bluuebunny/crossref_metadata_2025_split huggingface dataset:
Milo2.0 unlocks population genetic analyses of cell state abundance using a count-based mixed model
Authors: Alice Kluzer , Marioni John C , Morgan Michael D 
Published: November 2023

AbstractCell type proportions vary between individuals and are heritable, as demonstrated by statistical genetic analysis of flow cytometry data [1,2]. Higher-resolution cell states can be identified by single-cell RNA-sequencing, the scalability of which now makes it applicable to population-scale cohorts. However, the integration of statistical genetic analysis of cell states using cohort-scale single-cell data requires appropriate algorithms to account for and model the genetic relationships and complex batch-processing inherent to these studies. We describe Milo2.0, which enables the discovery of cell state quantitative trait loci (csQTL), scaling to millions of cells across hundreds of individuals. We identify > 500 csQTLs across peripheral blood immune states and investigate their relationship with the genetic regulation of gene expression. Moreover, we colocalise immune csQTLs with human traits and identify links between immune regulators, cell state abundance and immune-mediated disease.
Use of Multiple Pharmacodynamic Measures to Deconstruct the Nix-TB Regimen in a Short-Course Murine Model of Tuberculosis
Authors: Lyons M.A. , Obregon-Henao A. , Ramey M.E. , Bauman A.A. , Pauly S. , Rossmassler K. , Reid J. , Karger B. , Walter N.D. , Robertson G.T. 
Published: November 2023

ABSTRACTA major challenge for tuberculosis (TB) drug development is to prioritize promising combination regimens from a large and growing number of possibilities. This includes demonstrating individual drug contributions to the activity of higher-order combinations. A BALB/c mouse TB infection model was used to evaluate the contributions of each drug and pairwise combination in the clinically relevant Nix-TB regimen (bedaquiline-pretomanid-linezolid [BPaL]) during the first three weeks of treatment at human equivalent doses. RS ratio, an exploratory pharmacodynamic (PD) marker of ongoingMycobacterium tuberculosisrRNA synthesis, to-gether with solid culture CFU and liquid culture time to positivity (TTP) were used as PD markers of treatment response in lung tissue; and their time course profiles were mathematically modeled using rate equations with pharmacologically interpretable parameters. Antimicrobial interactions were quantified using Bliss independence and Isserlis formulas. Subadditive (or antagonistic) and additive effects on bacillary load, assessed by CFU and TTP, were found for bedaquiline-pretomanid and linezolid-containing pairs, respectively. In contrast, subadditive and additive effects on rRNA synthesis were found for pretomanid-linezolid and bedaquiline-containing pairs, respectively. Additionally, accurate predictions of the response to BPaL for all three PD markers were made using only the single-drug and pairwise effects together with an assumption of negligible three-way drug interactions. The results represent an experimental and PD modeling approach aimed at reducing combinatorial complexity and improving the cost-effectiveness ofin vivosystems for preclinical TB regimen development.
Unsaturated fatty acid alters the immune response in non-small cell lung adenocarcinoma through regulation of HMGB1 trafficking
Authors: Cole-Skinner Breanna , Andre Nicole M. , Blankenheim Zachary , Root Kate , Simmons Glenn E. 
Published: November 2023

AbstractCancer cell evasion of the immune response is critical to cancer development and metastases. The ability of clinicians to kickstart the immune system to target these rogue cells is an ever-growing area of research and medicine. In this study, we delved into the relationship between lipid metabolism, High Mobility Group Box 1 protein (HMGB1), and immune regulation within non-small cell lung adenocarcinoma (NSCLC), shedding light on novel therapeutic avenues and potential personalized approaches for patients. We found that the expression of stearoyl CoA desaturase 1 (SCD1) was decreased in NSCLC tumors compared to normal tissues. This emphasized the critical role of lipid metabolism in tumor progression. Interestingly, monounsaturated fatty acid (MUFA) availability impacted the expression of programmed death receptor ligand −1 (PD-L1), a pivotal immune checkpoint target in lung cancer cells and immune cells, suggesting a novel approach to modulating the immune response. This study uncovered a complex interplay between HMGB1, SCD1, and PD-L1, influencing the immunological sensitivity of tumors. Our work underscores the importance of understanding the intricate relationships between lipid metabolism and immune modulation to develop more effective NSCLC treatments and personalized therapies. As we continue to explore these connections, we hope to contribute to the ever-evolving field of cancer research, improving patient outcomes and advancing precision medicine in NSCLC.
Covert RNA viruses in medflies differ in their mode of transmission and tissue tropism
Authors: Hernández-Pelegrín Luis , Huditz Hannah-Isadora , García-Castillo Pablo , de Ruijter Norbert C.A. , van Oers Monique M. , Herrero Salvador , Ros Vera I.D. 
Published: November 2023

