes 548 patients with ALS and 106 with mimicking diseases. Our goal is to develop and validate a ML diagnostic model based exclusively on T1w MRI distinguishing the two classes. First, we extract a set of radiomic features and two sets of Deep Learning (DL)-based features from MRI scans. Then, using each representation, we train 8 binary classifiers. The best results were obtained by combining DL-based features with SVM classifier, reaching an F1-score of 0.91, and a Precision of 0.88, a Recall of 0.94, and an AUC of 0.7 considering the ALS group as the positive class in the testing set.
Fertility decline in the later phase of the COVID-19 pandemic: The role of policy interventions, vaccination programmes, and economic uncertainty
Authors: Winkler-Dworak Maria , Zeman Kryštof , Sobotka Tomáš 
Published: April 2024

AbstractBACKGROUNDDuring the COVID-19 pandemic, birth rates in most higher-income countries first briefly declined and then shortly recovered, showing no common trends afterwards until early 2022, when they unexpectedly dropped.STUDY FOCUSWe analyse monthly changes in total fertility rates in higher-income countries during the COVID-19 pandemic, with a special focus on 2022, when birth rates declined in most countries. We consider three broader sets of explanatory factors: economic uncertainty, policy interventions restricting mobility and social activities outside the home, and the role of vaccination programmes.STUDY DESIGN, DATAThis study uses population-wide data on monthly total fertility rates adjusted for seasonality and calendar effects provided in the Human Fertility Database (HFD, 2023). Births taking place between November 2020 and October 2022 correspond to conceptions occurring between February 2020 and January 2022, i.e., after the onset of the pandemic but prior to the Russian invasion of Ukraine. The data cover 26 countries, including 21 countries in Europe, the United States, Canada, Israel, Japan and the Republic of Korea.METHODSFirst, we provide a descriptive analysis of the monthly changes in the total fertility rate (TFR). Second, we estimate the effects of the explanatory factors on the observed fertility swings using linear fixed effects (within) regression models.MAIN RESULTSWe find that birth trends during the COVID-19 pandemic were associated with economic uncertainty, as measured by increased inflation, the stringency of pandemic policy interventions, and the progression of the COVID-19 vaccination campaign, whereas unemployment did not show any link to fertility during the pandemic.LIMITATIONS, REASONS FOR CAUTIONOur research is restricted to higher-income countries with relatively strong social support policies provided by the government as well as wide access to modern contraception. Our data do not allow analysing fertility trends by key characteristics, such as age, birth order and social status.WIDER IMPLICATIONS OF THE FINDINGSThis is the first multi-country study of the drivers of birth trends in a later phase of the COVID-19 pandemic. In the past, periods following epidemics and health crises were typically associated with a recovery in fertility. In contrast, our results show that the gradual phasing out of pandemic containment measures, allowing increased mobility and a return to more normal work and social life, contributed to declining birth rates in most countries. In addition, our analysis indicates that some women avoided pregnancy during the initial vaccination roll-out.
Secondary deficiency of neuraminidase 1 contributes to CNS pathology in neurological mucopolysaccharidoses via hypersialylation of brain glycoproteins
Authors: Xu TianMeng , Heon-Roberts Rachel , Moore Travis , Dubot Patricia , Pan Xuefang , Guo Tianlin , Cairo Christopher W. , Holley Rebecca , Bigger Brian , Durcan Thomas M. , Levade Thierry , Ausseil Jerôme , Amilhon Bénédicte , Gorelik Alexei , Nagar Bhushan , Sturiale Luisa , Palmigiano Angelo , Röckle Iris , Thiesler Hauke , Hildebrandt Herbert , Garozzo Domenico , Pshezhetsky Alexey V. 
Published: April 2024

AbstractMucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III and VII are associated with lysosomal accumulation of heparan sulphate and manifest with neurological deterioration. Most of these neurological MPS currently lack effective treatments. Here, we report that, compared to controls, neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of neurological MPS patients and in mouse models of MPS I, II, IIIA, IIIB and IIIC, but not of other neurological lysosomal disorders not presenting with heparan sulphate storage. We further show that accumulated heparan sulphate disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A (CTSA), β-galactosidase (GLB1) and glucosamine-6-sulfate sulfatase (GALNS) necessary to maintain enzyme activity, and that NEU1 deficiency is linked to partial deficiencies of GLB1 and GALNS in cortical tissues and iPSC-derived cortical neurons of neurological MPS patients. Increased sialylation of N-linked glycans in brain samples of human MPS III patients and MPS IIIC mice implicated insufficient processing of brain N-linked sialylated glycans, except for polysialic acid, which was reduced in the brains of MPS IIIC mice. Correction of NEU1 activity in MPS IIIC mice by lentiviral gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioural traits, and reduced levels of the excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1-/PSD95-positive puncta in cortical neurons derived from iPSC of an MPS IIIA patient. Together, our data demonstrate that heparan sulphate-induced secondary NEU1 deficiency and aberrant sialylation of glycoproteins implicated in synaptogenesis, memory, and behaviour constitute a novel pathological pathway in neurological MPS spectrum crucially contributing to CNS pathology.Graphical abstract
An integrated single-nucleus and spatial transcriptomics atlas reveals the molecular landscape of the human hippocampus
Authors: Thompson Jacqueline R. , Nelson Erik D. , Tippani Madhavi , Ramnauth Anthony D. , Divecha Heena R. , Miller Ryan A. , Eagles Nicholas J. , Pattie Elizabeth A. , Kwon Sang Ho , Bach Svitlana V. , Kaipa Uma M. , Yao Jianing , Hou Christine , Kleinman Joel E. , Collado-Torres Leonardo , Han Shizhong , Maynard Kristen R. , Hyde Thomas M. , Martinowich Keri , Page Stephanie C. , Hicks Stephanie C. 
Published: April 2024

AbstractThe hippocampus contains many unique cell types, which serve the structure’s specialized functions, including learning, memory and cognition. These cells have distinct spatial organization, morphology, physiology, and connectivity, highlighting the importance of transcriptome-wide profiling strategies that retain cytoarchitectural organization. Here, we generated spatially-resolved transcriptomics (SRT) and single-nucleus RNA-sequencing (snRNA-seq) data from adjacent tissue sections of the anterior human hippocampus in ten adult neurotypical donors to define molecular profiles for hippocampal cell types and spatial domains. Using non-negative matrix factorization (NMF) and label transfer, we integrated these data by defining gene expression patterns within the snRNA-seq data and inferring their expression in the SRT data. We identified NMF patterns that captured transcriptional variation across neuronal cell types and indicated that the response of excitatory and inhibitory postsynaptic specializations were prioritized in different SRT spatial domains. We used the NMF and label transfer approach to leverage existing rodent datasets, identifying patterns of activity-dependent transcription and subpopulations of dentate gyrus granule cells in our SRT dataset that may be predisposed to participate in learning and memory ensembles. Finally, we characterized the spatial organization of NMF patterns corresponding to non-cornu ammonispyramidal neurons and identified snRNA-seq clusters mapping to distinct regions of the retrohippocampus, to three subiculum layers, and to a population of presubiculum neurons. To make this comprehensive molecular atlas accessible to the scientific community, both raw and processed data are freely available, including through interactive web applications.
Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection
Authors: Belmont Laura , Contreras Maya , Cartwright-Acar Catiana H. , Marceau Caleb D. , Agrawal Aditi , Levoir Lisa M. , Lubow Jay , Goo Leslie 
Published: April 2024

AbstractDengue virus (DENV) can hijack non-neutralizing IgG antibodies to facilitate its uptake into target cells expressing Fc gamma receptors (FcgR) - a process known as antibody-dependent enhancement (ADE) of infection. Beyond a requirement for FcgR, host dependency factors for this non-canonical infection route remain unknown. To identify cellular factors exclusively required for ADE, here, we performed CRISPR knockout screens in anin vitrosystem permissive to infection only in the presence of IgG antibodies. Validating our approach, a top hit was FcgRIIa, which facilitates binding and internalization of IgG-bound DENV but is not required for canonical infection. Additionally, we identified host factors with no previously described role in DENV infection, including TBC1D24 and SV2B, both of which have known functions in regulated secretion. Using genetic knockout andtrans-complemented cells, we validated a functional requirement for these host factors in ADE assays performed with monoclonal antibodies and polyclonal sera in multiple cell lines and using all four DENV serotypes. We show that knockout of TBC1D24 or SV2B impaired binding of IgG-DENV complexes to cells without affecting FcgRIIa expression levels. Thus, we identify cellular factors beyond FcgR that are required for ADE of DENV infection. Our findings represent a first step towards advancing fundamental knowledge behind the biology of ADE that can ultimately be exploited to inform vaccination and therapeutic approaches.
Assessing genome conservation on pangenome graphs with PanSel
Authors: Zytnicki Matthias 
Published: April 2024

