bluuebunny/crossref_metadata_2025_split huggingface dataset:
LAIR1 prevents excess inflammatory tissue damage inS. aureusskin infection and Cutaneous T-cell Lymphoma
Authors: Dorando Hannah K. , Mutic Evan C. , Tomaszewski Kelly L. , Tian Ling , Stefanov Mellisa K. , Quinn Chaz C. , Veis Deborah J. , Wardenburg Juliane Bubeck , Musiek Amy C. , Mehta-Shah Neha , Payton Jacqueline E. 
Published: June 2024

ABSTRACTPatients with cutaneous T cell lymphoma (CTCL) experience high morbidity and mortality due toS. aureusskin infections and sepsis, but the causative immune defect is unclear. We previously identified high levels of LAIR2, a decoy protein for the inhibitory receptor LAIR1, in advanced CTCL. Mice do not have a LAIR2 homolog, so we usedLair1knock-out (KO) mice to model LAIR2 overexpression. In a model of subcutaneousS. aureusskin infection,Lair1KO mice had significantly larger abscesses and areas of dermonecrosis compared to WT.Lair1KO exhibited a pattern of increased inflammatory responses in infection and sterile immune stimulation, including increased production of proinflammatory cytokines and myeloid chemokines, neutrophil ROS, and collagen/ECM remodeling pathways. Notably,Lair1KO infected skin had a similar bacterial burden and neutrophils and monocytes had equivalentS. aureusphagocytosis compared to WT. These findings support a model in which lack of LAIR1 signaling causes an excessive inflammatory response that does not improve infection control. CTCL skin lesions harbored similar patterns of increased expression in cytokine and collagen/ECM remodeling pathways, suggesting that high levels of LAIR2 in CTCL recapitulatesLair1KO, causing inflammatory tissue damage and compromising host defense againstS. aureusinfection.
NLSDeconv: an efficient cell-type deconvolution method for spatial transcriptomics data
Authors: Chen Yunlu , Ruan Feng , Wang Ji-Ping 
Published: June 2024

AbstractSummarySpatial transcriptomics (ST) allows gene expression profiling within intact tissue samples but lacks single-cell resolution. This necessitates computational deconvolution methods to estimate the contributions of distinct cell types. This paper introduces NLSDeconv, a novel cell-type deconvolution method based on non-negative least squares, along with an accompanying Python package. Benchmarking against 18 existing deconvolution methods on various ST datasets demonstrates NLSDeconv’s competitive statistical performance and superior computational efficiency.Availability and implementationNLSDeconv is freely available with tutorial athttps://github.com/tinachentc/NLSDeconvas a Python package.
THE CELLS ARE ALL-RIGHT: Regulation of theLeftygenes by separate enhancers in mouse embryonic stem cells
Authors: Taylor Tiegh , Zhu Hongyu Vicky , Moorthy Sakthi D. , Khader Nawrah , Mitchell Jennifer A. 
Published: June 2024

ABSTRACTEnhancers play a critical role in regulating precise gene expression patterns essential for development and cellular identity; however, how gene-enhancer specificity is encoded within the genome is not clearly defined. To investigate how this specificity arises within topologically associated domains (TAD), we performed allele-specific genome editing of sequences surrounding theLefty1andLefty2paralogs in mouse embryonic stem cells. TheLeftygenes arose from a tandem duplication event and these genes interact with each other in chromosome conformation capture assays which place these genes within the same TAD. Despite their physical proximity, we demonstrate that these genes are primarily regulated by separate enhancer elements. Through CRISPR-Cas9 mediated deletions to remove the intervening chromatin between theLeftygenes, we reveal a distance-dependent dosage effect of theLefty2enhancer onLefty1expression. These findings indicate a potential role for both discrete CTCF bound regions of the genome and chromatin distance in insulating gene expression domains in theLeftylocus in the absence of architectural insulation.
Advancing source tracking: systematic review and source-specific genome database curation of fecally shed prokaryotes
Authors: Lindner Blake G. , Choudhury Rakin A. , Pinamang Princess , Bingham Lilia , D’Amico Isabelle , Hatt Janet K. , Konstantinidis Konstantinos T. , Graham Katherine E. 
Published: June 2024