AbstractNumerous studies have demonstrated the presence of covert viral infections in insects. These infections can be transmitted in insect populations via two main routes: vertical from parents to offspring, or horizontal between nonrelated individuals. Thirteen covert RNA viruses have been described in the Mediterranean fruit fly (medfly). Some of these viruses are established in different laboratory-reared and wild medfly populations, although variations in the viral repertoire and viral levels have been observed at different time points. To better understand these viral dynamics, we characterized the prevalence and levels of covert RNA viruses in two medfly strains, assessed the route of transmission of these viruses, and explored their distribution in medfly adult tissues. Altogether, our results indicated that the different RNA viruses found in medflies vary in their preferred route of transmission. Two iflaviruses and a narnavirus are predominantly transmitted through vertical transmission via the female, while a nodavirus and a nora virus exhibited a preference for horizontal transmission. Overall, our results give valuable insights into the viral tropism and transmission of RNA viruses in the medfly, contributing to the understanding of viral dynamics in insect populations.
Systematic Dissection of Sequence Features Affecting the Binding Specificity of a Pioneer Factor Reveals Binding Synergy Between FOXA1 and AP-1
Authors: Xu Cheng , Kleinschmidt Holly , Yang Jianyu , Leith Erik , Johnson Jenna , Tan Song , Mahony Shaun , Bai Lu 
Published: November 2023

AbstractDespite the unique ability of pioneer transcription factors (PFs) to target nucleosomal sites in closed chromatin, they only bind a small fraction of their genomic motifs. The underlying mechanism of this selectivity is not well understood. Here, we design a high-throughput assay called ChIP-ISO to systematically dissect sequence features affecting the binding specificity of a classic PF, FOXA1. Combining ChIP-ISO within vitroand neural network analyses, we find that 1) FOXA1 binding is strongly affected by co-binding TFs AP-1 and CEBPB, 2) FOXA1 and AP-1 show binding cooperativityin vitro, 3) FOXA1’s binding is determined more by local sequences than chromatin context, including eu-/heterochromatin, and 4) AP-1 is partially responsible for differential binding of FOXA1 in different cell types. Our study presents a framework for elucidating genetic rules underlying PF binding specificity and reveals a mechanism for context-specific regulation of its binding.
Cytoneme-mediated intercellular signaling in keratinocytes essential for epidermal remodeling
Authors: Wang Yi , He Qingan , Has Oliver , Forouzesh Kiarash , Eom Dae Seok 
Published: November 2023

SummaryThe skin, the largest organ, functions as a primary defense mechanism. Epidermal stem cells supply undifferentiated keratinocytes that differentiate as they migrate toward the outermost skin layer. Although such a replenishment process is disrupted in various human skin diseases, its underlying mechanisms remain elusive. With high-resolution live imaging and in vivo manipulations, we revealed that Notch signaling between keratinocytes is mediated by signaling filopodia called cytonemes and is essential for proper keratinocyte differentiation and proliferation. Inhibiting keratinocyte cytonemes reduced Notch expression within undifferentiated keratinocytes, leading to abnormal differentiation and hyperproliferation, resembling human skin disease phenotypes. Overproduction of Interleukin (IL)-17 signal, associated with skin diseases likepsoriasis, induces psoriatic phenotypes via cytonemes in zebrafish. Our study suggests that intercellular signaling between keratinocytes through cytonemes is critical for epidermal maintenance, and its misregulation could be an origin of human skin diseases.
Maternal sterol 27-hydroxylase is crucial for securing fetal development
Authors: Suzuki Mitsuyoshi , Nakano Satoshi , Miharada Natsumi , Takei Hajime , Prabhala Pavan , van der Garde Mark , Müller Catharina , Sigurdsson Valgardur , Aerken Maolake , Saito Kiyoka , Koide Shuhei , Westergren-Thorsson Gunilla , Magnusson Mattias , Kakiyama Genta , Nittono Hiroshi , Miharada Kenichi 
Published: November 2023

