bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined phylogenetic and geographic data can predict plant-pest interactions with high accuracy
Authors: Hernández-Gutiérrez Elvira , Nichols Richard A. , Kelly Laura J. 
Published: November 2024

SummaryBiological invasions are a major threat to biodiversity, often having destructive ecological and economic consequences. It is therefore essential to concentrate the limited resources available on managing the most serious risks. We build a robust Bayesian model to predict host species at risk fromAgrilus, a genus of plant-feeding beetles that includes one of the world’s most destructive tree pests. The model uses the interplay of phylogenetic and geographic distance between known and potential hosts to estimate the probability of newAgrilus-host interactions. We assess the risk these beetles pose toQuercusspecies (oaks), their most common host, and find that our model can assign the status of known hosts with an accuracy of 83.6% in leave-one-out analyses. We employ this model to identify oak species at risk fromAgrilus,providing data to inform more targeted efforts to prevent novelAgrilusintroductions. Our model correctly identifies recently acquired novel hosts ofAgrilusspecies that have invaded new areas, providing further evidence of its ability to accurately predict future potential interactions. Our approach makes use of readily available phylogenetic and geographic occurrence data and could be widely implemented to assess other potential invasive species, and help to prioritise counter measures against different threats worldwide.
NuclampFISH enables cell sorting based on nuclear RNA expression for chromatin analysis
Authors: Liu Yifang , Qiu Yuchen , Nian Keqing , Rouhanifard Sara H. 
Published: November 2024

AbstractTranscriptional bursts refer to periods when RNA polymerase interacts with a DNA locus, leading to active gene transcription. This bursting activity can vary across individual cells, and analyzing the differences in transcription sites can help identify key drivers of gene expression for a specific target. Scaffolding methods based on fluorescence in situ hybridization (FISH) have been widely used to amplify the fluorescent signal of mRNAs and sort cells based on mRNA expression levels. However, these methods are inefficient at targeting nuclear RNA, including transcription sites, due to the probes’ limited accessibility through cellular compartment membranes and crosslinked proteins. Additionally, the required formaldehyde fixation interferes with downstream analysis of chromatin and protein-binding interactions. To address these challenges, a platform that integrates amplified FISH with reversible crosslinkers and allows access to the nucleus is needed. In response, we developed nuclear clampFISH (nuclampFISH). This method amplifies the fluorescent signal of mRNAs using a reversible crosslinker, enabling the sorting of cells based on nuclear RNA expression and compatible with downstream biochemical analysis. This assay demonstrates that transcriptionally active cells have more accessible chromatin for a respective gene. Notably, the tools developed are highly accessible and do not require specialized computation or equipment.
Investigating Short-Chain Fatty Acids Effects on Extracellular Vesicles Production in Colorectal Cancer
Authors: Macedo D. , Abalde-Cela S. , Diéguez L. , Preto A. , Honrado C. 
Published: November 2024

AbstractColorectal cancer (CRC) is the third most diagnosed and the second leading cause of cancer-related deaths globally, often due to late detection and limited treatment options. Recent studies have linked alterations in gut microbiota to CRC, particularly emphasizing the role of short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate in shaping the tumor microenvironment (TME). SCFAs contribute to CRC pathogenesis by inducing lysosomal membrane permeabilization, cell cycle arrest, and apoptosis in cancer cells. Extracellular vesicles (EVs) are membrane-bound vesicles that facilitate intercellular communication and have gained attention as promising non-invasive biomarkers for cancer diagnosis and treatment monitoring. EVs participate in cellular response mechanisms to external stimuli by transferring proteins, lipids, and nucleic acids between cells, thus modulating target cell behavior and promoting coordinated responses to stress and environmental challenges. This process is essential for cellular adaptation and plays a significant role in pathophysiological processes, including tumor progression and immune modulation, making EVs highly relevant in clinical research. This study examined the impact of SCFAs on EV production and phenotype in CRC cells. The results indicated a notable increase in EV-sized particles following SCFA treatment of colorectal cell lines, particularly in the SW480 CRC cell line. For CRC cell lines, while co-precipitated protein levels remained stable, there was a slight decrease in cellular DNA and an increase in EV-associated DNA. KRAS-mutant SW480 cells exhibited the most pronounced response, emphasizing their heightened sensitivity to SCFA. Notably, microsatellite instability - a key biomarker for immunotherapy in CRC - was detected in both small and large EV populations from BRAF-mutant RKO cells after SCFA treatment, even at low DNA concentrations. These findings underscore the potential of EVs for non-invasive detection of molecular markers, paving the way for further exploration of their role in precision oncology.Abstract FigureGraphical Abstract.Effects of SCFA on EV production and characteristics in CRC cells. Treatment with SCFA led to a significant increase in the number of EV-sized particles, a decrease in cellular DNA and a corresponding increase in EV-DNA. This study also identified MSI in both s-EV and L-EV, even following SCFA treatment and at low DNA concentrations. Created using BioRender.
Unveiling a unique macrophage population in exocrine glands sustained by ILC2-derived GM-CSF
Authors: Westermann Frederike , Tuzlak Selma , Kreiner Victor , Bejarano David , Bijnen Mitchell , Cecconi Virginia , van Hove Hannah , Wang Haiting , Litscher Gioana , Ignacio Aline , Lindemann Rachel , Oberbichler Laura , DeFeo Donatella , Liu Zhaoyuan , Kipar Anja , McCoy Kathy , Nixon Iain , Bain Calum C , Schneider Christoph , Tugues Sonia , Greter Melanie , Ginhoux Florent , Schlitzer Andreas , Emmerson Elaine , Becher Burkhard 
Published: November 2024

