bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alpha-synuclein knockout impairs melanoma development and alters DNA damage repair in the TG3 mouse model in a sex-dependent manner
Authors: Arnold Moriah R. , Chen Suzie , Unni Vivek K. 
Published: December 2024

ABSTRACTStrong evidence suggests links between Parkinson’s Disease (PD) and melanoma, as studies have found that people with PD are at an increased risk of developing melanoma and those with melanoma are at increased risk of developing PD. Although these clinical associations are well-established, the cellular and molecular pathways linking these diseases are poorly understood. Recent studies have found a previously unrecognized role for the neurodegeneration-associated protein alpha-synuclein (αSyn) in melanoma; the overexpression of αSyn promotes melanoma cell proliferation and metastasis. However, to our knowledge, no studies have investigated the role of αSyn inin vivomelanoma models outside of a xenograft paradigm. Our study created and characterizedSncaknockout in the spontaneously developing melanoma TG3 mouse line, TG3+/+Snca-/-. We show that αSyn loss-of-function significantly delays melanoma onset and slows tumor growthin vivo. Furthermore, decreased tumor volume is correlated with a decreased DNA damage signature and increased apoptotic markers, indicating a role for αSyn in modulating the DNA damage response (DDR) pathway. Overall, our study provides evidence that targeting αSyn and its role in modulating the DDR and melanomagenesis could serve as a promising new therapeutic target.
Marine medaka responds differently to dioxin compared with its close freshwater relative, the Japanese medaka: the AHR molecular mechanism
Authors: Zhang Wanglong , Zong Yanjiao , Sun Ruize , Xue Zhenhong , Wan Wenhui , Ren Anran , Ma Yongchao , Tian Wenjing , Wang Renjun 
Published: December 2024

AbstractThe global water pollution now calls for precise risk assessment of chemicals, e.g., dioxins and the emerging dioxin-like compounds (DLCs). The freshwater and marine medaka have been widely implemented in the toxicity testing, and perhaps give mechanistic information for comparative biology. The question that ‘will they report equal results due to their close phylogenetic relation’ has been raised, therefore, we explored their physiological and molecular responses to dioxin. As the mediator of the dioxin toxicity, the aryl hydrocarbon receptor (AHR) of marine medaka (Oryzias melastigma) has not been functionally characterized and might be species-specific. In terms of sensitivity to dioxin—2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the EC50values of omeAHR1a (0.16±0.12 nM), omeAHR1b (2.96±2.96 nM), omeAHR2a (0.44±0.30 nM), and omeAHR2b (9.00±6.88 nM) exhibit marked variations. The omeAHR2a and omeAHR1a display heightened sensitivity compared to the freshwater Japanese medaka (Oryzias latipes) counterparts olaAHR2a and olaAHR1a, respectively. The results indicate the in vitro sensitivity of AHR among species can vary by one or two orders of magnitude. Physiologically, the marine medaka (LC50: 1.64 ng/L (95% CI: 1.05-2.55 ng/L)) also exhibits a pronounced sensitivity to TCDD than Japanese medaka (LC50: 3.42 ng/L (95% CI: 1.37-6.48 ng/L), aligning with the in vitro AHR sensitivity. Further mechanistic investigations using additional ligands and computational modeling reveal that: 1) most of omeAHR2a, olaAHR2a, dreAHR2, and hsaAHR interact with ligands in the affinity order of TCDD > PCB126 > BNF > indole, mirroring their AHR transactivation potency, but the docking poses and dynamics can vary; 2) one AHR subform’s high sensitivity to dioxin—TCDD may extend to DLCs but not to other types of ligands. These insights underscore the difference of AHR biology among species even the close relative species, and finger out the necessity for meticulous consideration when evaluating the toxicity of compounds and when extending predictive toxicity assessments to more species.
Ultra-early hematoma expansion is associated with ongoing hematoma growth and poor functional outcome
Authors: Mutimer Chloe A. , Wu Teddy Y. , Zhao Henry , Churilov Leonid , Campbell Bruce C.V. , Cheung Andrew , Meretoja Atte , Kleinig Timothy J. , Choi Philip M. , Ma Henry , Cloud Geoffrey C. , Grimley Rohan , Shah Darshan , Ranta Annemarei , Mahawish Karim , Yogendrakumar Vignan , Sharma Gagan , Donnan Geoffrey A. , Davis Stephen M. , Yassi Nawaf 
Published: December 2024