SummaryThe maternal body helps in providing nutrients and degrading toxic metabolites instead of the fetal body; disruptions in these mechanisms affect normal fetal development. Sterol 27-hydroxylase (Cyp27a1) is involved in the alternative pathway of bile acid synthesis, which is enhanced during pregnancy. However, its role in fetal development remains unclear. Here, we demonstrate that maternal Cyp27a1 activity is essential for progression of normal pregnancy and fetal organ formation. Depletion of maternalCyp27a1reduced the pregnancy rate and litter size. Newborn mice died of respiratory distress syndrome resulting from the absence of mature alveolar epithelial cells. These phenotypes were caused by 7α-hydroxycholesterol (7α-HC) accumulating inCyp27a1-deficient mice. Mechanistically, 7α-HC destabilized the Fau protein, mediating ribosome assembly, the downregulation of which caused poor polysome formation, lower protein synthesis, and impaired lung maturation. Overall, this study revealed an essential mechanism of securing fetal development by degrading a toxic metabolite in the maternal body.
An extra-genital cell population contributes to urethra closure during mouse penis development
Authors: Amato Ciro Maurizio , Xu Xin , Yao Humphrey Hung-Chang 
Published: November 2023

AbstractHypospadias, or incomplete closure of the urethra along the penis, is the second most common birth defect in the United States. We discovered a population of extra- genital mesenchymal cells that are essential for proper penile urethra closure in mouse embryos. This extra-genital population first appeared in the mesenchyme posterior to the hindlimb of the fetus after the onset of penis formation. These extra-genital cells, which transiently express a lineage markerNr5a1, migrated centrally and colonized the penis bilateral to the urethra epithelium. Removal of theNr5a1+extra-genital cells, using a cell-type specific ablation model, resulted in severe hypospadias. The absence of extra-genital cells had the most significant impacts on another mesenchymal cells, the peri-urethra that were immediately adjacent to theNr5a1+extra-genital cells. Single cell mRNA sequencing revealed that the extra-genital cells extensively interact with the peri-urethra, particularly through Neuregulin 1, an epidermal Growth Factor (EGF) ligand. Disruption of Neuregulin 1 signaling in theex-vivoslice culture system led to failure of urethra closure, recapitulating the phenotypes of extra-genital cell ablation. These results demonstrate that theNr5a1+extra-genital mesenchymal cells from outside of the fetal penis are indispensable for urethra closure through their interaction with the peri-urethra mesenchymal cells. This discovery provides a new entry point to understand the biology of penis formation and potential causes of hypospadias in humans.
Optimized protocols for RNA interference inMacrostomum lignano
Authors: Mouton Stijn , Mougel Alexandra , Ustyantsev Kirill , Dissous Colette , Melnyk Oleg , Berezikov Eugene , Vicogne Jérôme 
Published: November 2023

AbstractMacrostomum lignano, a marine free-living flatworm, has emerged as a potent invertebrate model in developmental biology for studying stem cells, germline, and regeneration processes. In recent years, many tools have been developed to manipulate this worm and to facilitate genetic modification. RNA interference is currently the most accessible and direct technique to investigate gene functions. It is obtained by soaking worms in artificial seawater containing dsRNA targeting the gene of interest. Although easy to perform, the original protocol calls for daily exchange of dsRNA solutions, usually until phenotypes are observed, which is both time- and cost-consuming. In this work, we have evaluated alternative dsRNA delivery techniques, such as electroporation and osmotic shock, to facilitate the experiments with improved time and cost efficiency. During our investigation to optimize RNAi, we demonstrated that, in the absence of diatoms, regular single soaking in artificial seawater containing dsRNA directly produced in bacteria or synthesizedin vitrois, in most cases, sufficient to induce a potent gene knockdown for several days with a single soaking step. Therefore, this new and highly simplified method allows a very significant reduction of dsRNA consumption and lab work. In addition, it enables performing experiments on a larger number of worms at minimal cost.
Analysis of the comparative strengths of intramural and extramural grant funding mechanisms
Authors: Zheng Xiang , Yang Qiyao , Potnuri Jai , Ni Chaoqun , Hutchins B. Ian 
Published: November 2023

AbstractScience funders utilize a variety of funding mechanisms to advance scientific discovery, and the comparative strengths of these approaches are frequently debated. One prominent example is the contrast between extramurally funded research, where grants are awarded to external institutions, and intramurally funded research, where scientists are directly hired by funding agencies. Each mechanism is backed by theoretical justifications. In this context, we quantify the comparative strengths of the National Institutes of Health’s extramural and intramural mechanisms. When adjusted for investment, extramural research excels at producing scholarly outputs such as publications and citations, which are standard metrics in academic assessment. In contrast, intramural research, whether basic or applied, stands out for producing research that influences subsequent clinical studies, aligning with its agency mission. These findings provide evidence that the institutional incentives associated with different funding mechanisms drive their comparative strengths.
MAB-5/Hox regulates the Q neuroblast transcriptome, includingcwn-1/Wnt,to mediate posterior migration inCaenorhabditis elegans
Authors: Paolillo Vitoria K. , Ochs Matthew E. , Lundquist Erik A. 
Published: November 2023

AbstractNeurogenesis involves the precisely-coordinated action of genetic programs controlling large-scale neuronal fate specification down to terminal events of neuronal differentiation. The Q neuroblasts inC. elegans, QL on the left and QR on the right, divide, differentiate, and migrate in a similar pattern to produce three neurons each. However, QL on the left migrates posteriorly, and QR on the right migrates anteriorly. The MAB-5/Hox transcription factor is necessary and sufficient for posterior Q lineage migration, and is normally expressed only in the QL lineage. To define genes controlled by MAB-5 in the Q cells, fluorescence-activated cell sorting was utilized to isolate populations of Q cells at a time in early L1 larvae when MAB-5 first becomes active. Sorted Q cells fromwild-type, mab-5loss-of-function (lof), andmab-5gain-of-function (gof) mutants were subject to RNA-seq and differential expression analysis. Genes enriched in Q cells included those involved in cell division, DNA replication, and DNA repair, consist with the neuroblast stem cell identity of the Q cells at this stage. Genes affected bymab-5included those involved in neurogenesis, neural development, and interaction with the extracellular matrix.cwn-1,which encodes a Wnt signaling molecule, showed a paired response tomab-5in the Q cells:cwn-1expression was reduced inmab-5(lof)and increased inmab-5(gof), suggesting that MAB-5 is required forcwn-1expression in Q cells. MAB-5 is required to prevent anterior migration of the Q lineage while it transcriptionally reprograms the Q lineage for posterior migration. Functional genetic analysis revealed that CWN-1 is required downstream of MAB-5 to inhibit anterior migration of the QL lineage, likely in parallel to EGL-20/Wnt in a non-canonical Wnt pathway. In sum, work here describes a Q cell transcriptome, and a set of genes regulated by MAB-5 in the QL lineage. One of these genes,cwn-1,acts downstream ofmab-5in QL migration, indicating that this gene set includes other genes utilized by MAB-5 to facilitate posterior neuroblast migration.
Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure
Authors: Guirette Mélanie , Lan Jessie , Mckeown Nicola , Brown Michael R , Chen Han , De Vries Paul S , Kim Hyunju , Rebholz Casey M , Morrison Alanna C , Bartz Traci M , Fretts Amanda M , Guo Xiuqing , Lemaitre Rozenn N. , Liu Ching-Ti , Noordam Raymond , de Mutsert Renée , Rosendaal Frits R , Wang Carol A , Beilin Lawrence , Mori Trevor A , Oddy Wendy H , Pennell Craig E , Chai Jin Fang , Whitton Clare , van Dam Rob M , Liu Jianjun , Tai E Shyong , Sim Xueling , Neuhouser Marian L , Kooperberg Charles , Tinker Lesley , Franceschini Nora , Huan TianXiao , Winkler Thomas W , Bentley Amy R , Gauderman W. James , Heerkens Luc , Tanaka Toshiko , Van Rooij Jeroen , Munroe Patricia B , Warren Helen R , Voortman Trudy , Chen Honglei , Rao D.C. , Levy Daniel , Ma Jiantao 
Published: November 2023