SummaryGranulocyte-macrophage colony-stimulating factor (GM-CSF) has a non-redundant role in the emergence and maintenance of alveolar macrophages (AMs). However, its role in developmental and steady-state myelopoiesis outside the lung is largely unexplored.Scanning through developing tissues using a Fate-map and reporter of GM-CSF mouse strain, we discovered that GM-CSF was produced by type 2 innate lymphoid cells (ILC2s) in the submandibular and sublingual salivary gland (SG) during postnatal development. GM-CSF producing ILC2s foster the development of a hitherto undescribed phagocyte subset, which we named adenophages. Detailed analysis focusing on phenotypic and transcriptional profiling revealed that adenophages display shared aspects of both, macrophages and dendritic cells (DCs). We found them to be homogenously distributed across the SG, but always in close proximity to GM-CSF producing ILC2s and myoepithelial cells. Importantly, adenophages were present throughout all analyzed exocrine glands such as lacrimal glands and mammary glands, and were also identified in human SG sections, indicating a conserved role in exocrine glands across species.
Identification of molecular and functional subtypes using chronic pancreatitis patient-derived organoid models
Authors: Osorio-Vasquez Victoria , Lumibao Jan C. , Peck Kristina L. , Lande Kathryn , Zhu Jonathan , Stamp McKenna , Okhovat Shira R. , Song Hyemin , Ogawa Satoshi , Hsu Jasper , Dai Yang , Rock Angelica , Bottomley Chelsea , Thomas Ethan , Fowler Alexandra , McGriff T’Onj , Larsen Siri , Abdulla Muhamad , Greer Phil , Gibson Jessica , Downes Michael , Evans Ronald , Zou Jingjing , Lowy Andrew M. , Whitcomb David C. , White Rebekah , Bellin Melena , Tiriac Herve , Engle Dannielle D. 
Published: November 2024

AbstractBackground and AimsChronic pancreatitis (CP) affects more than 200,000 Americans and 1 million individuals world wide, but treatment generally focuses on supportive care like pain management. 28-80% of CP cases are idiopathic and 10-15% are hereditary with mutations in PRSS1, SPINK1, CFTR, and other genes. Developing human models of pancreatitis to understand the drivers of the disease and targeting key players in this disease will provide novel therapeutic approaches for these patients who have limited options.MethodsUtilizing patient samples from surgical resections or TPIAT procedures we have generated a first-of-its-kind human CP patient derived organoid (PDO) biobank. This biobank is representative of hereditary mutations found across patients, includes idiopathic cases, and histologically recapitulates features of this disease. Genetic concordance was determined between PDO and primary specimens using whole genome sequencing. RNAseq and cytokine analysis was conducted on PDO to determine inflammatory features of this model. Forskolin induced swelling assays were conducted to determine the function of CFTR in PDO models.ResultsThere is a 98% concordance between PDO and primary tissue specimens showing the recapitulation of patient genotypes in our model. RNA-seq revealed that CP organoids are transcriptionally distinct from normal pancreas organoids and identified three distinct subtypes of CP that are driven by transcriptional features. Utilizing the PDO model, we identified a high prevalence of ductal CFTR dysfunction, which could be restored using a combination of CFTR correctors and potentiators.ConclusionsThere are three subtypes of CP that require further study to employ targeted therapeutics against these drivers. hCP PDO are a model that can be used to assess CFTR function and correction providing evidence for these drugs to be used in CP patients.
Structural basis of pseudoGTPase-mediated protein-protein interactions
Authors: Wang Bing , Yang Rui , Wan Chun , Tian Yuan , Wu Jingyi , Roy Sayantan , Li Suzhao , Shen Jingshi , Yin Qian 
Published: November 2024