1AbstractMotivationWith more and more telomere-to-telomere genomes assembled, pangenomes make it possible to capture the genomic diversity of a species. Because they introduce less biases, pangenomes, represented as graphs, tend to supplant the usual linear representation of a reference genome, augmented with variations. However, this major change requires new tools adapted to this data structure. Among the numerous questions that can be addressed to a pangenome graph is the search for conserved or divergent genes.ResultsIn this article, we present a new tool, named PanSel, which computes a conservation score for each segment of the genome, and finds genomic regions that are significantly conserved, or divergent.AvailabilityPanSel, written in C++11 with no dependency, is available athttps://github.com/mzytnicki/pansel.Contactmatthias.zytnicki@inrae.fr
Multivalent Afadin Interaction Promotes IDR-Mediated Condensate Formation and Junctional Separation of Epithelial Cells
Authors: Kuno Shuhei , Nakamura Ryu , Otani Tetsuhisa , Togashi Hideru 
Published: April 2024

SummaryIn epithelial cells, cell-cell adhesion is mediated by the apical junctional complex (AJC), which consists of tight junctions (TJs) and adherens junctions (AJs) aligned from the apical to the basal axis. However, the mechanism of AJC formation on the apical side and the separation of these junctions within AJCs are poorly understood. We found that multivalent interactions of afadin with adhesion molecules and the cytoskeleton lead to condensate formation in an intrinsically disordered region (IDR)-dependent manner, which promotes efficient accumulation in the linear AJ during initial junction formation. Furthermore, we found that afadin and ZO-1 were able to induce different condensate formations in the cell and that these molecules were differentially distributed from each other. These properties of afadin explain how it strictly localizes to AJs in epithelial cells and is involved in regulating the segregation of AJ and TJ within the AJC.
Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes
Authors: Al-Diwani Adam , Provine Nicholas M , Murchison Andrew , Laban Rhiannon , Swann Owen J , Koychev Ivan , Sheerin Fintan , Da Mesquita Sandro , Heslegrave Amanda , Zetterberg Henrik , Klenerman Paul , Irani Sarosh R 
Published: April 2024

AbstractIn animal models, brain neurodegeneration biomarkers drain into cervical lymph nodes (CLNs). If this occurred in humans, CLNs may provide a readily accessible source of these biomarkers, draining the site of primary pathology. We tested this hypothesis in discovery and validation cohorts using ultrasound-guided fine needle aspiration (FNA).We measured amyloid-beta 40 and 42, phospho-Tau-181, glial-fibrillary-acidic-protein, and neurofilament-light using single molecule array in CLN aspirates and plasma from: i) a discovery cohort of 25 autoimmune patients, and from ii) plasma, CLNs and capillary blood in four healthy volunteers, an optimisation-validation cohort.FNA was well-tolerated by all participants. In both cohorts, all biomarkers were detected in all plasmas and CLNs, other than neurofilament-light (8/17 of discovery cohort). CLN biomarker concentrations were significantly greater than plasma concentrations for all except neurofilament-light, most markedly for phospho-Tau-181 (266 fold;P<0.02), whose CLN concentrations decreased with age (Spearmanr=-0.66,P=0.001).This study presents the first evidence that neurodegenerative biomarkers are detectable in human CLNs. Raised CLN:plasma biomarker ratios suggest their concentration in CLNs, which may offer a sensitive compartment for minimally-invasive sampling in clinical trials. Further, age-associated phospho-Tau-181 reduction with age suggests FNA of CLNs may measure the integrity of brain lymphatic drainagein vivo.
Spatial mapping of dextran sodium sulphate-induced intestinal inflammation and its systemic effects
Authors: Adams Lauren , Rasid Orhan , Hulme Heather , Quon Tezz , Burchmore Richard , Milling Simon , Goodwin Richard J.A. , Wall Daniel M. 
Published: April 2024