AbstractObjectiveWe examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).MethodsWe analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.ResultsWe identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched withcis-expression quantitative trait loci (eQTL) variants (P = 4e-273) andcis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 isMTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for geneST20at 15q25.1.ConclusionWe demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.
UPRER–immunity axis acts as physiological food evaluation system that promotes aversion behavior in sensing low-quality food
Authors: Liu Pengfei , Liu Xinyi , Qi Bin 
Published: November 2023

AbstractTo survive in challenging environments, animals must develop a system to assess food quality and adjust their feeding behavior accordingly. However, the mechanisms that regulate this chronic physiological food evaluation system, which monitors specific nutrients from ingested food and influences food-response behavior, are still not fully understood. Here, we established a low-quality food evaluation assay system and found that heat-killedE. coli(HK-E. coli),a low sugar food, triggers cellular UPRERand immune response. This encourages animals to avoid low-quality food. The physiological system for evaluating low-quality food depends on the UPRER(IRE-1/XBP-1) – Innate immunity (PMK-1/p38 MAPK) axis, particularly its neuronal function, which subsequently regulates feeding behaviors. Moreover, animals can adapt to a low-quality food environment through sugar supplementation, which inhibits the UPRER–PMK-1 regulated stress response by increasing vitamin C biosynthesis. This study reveals the role of the cellular stress response pathway as physiological food evaluation system for assessing nutritional deficiencies in food, thereby enhancing survival in natural environments.
Axonal PLC-γ activity is required for BDNF long-distance signaling
Authors: Moya-Alvarado G , Valero-Peña X , Aguirre-Soto A , Bronfman FC 
Published: November 2023

ABSTRACTBrain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase receptor B (TrkB) are important signaling proteins that regulate dendritic growth and maintenance in the central nervous system (CNS). After binding of BDNF, TrkB is endocytosed into endosomes and continues signaling within the cell soma, dendrites, and axon. We showed that BDNF signaling initiated in axons triggers long-distance signaling, inducing dendritic arborization in a CREB-dependent manner in cell bodies, processes that depend on axonal dynein and TrkB activities. The binding of BDNF to TrkB triggers the activation of different signaling pathways, including the ERK1/2, PLC-γ and PI3K-mTOR pathways, to induce dendritic growth and synaptic plasticity. How TrkB downstream pathways regulate long-distance signaling is unclear. Here, we studied the role of PLC-γ-Ca2+in BDNF/TrkB-induced long-distance signaling using compartmentalized microfluidic cultures. We found that dendritic branching and CREB phosphorylation induced by axonal BDNF stimulation require the activation of PLC-γ in the axons of cortical neurons. Locally on axons, BDNF increases PLC-γ phosphorylation and induces intracellular Ca2+waves in a PLC-γ-dependent manner. Moreover, the transport of BDNF-containing signaling endosomes to the cell body was dependent on PLC-γ activity and intracellular Ca2+stores. Furthermore, the activity of PLC-γ is required for BDNF-dependent TrkB endocytosis, suggesting a role for the TrkB/PLC-γ signaling pathway in axonal signaling endosome generation.