AbstractGTPases regulate various cellular processes through conformational changes triggered by GTP or GDP binding. Recently, pseudoGTPases, the catalytically inactive counterparts of GTPases, have been identified across species from bacteria to human, although their functions and mechanisms remain unexplored. In this study, we demonstrate that the N-terminal region of the assembly chaperone AAGAB is a type i pseudoGTPase using biochemistry and X-ray crystallography. Furthermore, we discovered that the AAGAB pseudoGTPase domain (psGD) interacts with the σ subunits of AP1 and AP2 adaptor complexes, heterotetrameric complexes involved in clathrin-mediated membrane trafficking. AAGAB psGD engages the σ subunits via a unique interface distinct from the conventional GTPase interacting regions. Further biochemical and cell-based assays confirmed the crucial role of the newly identified interface in binding and membrane trafficking. Collectively, our results establish AAGAB pseudoGTPase domain as a critical protein-protein interaction module. These findings offer new insight into the structural basis and molecular mechanisms of pseudoGTPases.HighlightsAAGAB N-terminal region is a pseudoGTPaseAAGAB pseudoGTPase domain interacts with and stabilizes AP1 and AP2 σ subunitsThe crystal structure of AAGAB psGD:AP1σ3 is the first reported psGD complex structure, revealing a unique interface independent of guanine nucleotide regulationThe psGD:AP1σ3 structure offers mechanistic insights into σ subunits stabilization and protection through adaptor complex assembly
Regulation of heterosis-associated gene expression complementation in maize hybrids
Authors: Pitz Marion , Baldauf Jutta , Piepho Hans-Peter , Yu Peng , Schoof Heiko , Mason Annaliese S. , Li Guoliang , Hochholdinger Frank 
Published: November 2024

AbstractThe dominance model of heterosis explains the superiority of F1-hybrids via the complementation of unfavorable by beneficial alleles in many genes. Consistent with this model, genes active in only one parent and the hybrid display single-parent expression (SPE) complementation. Here we demonstrated, that SPE can explain up to 29% of heterotic variance in maize (Zea maysL.). Moreover, expression quantitative trait loci (eQTL) revealed, that the genotype of the active parent determines the regulation mode of SPE patterns incisortrans, which might explain how phylogenetic distance translates to transcriptomic diversity and heterosis in hybrids. Furthermore, we showed that most eQTL are located in heterozygous regions of the genome and that atranseQTL controls the activity of a SPE gene which regulates lateral root density in hybrids. We anticipate that our study will stimulate further research elucidating the regulation and molecular mechanisms underlying heterosis.
Gene Therapy with the N-terminal Fragment of Nav1.5 for Cardiac Channelopathies: A Novel Transcomplementation Mechanism Potentiating the Cardiac Sodium Current
Authors: Gizon Marie , Ferrand Marine C. , Fontaine Vincent , Mougenot Nathalie , Laporte Pierre-Léo , Gaborit Nathalie , Extramiana Fabrice , Baró Isabelle , Guicheney Pascale , Charpentier Flavien , Doisne Nicolas , Neyroud Nathalie 
Published: November 2024

ABSTRACTBACKGROUNDCardiac channelopathies, caused by mutations in ion-channel genes, can lead to sudden cardiac death (SCD)viaventricular arrhythmias. Brugada syndrome (BrS) is a rare inherited channelopathy characterized by a unique ECG pattern and a high incidence of ventricular fibrillation leading to SCD in the absence of structural heart defects. The main gene responsible for 20-25% of BrS cases isSCN5A, encoding the cardiac sodium channel α-subunit Nav1.5, which carries the sodium current (INa) responsible for the rapid depolarization phase of the action potential (AP). While current treatments do not target the genetic cause of channelopathies, this study explores the therapeutic potential of overexpressing the N-terminal region of Nav1.5 (Nter) to restore electrical activity by rescuingINa, in the context ofSCN5Adeficiency.METHODSWe overexpressed the Nter peptide using viral vectors inScn5a+/-mice, in CRISPR/Cas9 edited-SCN5A+/-cardiomyocytes derived from induced-pluripotent stem cells (iPSC-CMs) and in BrS patient iPSC-CMs. We assessed molecular and functional effects of Nter overexpressionin vitroandin vivoby measuring Nav1.5 subcellular expression and electrophysiological activity and by recording ECGs and arrhythmias.RESULTSWhereasScn5a+/-mice showed an impairedINaassociated with a slowed-cardiac conduction characteristic of the BrS phenotype, cardiac-specific overexpression of Nter corrected AP parameters by restoringINadensity inScn5a+/-mouse cardiomyocytes. This increase inINadensity was caused by a translocation of Nav1.5 to the cell membrane in Nter-overexpressing mice. Most importantly, Nter overexpression normalized atrioventricular and ventricular conduction and protectedScn5a+/-mice from arrhythmias triggered by programmed electrical stimulation. Similarly, Nter overexpression inSCN5A+/-human iPSC-CMs led to a 2-fold increase in Nav1.5 cell-surface expression, resulting in normalization ofINaand AP parameters and abolition of early after depolarizations observed during spontaneous AP recordings. Similar results were obtained in iPSC-CMs derived from a BrS patient, confirming the potential of this therapy in human models.CONCLUSIONSThis study identified a novel therapeutic peptide effective in restoring cardiac excitability in animal and cellular models of BrS, paving the way for future development of therapies for life-threatening arrhythmias in patients withSCN5Adeficiency.
Crosstalk Between Drought-Induced ROS Regulation and Resistance to Xanthomonas oryzae Infection in Rice Plants
Authors: Ramu Dhruv , Reddy B. R. Brahmesh , Sheshshayee M. S. , Kumar M. K. Prasanna 
Published: November 2024

AbstractThis study investigates the resilience of two genotypes ofOryza sativa(rice) with varying levels of tolerance to drought stress, focusing on their production of reactive oxygen species (ROS) and chlorophyll retention when exposed to Xanthomonas oryzae infection. A total of 36 high ATT (AC 39000) and low ATT (BPT5204) plants were subjected to three drought treatments: 100% field capacity (control), gradual drought (reduction to 50% field capacity over 10 days), and rapid drought (immediate reduction to 50%). ROS production was quantified using Evans Blue staining and thiobarbituric acid reactive substances (TBARS) assays, while chlorophyll content was measured using the Arnon method. Membrane damage was higher in the control and rapid stress groups (971 and 1053 ng respectively) compared to gradual drought stress (848.5 ng) on day 12. High-tolerance genotypes demonstrated superior ROS regulation under gradual drought conditions, with the Evans Blue content exceeding that of low-tolerance genotypes by 13 ng. Similarly, chlorophyll retention was significantly higher (p = 0.0005) in high tolerance genotypes (1.166 mg · g−1FW) compared to low tolerance genotypes (0.966 mg · g−1FW). The results indicate that gradual drought stress increases resilience to bacterial infection through enhanced ROS-scavenging mechanisms, which is accentuated in the High ATT genotype, allowing for the development of dual resistant rice varieties capable of withstanding both abiotic and biotic stresses.
BTS: scalable Bayesian Tissue Score for prioritizing GWAS variants and their functional contexts across omics data
Authors: Kuksa Pavel P. , Ionita Matei , Carter Luke , Cifello Jeffrey , Clark Kaylyn , Valladares Otto , Leung Yuk Yee , Wang Li-San 
Published: November 2024

AbstractMotivationSummary statistics from genome-wide association studies (GWAS) are widely used in fine-mapping and colocalization analyses to identify causal variants and their enrichment in functional contexts, such as affected cell types and genomic features. With the expansion of functional genomic (FG) datasets, which now include hundreds of thousands of tracks across various cell and tissue types, it is critical to establish scalable algorithms integrating thousands of diverse FG annotations with GWAS results.ResultsWe propose BTS (Bayesian Tissue Score), a novel, highly efficient algorithm uniquely designed for 1) identifying affected cell types and functional elements (context-mapping) and 2) fine-mapping potentially causal variants in a context-specific manner using large collections of cell type-specific FG annotation tracks. BTS leverages GWAS summary statistics and annotation-specific Bayesian models to analyze genome-wide annotation tracks, including enhancers, open chromatin, and histone marks. We evaluated BTS on GWAS summary statistics for immune and cardiovascular traits, such as Inflammatory Bowel Disease (IBD), Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), and Coronary Artery Disease (CAD). Our results demonstrate that BTS is over100xmore efficient in estimating functional annotation effects and context-specific variant fine-mapping compared to existing methods. Importantly, this large-scale Bayesian approach prioritizes both known and novel annotations, cell types, genomic regions, and variants and provides valuable biological insights into the functional contexts of these diseases.Availability and implementationDocker image is available athttps://hub.docker.com/r/wanglab/btswith pre-installed BTS R package (https://bitbucket.org/wanglab-upenn/BTS-R) and BTS GWAS summary statistics analysis pipeline (https://bitbucket.org/wanglab-upenn/bts-pipeline).
Lifespan in rodents with MYT1L heterozygous mutation
Authors: Schreiber Allyson , Swift Raylynn G. , Wilson Leslie , Kroll Kristen L. , Dougherty Joseph D. , Maloney Susan E. 
Published: November 2024

AbstractMYT1L syndrome is a newly recognized disorder characterized by intellectual disability, speech and motor delay, neuroendocrine disruptions, ADHD, and autism. In order to study this gene and its association with these phenotypes, our lab recently created aMyt1lheterozygous mutant mouse inspired by a clinically relevant mutation. This model recapitulates several of the physical and neurologic abnormalities seen in humans with MYT1L syndrome, such as weight gain, microcephaly, and behavioral disruptions. The majority of patients with this syndrome are young, and little is known about the impact of age on health and mortality in these patients. Using aMyt1lmutant mouse, we examined the impact ofMyt1lmutation on body weights, lifespan, and histopathology findings of mice at the end of life. This cohort of heterozygous mice demonstrated increased body weight across the lifespan, however there was no significant difference in lifespan, apparent cause of death, or end of life histopathological findings betweenMyt1lheterozygous and wildtype mice. These findings suggest whileMyt1lheterozygous mutation may influence overall brain development, it does not strongly impact other organ systems in the body over time.
PlacentalhIGF1nanoparticle gene therapy in guinea pigs ameliorates fetal growth restriction-associated changes in hepatic lipid and glucose metabolism-related signaling pathways in a fetal sex-specific manner
Authors: Davenport Baylea N , Williams Alyssa , Regnault Timothy RH , Jones Helen N , Wilson Rebecca L 
Published: November 2024

ABSTRACTFetal development in an adverse in utero environment significantly increases the risk of developing metabolic diseases in later life, including dyslipidemia, non-alcoholic fatty liver diseases and diabetes. The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate fetal growth restriction (FGR)-associated dysregulation of fetal hepatic lipid and glucose metabolism-related signaling pathways. Using the guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, placenta efficiency was significantly improved following three administrations of a non-viral polymer-based nanoparticle gene therapy to the placenta from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression ofhuman insulin-like growth factor 1(hIGF1) in placenta trophoblast. Fetal liver tissue was collected near-term at gestational day 60. Fetal sex specific differences in liver gene and protein expression of pro-fibrosis and glucose metabolism-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placentalhIGF1nanoparticle treatment. Increased plasma bilirubin, and indirect measure of hepatic activity, was also increased with placentalhIGF1nanoparticle treatment. We speculate that the changes in liver gene and protein expression and increased liver activity that result in similar expression profiles to appropriately growing Control fetuses might confer protection against increased susceptibility to aberrant liver physiology in later-life. Overall, this work opens avenues for future research assessing the translational prospect of mitigating FGR-induced metabolic derangements.NEW AND NOTEWORTHYA placenta-specific non-viral polymer-based nanoparticle gene therapy that improves placenta nutrient transport and near-term fetal weight ameliorates growth restriction-associated changes to fetal liver activity, and cholesterol and glucose/nutrient homeostasis genes/proteins that might confer protection against increased susceptibility to aberrant liver physiology in later-life. This knowledge may have implications towards removing predispositions that increase the risk of metabolic diseases including diabetes, dyslipidemia and non-alcoholic fatty liver disease in later life.