AbstractINTRODUCTIONThere are limited data on ultra-early hematoma growth dynamics and their clinical impact in primary intracerebral hemorrhage (ICH). We aimed to (a) estimate the incidence of hematoma expansion within the hyperacute period of ICH, (b) describe hematoma dynamics over time, (c) investigate the associations between ultra-early hematoma expansion and clinical outcomes after ICH, and (d) assess the effect of tranexamic acid on ultra-early hematoma expansion.METHODSWe performed a planned secondary analysis of the STOP-MSU international multicenter randomized controlled trial. The trial compared tranexamic acid with placebo in 201 patients with primary ICH presenting within 2 hours of symptom onset. Repeat CT imaging ∼1 hour after treatment commencement was encouraged.Patients who underwent re-imaging up to 3 hours from baseline imaging were included in this descriptive study. Hematoma expansion was defined as either a ≥33% or ≥6 ml increase from baseline hematoma volume.RESULTSWe included 105 of the 201 patients who had 1-hour imaging (median age 66 years, 40% female, 53% tranexamic acid). Median time from onset to baseline imaging was 74min (IQR 56-87 min), and between baseline and 1-hour imaging was 95 min (IQR 74-132 min). Forty-one patients (39%) had ultra-early hematoma expansion. These patients had larger baseline hematoma volumes (15.9 ml vs 9.1 ml, p=0.03) compared to those with no early hematoma expansion.Hematoma growth rate declined over time compared to the onset-to-baseline imaging period (clustered median regression p<0.01). In 92 patients with both 1-hour and 24-hour re-imaging, 9/31 (29%) of those with ultra-early hematoma expansion had further expansion between the 1-hour and 24-hour scan, compared to only 4/61(6.6%) without ultra-early expansion (p<0.01). Of those 61 patients, there were 10 (16.4%) who fulfilled the expansion definition by 24 hours.Ultra-early hematoma expansion was associated with poor functional outcomes (mRS 3-6; aOR 3.87 [1.21-12.40], p=0.02) and mortality (aOR 6.16 [95% CI 2.15-17.68], p<0.01), adjusted for treatment group.There was no observed effect of tranexamic acid treatment on ultra-early hematoma expansion (41% vs. 37%, p=0.65).CONCLUSIONSMost hematoma growth occurs in the ultra-early period. The presence of hyperacute hematoma expansion is associated with ongoing hematoma growth, poor functional outcomes and mortality, and represents a target for therapeutic intervention.
Yo-yo dieting deregulates feeding behavior in mice via the induction of durable gut dysbiosis
Authors: Fouesnard Mélanie , Salin Adélie , Ribes Sandy , Monnoye Magali , Champeil-Potokar Gaëlle , Hjeij Marie-Sabelle , Randuineau Gwénaëlle , Gleau Léa Le , Fradj Selma Ben , Philippe Catherine , Benani Alexandre , Denis Isabelle , Douard Véronique , Boudry Gaëlle 
Published: December 2024

AbstractBackground & AimsAlternating periods of excessive and restrained eating results in weight cycling, a known risk factor for eating behavior dysregulation such as binge eating. Diet alternation also induces changes in intestinal microbiota composition. We tested the hypothesis that recurrent diet alternation alters hedonic feeding regulation by changing either or both intestinal microbiota and brain homeostasis in mouse.MethodsC57BL/6 mice underwent 3 cycles of 1 week of western diet (WD, 45% kcal from fat) separated by 2 weeks of chow diet (CYCL group) or staid under chow diet (CTRL group). Food intake was monitored after each dietary change. Striatum, hypothalamus, brainstem and caecal content were collected before the third WD introduction in CYCL mice and in CTRL mice. Microbiota transfer from CYCL or CTRL mice into naive recipient mice was performed to investigate whether gut microbiota per se could explain differences in eating behavior during weight cycling.ResultsDiet alternation in CYCL mice resulted in weight cycling, with enhanced weight gain upon each WD feeding phase. CYCL mice increased their energy intake specifically during the first hours following WD re-introduction, reminiscent of binge-eating episodes. Expression of reward-related genes in the striatum and thickness of the astro-glial barrier in the brain stem were enhanced in CYCL compared to CTRL mice. Diet alternation also induced caecal dysbiosis in CYCL mice. Gut microbiota transfer from CYCL mice to naive recipient mice recapitulated the altered eating behavior upon WD exposure.ConclusionsAlternation between high-energy and standard diet durably remodels the gut microbiota and the brain towards a profile associated with an increase in hedonic appetite. Using gut microbiota transfer, we established that this microbiota signature affects hedonic feeding regulation. These results open the ways to microbiota-targeted strategies to prevent development of eating disorders in weight cycling patients.
Cytokine Dynamics and Oxidative Stress in Host Cells Stimulated with Drug-Resistant and SensitiveMycobacterium tuberculosisIsolates
Authors: Kumar Kavitha , Giribhattanavar Prashant , Sagar B. K. Chandrasekhar , Patil Shripad A. 
Published: December 2024