AbstractInflammatory bowel disease (IBD) is a multifactorial disease and patients frequently experience extraintestinal manifestations affecting multiple sites. Causes of systemic inflammation remain poorly understood but molecules originating from the intestine likely play a role, with microbial and host small molecules polarizing host immune cells towards a pro- or anti-inflammatory phenotype. Using the dextran sodium sulphate (DSS) mouse model, which mimics the disrupted barrier function, microbial dysbiosis and immune cell dysregulation of IBD, we investigated metabolomic and phenotypic changes at intestinal and systemic sites. Using spatial biology approaches we mapped distribution and relative abundance of molecules and cell types across a range of tissues revealing significant changes in DSS-treated mice. Molecules identified as contributing to the statistical separation of treated from control mice were spatially localized within organs to determine their effects on cellular phenotypes through imaging mass cytometry. This spatial approach identified both intestinal and systemic molecular drivers of inflammation, including several not previously implicated in inflammation linked to IBD or the systemic effects of intestinal inflammation. Metabolic and inflammatory pathway interplay underpins systemic disease and determining drivers at the molecular level may aid the development of new targeted therapies.
Jumping DNA polymerases in bacteriophages
Authors: Yutin Natalya , Tolstoy Igor , Mutz Pascal , Wolf Yuri I , Krupovic Mart , Koonin Eugene V 
Published: April 2024

AbstractViruses with double-stranded (ds) DNA genomes in the realmDuplodnaviriashare a conserved structural gene module but show a broad range of variation in their repertoires of DNA replication proteins. Some of the duplodnaviruses encode (nearly) complete replication systems whereas others lack (almost) all genes required for replication, relying on the host replication machinery. DNA polymerases (DNAPs) comprise the centerpiece of the DNA replication apparatus. The replicative DNAPs are classified into 4 unrelated or distantly related families (A-D), with the protein structures and sequences within each family being, generally, highly conserved. More than half of the duplodnaviruses encode a DNAP of family A, B or C. We showed previously that multiple pairs of closely related viruses in the orderCrassviralesencode DNAPs of different families. Here we identify four additional groups of tailed phages in the classCaudoviricetesin which the DNAPs apparently were swapped on multiple occasions, with replacements occurring both between families A and B, or A and C, or between distinct subfamilies within the same family. The DNAP swapping always occurs “in situ”, without changes in the organization of the surrounding genes. In several cases, the DNAP gene is the only region of substantial divergence between closely related phage genomes, whereas in others, the swap apparently involved neighboring genes encoding other proteins involved in phage replication. We hypothesize that DNAP swapping is driven by selection for avoidance of host antiphage mechanisms targeting the phage DNAP that remain to be identified, and/or by selection against replicon incompatibility. In addition, we identified two previously undetected, highly divergent groups of family A DNAPs that are encoded in some phage genomes along with the main DNAP implicated in genome replication.
Transglutaminase 2 is an RNA-binding protein: Experimental verification and characterisation of a novel transglutaminase feature
Authors: Csaholczi Bianka , Csuth Anna Renáta , Korponay-Szabó Ilma Rita , Fésüs László , Király Róbert 
Published: April 2024

AbstractTransglutaminase 2 (TG2) is a uniquely versatile protein with diverse catalytic activities, such as transglutaminase, protein disulfide isomerase, GTPase, protein kinase, and participates in several biological processes. According to information available in the RBP2GO database, TG2 can be an RNA-binding protein (RBP). RBPs participate in posttranscriptional gene expression regulation, influencing RNAs’ function, while RNA molecules can also modulate RBPs’ biological activity. Our goal was to confirm this novel character of TG2 in human umbilical cord vein endothelial cells (HUVEC), which physiologically express TG2.First, UV cross-linked RNA-protein complexes were isolated from immortalised HUVEC using orthogonal organic phase separation. Compared with the RBP2GO database, mass spectrometry identified 392 potential RBPs, including TG2 and 20 novel, endothelium-related RBPs. Total RNA from HUVEC pulled down recombinant human TG2. Complex formation between TG2 and a 43-mer RNA molecule with a secondary structure as well as a homo-oligomeric single-stranded poly(dG), but not poly(dA), could be observed in magnetic RNA-protein pull-down experiments. Experiments with TG2 inhibitors NC9 and GTPγS, which stabilise its open and closed conformation, respectively, revealed that the open conformation of the enzyme favoured RNA-binding. Biolayer interferometry revealed a high binding affinity between TG2 and RNA with a KDvalue of 88 nM.We propose that superficial residues on the catalytic core and C-terminal β-barrel domains, being in a hidden position in the closed TG2, are involved in RNA binding. Our study demonstrates TG2’s previously uncharacterised RNA-binding ability, opening new avenues for understanding its multi-functionality.Graphical abstractTransglutaminase 2 (TG2) is a unique multifunctional protein demonstrating large conformational changes. It has various transglutaminase and other catalytic and non-catalytic activities which show conformation dependency. Our study has characterised a novel, open conformation-related biological activity of TG2 and its RNA-binding ability.