AbstractApproaches for shotgun metagenomic sequencing are being adapted to many environmental monitoring tasks but remain poorly suited for source attribution within fecal source tracking (FST) studies due to a lack of knowledge regarding the source specificity of fecally shed microbial populations. To address this gap, we performed a systematic literature review and curated a large collection of genomes (n=26,018) representing fecally shed prokaryotic species across broad and narrow source categories commonly implicated in FST studies of recreational waters (i.e., cats, dogs, cows, seagulls, chickens, pigs, birds, ruminants, human feces, and wastewater). These data include genome sequences recovered from metagenomic and isolation-based studies which we examined extensively with comparative genomic approaches to characterize trends across source categories and produce a finalized genome database for each source category which is available online (n=12,730). We find that across these sources, the total number of genomes recovered varies substantially: from none in seagulls to 9,085 in pigs.According to available data, on average 81% of the genomes representing species-level populations occur only within a single source. Using fecal slurries to test the performance of each source database, we report read capture rates that vary with fecal source alpha diversity and database size. Lastly, while extensive work has been performed on the rumen system of cows and other ruminants, we note the scarcity of genomic characterization of prokaryotes in the feces of these animals. We expect this resource to be useful to FST-related objectives, One Health research, and sanitation efforts globally.Table of Contents Graphical AbstractSynopsisWe curate nine prokaryotic genomic databases for fecal source-tracking, summarize their source-specificity, and show their usefulness by bioinformatically testing mock impaired surface water samples.
Cancer Cachexia in STK11/LKB1-mutated NSCLC is Dependent on Tumor-secreted GDF15
Authors: Yu Jinhai , Guo Tong , Gupta Arun , Llano Ernesto M. , Wajahat Naureen , Slater Sean , Deng Qing , Akbay Esra A. , Shelton John M. , Evers Bret M. , Wu Zhidan , Tzameli Iphigenia , Pashos Evanthia , Minna John D. , Iyengar Puneeth , Infante Rodney E. 
Published: June 2024

ABSTRACTCachexia is a wasting syndrome comprised of adipose, muscle, and weight loss observed in cancer patients. Tumor loss-of-function mutations inSTK11/LKB1, a regulator of the energy sensor AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are associated with cancer-related weight loss in NSCLC patients. Here we characterized the relevance of the NSCLC-associated cachexia factor growth differentiation factor 15 (GDF15) in several patient-derived and genetically engineeredSTK11/LKB1-mutant NSCLC cachexia lines. Both tumor mRNA expression and serum concentrations of tumor-derived GDF15 were significantly elevated in multiple mice transplanted with patient-derivedSTK11/LKB1-mutated NSCLC lines. GDF15 neutralizing antibody administered to mice transplanted with patient- or mouse-derivedSTK11/LKB1-mutated NSCLC lines suppressed cachexia-associated adipose loss, muscle atrophy, and changes in body weight. The silencing ofGDF15in multiple human NSCLC lines was also sufficient to eliminatein vivocirculating GDF15 levels and abrogate cachexia induction, suggesting that tumor and not host tissues represent a key source of GDF15 production in these cancer models. Finally, reconstitution of wild-typeSTK11/LKB1in a humanSTK11/LKB1loss-of-function NSCLC line that normally induces cachexiain vivocorrelated with the absence of tumor-secreted GDF15 and rescue from the cachexia phenotype. The current data provide evidence for tumor-secreted GDF15 as a conduit and a therapeutic target through which NSCLCs withSTK11/LKB1loss-of-function mutations promote cachexia-associated wasting.
Social influences complement environmental cues to stimulate migrating juvenile salmon
Authors: Kururvilla Maria , Quinn Thomas P. , Anderson Joseph H. , Scheuerell Mark D. , Miller Erika M. , Berger Andrew G. , Okasaki Connie , McMillan John R. , Pess George R. , Westley Peter A.H. , Berdahl Andrew M. 
Published: June 2024