AbstractBackgroundThe immune response toMycobacterium tuberculosis(M. tuberculosis) is central to the pathogenesis of tuberculosis (TB), yet the immune dynamics induced by drug-resistant strains remain underexplored. Understanding the host’s immune response to both drug-sensitive and drug-resistantM. tuberculosisisolates is crucial for elucidating the mechanisms of pathogenesis and resistance. This study aims to assess the cellular immune responses, including PBMC proliferation, cytokine secretion (IL-4 and IL-17a), and reactive oxygen species (ROS) production in response to live drug-sensitive and drug-resistantM. tuberculosisclinical isolates.MethodsPeripheral blood mononuclear cells (PBMCs) from PPD-negative and PPD-positive healthy volunteers were stimulated with liveM. tuberculosisisolates, including MDR, SI-resistant, and sensitive strains. The immune responses were assessed by evaluating cell proliferation, secretion of IL-4 and IL-17a cytokines, and ROS production over a 9-day period.ResultsPBMCs from PPD-positive individuals exhibited a higher proliferative response compared to PPD-negative individuals, indicating more robust immune memory. IL-4 secretion was low but varied among samples, with higher levels observed in response to MDR isolates, suggesting a potential role in immunopathology. IL-17a levels increased over time, particularly in PPD-positive individuals, and MDR strains elicited a stronger response than sensitive isolates. ROS production was significantly elevated in response to resistant strains, reflecting the host’s oxidative defense mechanisms.ConclusionThis study demonstrates distinct immune responses to drug-resistantM. tuberculosisisolates, with variations in cell proliferation, cytokine secretion, and ROS production. These findings provide insights into the immune dynamics during infection with resistant strains and underscore the importance of genotype-environment interactions in TB pathogenesis.Graphical Abstract
Uncovering Genes Essential in Domestication and Breeding of Sugar Beet
Authors: Dhiman Amar Singh , Emrani Nazgol , Holtgrewe-Stukenbrock Eva , Varrelmann Mark , Jung Christian 
Published: December 2024

AbstractThe genusBetaencompasses economically important root crops such as sugar and table beet. ABetadiversity set including the wild relativeB. vulgarisssp.maritimawas grown in the field, and a large phenotypic diversity was observed. The genomes of 290 accessions were sequenced, and more than 10 million high-quality SNPs were employed to study genetic diversity. A genome-wide association study was performed, and marker-trait associations were found for nine phenotypic traits. The candidate gene within theMlocus controlling monogermity on chromosome 4 was previously unknown. The most significant association for monogermity was identified at the end of chromosome 4. Within this region, a non-synonymous mutation within the Zinc-Finger domain of theWIP2gene co-segregated with monogermity. This gene plays a regulatory role inAGL8/FULin Arabidopsis. Intriguingly, commercial hybrids are in a heterozygous state at this position. Thus, the long-sought gene for monogermity was identified in this study. Red and yellow pigmentation due to betalain accumulation in shoots and roots is an important characteristic of table and leaf beets. The strongest associations were found upstream or downstream of two genes encoding Cytochrome P450 and anthocyanin MYB-like transcription factor proteins involved in betalain biosynthesis. Significant associations forCercosporaleaf spot resistance were identified on chromosomes 1, 2, 7, and 9. The associated regions harbor genes encoding proteins with leucine-rich repeats and nucleotide binding sites whose homologs are major constituents of plant-pathogen defense.
ERGA-BGE Reference Genome ofGluvia dorsalis: An Endemic Sun Spider from Iberian Arid Regions
Authors: Lozano-Fernandez Jesus , Domènech Marc , Ibos Attila , Marcussen Thomas , Struck Torsten H. , Oomen Rebekah , Böhne Astrid , Monteiro Rita , Aguilera Laura , Gut Marta , Câmara Ferreira Francisco , Cruz Fernando , Gómez-Garrido Jèssica , Alioto Tyler S. , De Panis Diego 
Published: December 2024

AbstractThe reference genome ofGluvia dorsalisis the first of its order Solifugae (sun spiders), offering insights into adaptations to arid environments and the evolutionary history of arachnids. The entirety of the genome sequence was assembled into 5 contiguous chromosomal pseudomolecules. This chromosome-level assembly encompasses 787 Mb, composed of 51 contigs and 10 scaffolds (including the mitogenome), with contig and scaffold N50 values of 38 Mb and 199 Mb, respectively.
Opposing lineage specifiers induce a pro-tumor hybrid-identity state in lung adenocarcinoma
Authors: Fort Gabriela , