bluuebunny/crossref_metadata_2025_split huggingface dataset:
New AAV9 engineered variants with enhanced neurotropism and reduced liver off-targeting in mice and marmosets
Authors: Giannelli Serena Gea , Luoni Mirko , Bellinazzi Benedetta , Iannielli Angelo , Middeldorp Jinte , Philippens Ingrid , Körbelin Jakob , Broccoli Vania 
Published: June 2023

SummaryAdeno-Associated Virus 9 (AAV9) is a delivery platform highly exploited to develop gene-based treatments for neurological disorders given its low pathogenicity and brain tissue tropism. However, the efficacy of this vector is dampened by its relatively low efficiency to cross the adult blood-brain barrier (BBB) and inherent targeting to the liver upon intravenous delivery. We generated a new peptide display library starting from a galactose binding-deficient AAV9 capsid and selected two new AAV9 engineered capsids, named AAV-Se1 and AAV-Se2, with an enhanced targeting in mouse and marmoset brains after intravenous delivery. Interestingly, the loss of the galactose binding strongly reduced the undesired targeting to peripheral organs, and above all liver, while not compromising the transduction of the brain vasculature. However, we had to reconstitute the galactose binding in order to efficiently infect non-endothelial brain cells. Thus, the combinatorial actions of the galactose-binding domain and the installed exogenous displayed peptide are crucial to enhance BBB crossing together with brain cell transduction. We also identified Ly6C1 as primary receptor for AAV-Se2 which is a Ly6A homologue highly expressed in the brain endothelial cells. This study describes a new strategy to select neurotropic AAV9 variants and identifies two novel capsids with high brain endothelial infectivity and extremely low liver targeting based on manipulating the AAV9 galactose binding domain.
Sequenced-based GWAS for linear classification traits in Belgian Blue beef cattle reveals new coding variants in genes regulating body size in mammals
Authors: Gualdron Duarte JL , Yuan C , Gori AS , Moreira GCM , Takeda H , Coppieters W , Charlier C , Georges M , Druet T 
Published: June 2023

AbstractCohorts of individuals that have been genotyped and phenotyped for genomic selection programs offer the opportunity to better understand genetic variation associated with complex traits. Here, we perform an association study for traits related to body size and muscular development in intensively selected beef cattle. We leveraged multiple trait information to refine and interpret the significant associations. After a multiple-step genotype imputation to the sequence-level for 14,762 Belgian Blue beef (BBB) cattle cows, we performed a GWAS for 11 traits related to muscular development and body size. The 37 identified genome-wide significant QTL could be condensed in 11 unique QTL regions based on their position. There was evidence for pleiotropic effects in most of these regions (e.g., correlated association signals, overlap between credible sets of candidate variants – CSCV). We consequently applied a multiple-trait approach to combine information from different traits to refine the CSCV. In several QTL regions, we identified strong candidate genes known to be related to growth and height in other species such asLCORL-NCAPGorCCND2. For some of these genes, relevant candidate variants were identified in the CSCV, including three new missense variants inEZH2,PAPPA2andADAM12, possibly two additional coding variants inLCORL, and candidate regulatory variants linked toCCND2andARMC12. Strikingly, four other QTL regions were related to five (recessive) deleterious coding variants previously identified. Heterozygotes for several of these mutations have favorable effects for muscular development traits. Our study further supports that a set of common genes controls body size across mammalian species. In particular, we added new genes to the list of those associated with height in both human and cattle. We also identified new strong candidate causing variants in some of those genes, strengthening the evidence of the causality of these genes. Several breed-specific recessive deleterious variants were identified in our QTL regions, probably as a result of the extreme selection for muscular development in BBB cattle.
GIFT – an R package to access the Global Inventory of Floras and Traits
Authors: Denelle Pierre , Weigelt Patrick , Kreft Holger 
Published: June 2023

AbstractAdvancing knowledge of biodiversity requires open-access global databases and workflows. This appears particularly crucial for plants, as ongoing changes pose major threats to this central group of organisms. Having large-scale information on plant distributions, functional traits and evolutionary history will enable the scientific community to improve its understanding of the patterns and drivers of plant diversity on a global scale.The Global Inventory of Floras and Traits (GIFT) is a global database of regional plant checklists that has proven successful in documenting biogeographical and geographical patterns of plants. Since the release of the first version of GIFT, the database kept on expanding. We introduce GIFT version 3.0, which contains 5,169 checklists referring to 3,400 regions. These checklists include a total of 371,148 land plant species, mostly vascular plants, of which 354,848 are accepted species names, and 109 functional traits. This new version uses new resources for taxonomic name standardization, is matched to a new plant phylogeny, comes with a new trait aggregation workflow, and includes additional environmental variables.We also present theGIFT R-package, which contains all necessary functions to retrieve distributional, functional, phylogenetic, and environmental data from the GIFT database. The package comes with a dedicated website,https://biogeomacro.github.io/GIFT/, which includes three rich vignettes to guide users in retrieving data from GIFT.The recent development of GIFT and its associatedR-package provide ecologists with access to one of the largest plant databases. This will foster research into regional to global patterns of plant diversity and their underlying mechanisms. Proper versioning of the database and the ability to retrieve and cite data from any previous and current instance of the GIFT database will ensure the reproducibility of studies that utilize it.
Mixed data analysis detected Endocrine Fibroblast Growth Factors (FGF19, FGF21, and FGF23) as Prognostic and Diagnostic Markers of Colorectal Neoplasia and Carcinoma
Authors: Rejali Leili , Piroozkhah Moein , Jahanbin Mana , Jalali Pooya , Khanabadi Binazir , Abkenar Elahe Daskar , Tavallaei Mehdi , Niasar Mahsa Saeedi , Hashemi Mehrdad , Sadeghi Amir , Salehi Zahra , Nazemalhosseini-Mojarad Ehsan 
Published: June 2023

BackgroundEndocrine fibroblast growth factors (eFGFs) play important roles in various cellular signaling processes such as development and differentiation. These genes were also found to be significantly related to several cancer. However, little is known about the role of eFGFsin colon neoplasia and colon adenocarcinoma (COAD).MethodsWe performed systematically and comprehensively investigated the gene expression, DNA methylation, prognostic significance, genetic alteration, co-expressed genes, protein-protein interaction, small molecules pathway, and drug interactions ofeFGFsbased on the TIMER2.0, GEPIA2, UALCAN, OncoDB, cBioPortal, LinkedOmics, STRING, SMPDB, htfTarget, mirTarBase, circBank and DGIdb databases. Ultimately, the correlations ofeFGFsexpressions between polyp and COAD tissues compared to normal mucosa were validated using qRT-PCR as a cross-sectional part of our study.ResultsThe results indicated thateFGFsare highly expressed in COAD, and abnormal gene expressions may be related to promoter methylation. In this matter, methylation analysis revealed promotor hypermethylation ofFGF19andFGF21. Conversely,FGF23was shown to have a tendency for promotor hypomethylation. Moreover, hypermethylation ofFGF21andFGF23and downregulation ofFGF23were found to be detrimental to the survival of COAD patients. KEGG pathway analyses indicated that the co-expressed genes ofeFGFfamily members were mainly related to the regulation of the actin cytoskeleton and, more notably, in Ras signaling, PI3k-Akt signaling, Rap1 signaling, and cancer pathways. Based on qRT-PCR results,FGF21was significantly overexpressed in the colon polyps compared to normal mucosa. Additionally, RNA expression ofFGF21andFGF23was markedly elevated in adenomatous polyps as opposed to hyperplastic polyps.ConclusionCollectively, these findings reveal the critical roles ofeFGFsin COAD tumorigenesis and suggesteFGFfamily members as promising prognostic and diagnostic markers for CRC as well as discriminating markers for high-risk from low-risk polyps.
Identification of a recombinant human astrovirus type 5 strain from an acute gastroenteritis outbreak in Beijing, China
Authors: Mao Tongyao , Zhang Peng , Li Lili , Yang Mengyao , Wang Yalu , Ma Yalin , Li Dandi , Li Jinsong , Duan Zhaojun 
Published: June 2023

AbstractTwo samples positive for the same strain (2103CP) of human astrovirus (HAstV) were identified during an acute gastroenteritis outbreak in Beijing, China. A full genomic analysis showed that for both samples, open reading frame 1a (ORF1a) clustered with HAstV-1, whereas ORF1b and ORF2 clustered with HAstV-5. The recombination site was detected upstream of the region where ORF1a and ORF1b overlapped. Recombinant HAstV-5 strains were reported previously in China in 2013 and 2021. Our results indicate the need for continuous surveillance of the prevalence and evolution of this recombinant HAstV-5 in China.
A role for BCL6 in maintaining CX3CR1+CD4+T cells during helminth infection
Authors: Loredan Denis G. , Devlin Joseph C. , Khanna Kamal M. , Loke P’ng 
Published: June 2023

AbstractDistinct subsets of T lymphocytes express CX3CR1 under inflammatory conditions, but little is known about CX3CR1+CD4+T cells during Type 2 inflammation in helminth infections. Here, we used a fate-mapping mouse model to characterize CX3CR1+CD4+T cells during both acuteNippostrongylus brasiliensisand chronicSchistosoma mansonihelminth infections, revealing CX3CR1+CD4+T cells to be an activated tissue homing subset with varying capacity for cytokine production. Tracking these cells over time revealed that maintenance of CX3CR1 itself along with a TH2 phenotype conferred a survival advantage in the inflamed tissue. Single-cell RNA-sequencing analysis of fate-mapped CX3CR1+CD4+T cells from both the peripheral tissue and the spleen revealed a considerable level of diversity and identified a distinct population of BCL6+TCF-1+PD1+CD4+T cells in the spleen during helminth infections. Conditional deletion of BCL6 in CX3CR1+cells result in fewer CX3CR1+CD4+during infection, indicating a role in sustaining CD4+T cell responses to helminth infections. Overall, our studies revealed the behavior and heterogeneity of CX3CR1+CD4+T cells during Type 2 inflammation in helminth infections and identified BCL6 to be important in their maintenance.
Direct and indirect fitness effects of plant metabolites and genetic constraints limit evolution of allelopathy in an invading plant
Authors: Honor Richard , Marcellus Mia , Colautti Robert I. 
Published: June 2023

AbstractInvading species encounter novel communities of consumers, pathogens, and competitors. Both phenotypic plasticity and rapid evolution can facilitate invasion across these heterogenous communities. However, the rate and extent of adaptive evolution on contemporary timescales can be constrained by adaptive phenotypic plasticity and the genetic architecture of traits under selection.We measured phenotypic plasticity and quantified genetic variation for growth, leaf chlorophylla(Chla) and glucosinolates, and lifetime fitness among 23 naturally inbred seed families ofAlliaria petiolata(garlic mustard) collected across its invasive range in eastern North America. After growing a self-pollinated generation in a uniform common garden to reduce maternal effects, we reared second-generation plants in a two-year greenhouse and field experiment with naïve soil from an uninvaded habitat. We estimated selection gradients and causal factors affecting lifetime fitness when reared alone, with an intraspecific competitor, and under interspecific competition with naïveAcer saccharum(sugar maple) saplings.We defined Total Metabolite Production (TMP) as the first principal component of Chlaand glucosinolate concentrations, accounting for 84% of variation in these two traits. TMP was significantly plastic across growing environments (p< 0.001) with limited broad-sense heritability (H2= 2.91;p= 0.08). Path analysis revealed that plastic phenotypes with higher TMP had an indirect positive effect onA. petiolatafitness via a direct, negative effect on performance ofA. saccharumcompetitors. In contrast, the second principal component defined Relative Glucosinolate Investment (RGI), which was significantly heritable (H2= 16.91, p < 0.001) with no detectable plasticity across treatments. Variation in RGI amongA. petiolatagenotypes had a direct, positive effect onA. saccharumperformance and an indirect negative effect onA. petiolatafitness.Synthesis.Adaptive evolution of allelopathy during invasion has been constrained by (i) a lack of heritable genetic variation for allelopathy, (ii) high plasticity for TMP across competition treatments, and (iii) selection for lower RGI under interspecific and intraspecific competition. As an alternative to eco-evolutionary feedbacks, plasticity in TMP may be an overlooked explanation for variable performance ofA. petiolataacross its introduced range.
Two birds with one stone: human SIRPα nanobodies for functional modulation and in vivo imaging of myeloid cells
Authors: Wagner Teresa R. , Blaess Simone , Leske Inga B. , Frecot Desiree I. , Gramlich Marius , Traenkle Bjoern , Kaiser Philipp D. , Seyfried Dominik , Maier Sandra , Rezza Amélie , Sônego Fabiane , Thiam Kader , Pezzana Stefania , Zeck Anne , Gouttefangeas Cécile , Scholz Armin M. , Nueske Stefan , Maurer Andreas , Kneilling Manfred , Pichler Bernd J. , Sonanini Dominik , Rothbauer Ulrich 
Published: June 2023

AbstractSignal-regulatory protein α (SIRPα) expressed by myeloid cells is of particular interest for therapeutic strategies targeting the interaction between SIRPα and the "don’t eat me" ligand CD47 and as a marker to monitor macrophage infiltration into tumor lesions. To address both approaches, we developed a set of novel human SIRPα (hSIRPα)-specific nanobodies (Nbs). We identified three high-affinity Nbs targeting the hSIRPα/hCD47 interface, thereby enhancing antibody-dependent cellular phagocytosis (ADCP). For non-invasivein vivoimaging, we chose S36 Nb as a non-modulating binder. By quantitative positron emission tomography (PET) in novel hSIRPα/hCD47 knock-in (KI) mice, we demonstrated the applicability of64Cu-hSIRPα-S36 Nb to visualize tumor infiltration of myeloid cells. We envision that the hSIRPα-Nbs presented in this study have potential as versatile probes, including novel myeloid-specific checkpoint inhibitors for combinatorial treatment approaches and forin vivostratification and monitoring of individual responses during cancer immunotherapies.
Data-driven identification of potentially successful intervention implementations: a proof of concept using five years of opioid prescribing data from over 7000 practices in England
Authors: Hopcroft Lisa E. M. , Curtis Helen J. , Croker Richard , Pretis Felix , Inglesby Peter , Evans Dave , Bacon Seb , Goldacre Ben , Walker Alex J. , MacKenna Brian 
Published: June 2023

AbstractBackgroundWe have previously demonstrated that opioid prescribing increased by 127% between 1998 and 2016. New policies aimed at tackling this increasing trend have been recommended by public health bodies and there is some evidence that progress is being made. We sought to extend our previous work and develop an unbiased, data-driven approach to identify general practices and clinical commissioning groups (CCGs) whose prescribing data suggest that interventions to reduce the prescribing of opioids may have been successfully implemented.MethodsWe analysed five years of prescribing data for three opioid prescribing measures: one capturing total opioid prescribing and two capturing regular prescribing of high dose opioids. Using a data-driven approach, we applied a modified version of our change detection Python library to identify changes in these measures over time, consistent with the successful implementation of an intervention. This analysis was carried out for general practices and CCGs, and organisations were ranked according to the change in prescribing rate.ResultsWe present data for the three CCGs and practices demonstrating the biggest reduction in opioid prescribing across the three opioid prescribing measures. We observed a 40% drop in the regular prescribing of high dose opioids (measured as a percentage of regular opioids) in the highest ranked CCG (North Tyneside); a 99% drop in this same measure was found in several practices. Decile plots demonstrate that CCGs exhibiting large reductions in opioid prescribing do so via slow and gradual reductions over a long period of time (typically over two years); in contrast, practices exhibiting large reductions do so rapidly over a much shorter period of time.ConclusionsBy applying one of our existing analysis tools to a national dataset, we were able to rank NHS organisations by reduction in opioid prescribing rates. Highly ranked organisations are candidates for further qualitative research into intervention design and implementation.Contributions to the literatureDemonstrating that a data-driven approach can identify and quantify changes in important clinical measures in publicly available NHS dataIdentifying changes in this way allows the unbiased identification of candidates for further qualitative research into intervention design and implementationLarge reductions observed at the CCG level (which are more robust to local circumstances) demonstrate that it is possible to reduce opioid prescribing and that continued and wider success in reducing opioid prescribing is dependent, at least in part, to closing an implementation gap
Investigating of the causes of seizures in children admitted to Kerman hospitals in 2017
Authors: Ghaedamini Hossein , Nejad Biglari Habibe , Saghafi Zahra , Hosseininasab Ali , Amirbeigi Ali , Ahmadabadi Farzad , Ghaedamini Amirmahdi 
Published: June 2023