AbstractBackgroundThe large-scale seasonal migrations undertaken by many species require complex navigational and timing decisions. Animals migrating in groups might benefit from collective decision making, especially if the environment is noisy (i.e., has high degree of local variation rather than smooth gradients in, for example, salinity or temperature), unpredictable, or the migrants cannot rely on individually acquired information. We focus on juvenile salmon whose migration from fresh water to the ocean is timed to match suitable conditions for growth and survival. While the environmental and physiological factors that influence the timing of migration have been well studied, the influence of social interactions on migration timing is poorly understood.MethodWe compiled juvenile salmon data, collected at trap over 19 years, during their downstream seaward migration in three rivers in Washington state along with a suite of relevant environmental time series. We developed state space statistical models to estimate the influence of hatchery-produced salmon to stimulate the downstream migration of wild salmon, while also incorporating potential environmental stimuli.ResultsOur results are consistent with the “pied-piper” hypothesis that large numbers of migrating hatchery-origin salmon provide a social cue stimulating migration of co-occurring wild salmon. The number of hatchery salmon counted at the trap was a strong predictor of the number of wild sub-yearling Chinook salmon in the Dungeness and Puyallup rivers and on yearling coho salmon in the Puyallup and Skagit rivers. Migration timing was also influenced by a suite of physical factors related to temperature, river flow, photoperiod, and lunar phase.ConclusionsOur findings highlight the potential for social cues to affect migration timing of downstream migrating salmon, in concert with environmental factors. Incorporating social information into timing decisions may allow animals to benefit from collective decision making strategies and better time their migrations. Moreover, understanding the effects of large-scale hatchery releases on wild salmon migration may provide valuable insights for planning the timing and duration of hatchery releases.
Chromosome-scaleSalvia hispanicaL. (Chia) genome assembly reveals rampantSalviainterspecies introgression
Authors: Brose Julia , Hamilton John P. , Schlecht Nicholas , Zhao Dongyan , Mejía-Ponce Paulina M. , Pérez Arely Cruz , Vaillancourt Brieanne , Wood Joshua C. , Edger Patrick P. , Montes-Hernandez Salvador , Orozco de Rosas Guillermo , Hamberger Björn , Jaramillo Angélica Cibrian , Buell C. Robin 
Published: June 2024

ABSTRACTSalvia hispanicaL. (Chia), a member of the Lamiaceae, is an economically important crop in Mesoamerica, with health benefits associated with its seed fatty acid composition. Chia varieties are distinguished based on seed color including mixed white and black (Chia pinta) and black (Chia negra). To facilitate research on Chia and expand on comparative analyses within the Lamiaceae, we generated a chromosome-scale assembly of a Chia pinta accession and performed comparative genome analyses with a previously published Chia negra genome assembly. The Chia pinta and negra genome sequences were highly similar as shown by a limited number of single nucleotide polymorphisms and extensive shared orthologous gene membership. There is an enrichment of terpene synthases in the Chia pinta genome relative to the Chia negra genome. We sequenced and analyzed the genomes of 20 Chia accessions with differing seed color and geographic origin revealing population structure withinS. hispanicaand interspecific introgressions ofSalviaspecies. As the genusSalviais polyphyletic, its evolutionary history remains unclear. Using large-scale synteny analysis within the Lamiaceae and orthologous group membership, we resolved the phylogeny ofSalviaspecies. This study and its collective resources further our understanding of genomic diversity in this food crop and the extent of inter-species hybridizations inSalvia.PLAIN LANGUAGE SUMMARYChia pinta is an economically important crop due to the high fatty acid present in the seeds. There are multiple types of Chia based on the seeds color including mixed which and black (Chia pinta), black (Chia negra), and white (Chia blanca). We generated a genome assembly of Chia pinta and compared it to existing genome assemblies. While the assemblies are highly similar there are key differences in terpene synthase composition between Chia pinta and Chia negra. We also sequenced 20 other Chia accessions with different seed color and geographic origin to determine a population structure within Chia. We generated genomic resources to further our understanding of this food crop.ABBREVIATIONSBGC Biosynthetic gene clusterBUSCO Benchmarking Universal Single Copy Orthologs GO Gene ontologySNP Single nucleotide polymorphism TIR Terminal inverted repeatTPS Terpene synthaseWGS Whole genome shotgun
The C-terminal regulatory domain of IPMS enzyme maintains leucine homeostasis by bypassing a hidden negative feedback loop in plants
Authors: Varghese Mohan , Kumar Roshan , Sharma Aprajita , Lone Asif , Gershenzon Jonathan , Bisht Naveen C 
Published: June 2024

AbstractIn the leucine biosynthesis pathway, homeostasis is achieved through a feedback regulatory mechanism facilitated by binding of the end-product Leu at the C-terminal regulatory domain of the first committed enzyme, isopropylmalate synthase (IPMS).In-vitrostudies showed that removal of the regulatory domain abolishes the feedback regulation on plant IPMS while retaining its catalytic activity. However, the physiological consequences and underlying molecular regulation upon removal of the IPMS C-terminal domain on the Leu flux have not been previously explored in plants. Here, we show that in the absence of its regulatory domain, an unexpected alternative regulatory loop acts to control plant IPMS catalysis. Removal of IPMS regulatory domain using CRISPR/Cas9 significantly reduced the formation of end-product Leuin-planta, but increased the levels of Leu pathway intermediates. Additionally, delayed growth was observed when IPMS devoid of regulatory domain was introduced intoIPMS-null mutants of E.coliandArabidopsis. Combining the metabolomic and biochemical analysis, we found that the Leu pathway intermediate, α-ketoisocaproate, was a competitive inhibitor of IPMS with a truncated regulatory domain. Thus, we demonstrate that the C-terminal regulatory domain of IPMS is biologically favored since it maintains Leu homeostasis while bypassing the possibility of competitive inhibition by a pathway intermediate.SignificanceTill date it was known that the limited profile of essential amino acid-leucine in plants, is majorly due to the feedback inhibition of its pathway enzyme, IPMS, by the binding of accumulating leucine at its regulatory domain. So, can we increase the leucine pool in plants by removing the IPMS regulatory domain? Herein we show that, the targeted removal of this domain under native condition had led to low leucine pool and compromised growth phenotype but observed an accumulation in the leucine pathway intermediates. We uncover a hidden function of the IPMS regulatory domain to avoid an intermediate inhibition on IPMS activity, which could limit the end-product. The study brings an unknown regulatory checkpoint in maintaining leucine homeostasis in plants.
Non-destructive viability assessment of cancer cell spheroids using dynamic optical coherence tomography with trypan blue validation
Authors: Tan Ko Hui , Ang Joel Lang Yi , Yong Alexander Si Kai , Lim Stefanie Zi En , Kng Jessica Sze Jia , Liang Kaicheng 
Published: June 2024

Abstract3D cell cultures are widely used in biomedical research for the recapitulation ofin vivomicroenvironments. Viability assessment and monitoring of these intricate conformations remain an open problem as standard cell viability protocols based on colorimetry or microscopy are not directly applicable to intact 3D samples. Optical coherence tomography (OCT) has been explored extensively for subsurface structural and quasi-functional analysis of 3D cell cultures and tissue. Recent studies of dynamic OCT as a source of cellular contrast have found qualitative associations with necrosis in cell spheroids, suggesting potential as a viability marker. We present empirical and validated evidence for dynamic OCT as a quantitative indicator of cell viability in 3D cultures. We analysed over 240 MCF-7 cancer cell spheroids with dynamic OCT and corresponding viability measurements using the trypan blue exclusion assay. Significant effects of common reagents Dimethyl sulfoxide (DMSO) and Phosphate-Buffered Saline (PBS) on OCT readouts were noted. We proposed a regression-based OCT brightness normalisation technique that removed reagent-induced OCT intensity biases and helped improve correspondence to the viability assay. These results offer a quantitative biological foundation for further advances of dynamic OCT as a novel non-invasive modality for 3D culture monitoring.
GSEA and co-expression network approach to identify molecular processes affected in Porto-sinusoidal Vascular Disease
Authors: Iyer Aishwarya , Kutmon Martina , Evelo Chris T. , Doornbos Cenna , Ehrhart Friederike 
Published: June 2024

AbstractBackground & AimsPorto-sinusoidal vascular disease (PSVD) is a complex rare liver disease characterized by the absence of cirrhosis with or without the presence of portal hypertension or histological lesions. Given the knowledge gaps in the mechanisms involved in this disease with unknown etiology, we used omics-based approaches to further elucidate the pathways affected in PSVD thereby facilitating an improvement in the prognosis, diagnosis, and treatment options for these patients.MethodsFor this study we used a microarray dataset (GEO:GSE77627) of 11 histologically normal liver biopsies and 18 PSVD liver biopsies. First approach, differential gene expression analysis was performed and next gene set enrichment analysis was used to identify enriched biological pathways. A network-based approach of weighted gene coexpression analysis was implemented to identify modules of interconnected genes related to the diagnosis of the patients. We further studied the pathways enriched in these modules to allow identification of processes explaining the mechanisms involved in PSVD, while the gene network could also be used to understand the connections between the processes.ResultsGene set enrichment of differentially expressed genes indicated an increase in signaling and cell-cycle related processes and a decrease in metabolism-related processes. Coexpression network and module analysis further validated these results by elucidating connections between GPCR signaling, energy metabolism and cell-migration related processes. Furthermore, an additional connection between fibrin clot formation processes, inflammation and immune response and cell cycle and respiration processes was identified.ConclusionSignaling and metabolism-related processes are deregulated in PSVD patients. Furthermore, two triangular connections (GPCR signaling-energy metabolism-cell migration and fibrin-clot formation-inflammation and immune response - cell -cycle and respiration) revealed unique unknown connections involved in PSVD etiology.Impact and implicationsPSVD is a complex rare liver disease with significant knowledge gaps in the understanding of the mechanisms and pathways affected at the molecular level. In this study, we use publicly available transcriptomics data and bioinformatics tools to elucidate pathways affected in PSVD patients. In this study, we found potential novel relations between pathways with the two triangular connections (GPCR signaling-energy metabolism-cell migration and fibrin-clot formation-inflammation and immune response - cell -cycle and respiration). These newfound connections between pathways might shed light on the etiology of this disease and help researchers develop effective diagnosis and prognosis for patients suffering from PSVD.
Tumor microenvironment acidosis favors pancreatic cancer stem cell properties andin vivometastasis
Authors: Rolver Michala G. , Roda Juan C. , Dai Yifan , Flinck Mette , Ialchina Renata , Hindkær Julie , Dyhr Rigmor T. , Bodilsen August N. , Prasad Nanditha S. , Baldan Jonathan , Yao Jiayi , Sandelin Albin , Arnes Luis , Pedersen Stine F. 
Published: June 2024

AbstractThe acidic tumor microenvironment favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether acidic environments select for cancer stem cell (CSC) properties. Bulk RNA-seq of Panc-1 human pancreatic cancer cells adapted to extracellular pH 6.5 revealed upregulation of CSC markers including CD44, EpCam, Nestin and aldehyde dehydrogenases, and CSC pathway enrichment. We therefore assessed CSC characteristics of acid-adapted (AA) and non-adapted (Ctrl) PaTu8988s and MiaPaca-2 pancreatic cancer cells. Compared to Ctrl, AA cells exhibited increased ALDH- and β-catenin activity and pancreatosphere-forming efficiency, classical CSC characteristics. Panc-1, PaTu8988s and MiaPaCa-2 AA cells differed in CSC marker expression, and AA cells did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing identified the acid adaptation-induced emergence of a population with clear CSC characteristics. Finally, in an orthotopic mouse model, AA Panc-1 cells drove strongly increased aggressiveness and liver metastasis compared to Ctrl cells.We conclude that acid-adaptation of pancreatic cancer cells leads to enrichment of a CSC phenotype with unusual traits, providing new insight into how acidic tumor microenvironments favor cancer aggressiveness.
Sphingomyelins in mosquito saliva modify the host lipidome to enhance transmission of flaviviruses by promoting viral protein levels
Authors: Medkour Hacène , Pruvost Lauryne , Miot Elliott , Gong Xiaoqian , Vaissayre Virginie , Boutinaud Pascal , Revel Justine , Hitakarun Atitaya , Sornjai Wannapa , Zoladek Jim , Smith R. Duncan , Nisole Sébastien , Nolte-‘t Hoen Esther , Bertrand-Michel Justine , Missé Dorothée , Marti Guillaume , Pompon Julien 
Published: June 2024

AbstractMosquito saliva plays a determining role in flavivirus transmission. Here, we discover and elucidate how salivary lipids enhance transmission. Building upon our discovery of salivary extracellular vesicles (EV), we determined that lipids within mosquito EVs, and neither within human EVs nor virions, enhance infection for flaviviruses in primary cell types relevant for transmission. Mechanistically, mosquito EV-lipids specifically promote viral protein levels by reducing ER-associated degradation. Infection enhancement is caused by sphingomyelins within mosquito salivary EVs that elevate sphingomyelin concentration within host cells. Transmission assays showed that mosquito EV-lipids exacerbate disease severity. Our study reveals that EV-associated sphingomyelins within mosquito saliva enhance transmission for multiple flaviviruses by reconfiguring the host lipidome to promote viral protein levels and the resulting skin infection. Our findings open a new dimension centered on lipids in the interplay between hosts, mosquitoes and flaviviruses that determine transmission, unveiling lipids as a new pan-flavivirus target.HighlightsLipids within mosquito extracellular vesicles (EVs) enhance infection in primary skin and immune cells for multiple flaviviruses.Mosquito EV-lipids increase flaviviral protein levels by dampening ER-associated degradation.Sphingomyelins within salivary EVs are responsible for the infection enhancement by altering host lipidome.Co-injection of mosquito EV-lipids exacerbate disease severity.