AbstractIntroductionSeizure in children with the prevalence of 4 to 6 cases in 1000 is the most common neurological disorder in pediatrics. This study aimed to determine the causes of seizures in children admitted to Kerman hospitals in 2017Materials and methodsIn this retrospective study, 250 hospitalized children suffering from seizure were selected through census method. Data collection tool was a checklist. The obtained data was analyzed employing SPSS24software, using chi-square, and correlation coefficient statistical tests at the significant level P < 0.05.ResultsOut of 250 children studied, 55.6%were male and 44.4%were female. The mean age of the children was 10.54 ± 3.7 years. 80.4%were born with vaginal delivery and 19.6%were born with cesarean section. 44%of the patients had febrile seizure, 23.2%epilepsy, 12.4%infection, 10%gastroenteritis, 5.2%static encephalopathy, 2.8%meningitis, 1.6%hypocalcaemia, 0.4 %metabolic disorders and 0.4 %tumor. That underlying factors of febrile seizure were upper respiratory infection (43.6%), gastroenteritis (15.7%), shigellosis (10.5%), urinary infection (9.9%), pneumonia (8.1%), unidentified fever (7.8%), otitis (3%) and dental abscess (1.4%) respectively.ConclusionAccording to this study, the most common cause of the seizure is a febrile seizure, which confirms the results of other studies. Common seizure require diagnosis, planning, and special treatments that can be obtained by taking a complete history, accurate examination, and effective Para clinical evaluations.
Crystal structures reveal nucleotide-induced conformational changes in G motifs and distal regions in guanylate-binding protein 2
Authors: Roy Sayantan , Wang Bing , Tian Yuan , Yin Qian 
Published: June 2023

AbstractGuanylate-binding proteins (GBPs) are interferon-inducible GTPases that confer protective immunity against a variety of intracellular pathogens including bacteria, viruses, and protozoan parasites. GBP2 is one of the two highly inducible GBPs, yet the precise mechanisms underlying the activation and regulation of GBP2, in particular the nucleotide-induced conformational changes in GBP2, remain poorly understood. In this study, we elucidate the structural dynamics of GBP2 upon nucleotide binding through crystallographic analysis. GBP2 dimerizes upon GTP hydrolysis and returns to monomer state once GTP is hydrolyzed to GDP. By determining the crystal structures of GBP2 G domain (GBP2GD) in complex with GDP and nucleotide-free full-length GBP2, we unveil distinct conformational states adopted by the nucleotide-binding pocket and distal regions of the protein. Our findings demonstrate that the binding of GDP induces a distinct closed conformation both in the G motifs and the distal regions in the G domain. The conformational changes in the G domain are further transmitted to the C-terminal helical domain, leading to large-scale conformational rearrangements. Through comparative analysis, we identify subtle but critical differences in the nucleotide-bound states of GBP2, providing insights into the molecular basis of its dimer-monomer transition and enzymatic activity. Overall, our study expands the understanding of the nucleotide-induced conformational changes in GBP2, shedding light on the structural dynamics governing its functional versatility. These findings pave the way for future investigations aimed at elucidating the precise molecular mechanisms underlying GBP2’s role in the immune response and may facilitate the development of targeted therapeutic strategies against intracellular pathogens.
Lipid droplets as substrates for protein phase separation
Authors: Kamatar Advika , Bravo Jack P.K. , Yuan Feng , Wang Liping , Lafer Eileen M. , Taylor David W. , Stachowiak Jeanne C. , Parekh Sapun H. 
Published: June 2023

AbstractMembrane-associated protein phase separation plays critical roles in cell biology, driving essential cellular phenomena from immune signaling to membrane traffic. Importantly, by restricting diffusion to a two-dimensional surface, lipid bilayers can nucleate phase separation at far lower concentrations compared to those required for phase separation in solution. How might other intracellular lipid substrates, such as lipid droplets, contribute to nucleation of phase separation? Distinct from bilayer membranes, lipid droplets consist of a phospholipid monolayer surrounding a core of neutral lipids, and they are energy storage organelles that protect cells from lipotoxicity and oxidative stress. Here, we show that intrinsically disordered proteins can undergo phase separation on the surface of synthetic and cell-derived lipid droplets. Specifically, we find that model disordered domains, FUS LC and LAF1-RGG, separate into protein-rich and protein-depleted phases on the surfaces of lipid droplets. Owing to the hydrophobic nature of interactions between FUS LC proteins, increasing ionic strength drives an increase in its phase separation on droplet surfaces. The opposite is true for LAF1-RGG, owing to the electrostatic nature of its interprotein interactions. In both cases, protein-rich phases on the surfaces of synthetic and cell-derived lipid droplets demonstrate molecular mobility indicative of a liquid-like state. Our results show that lipid droplets can nucleate protein condensates, suggesting that protein phase separation could be key in organizing biological processes involving lipid droplets.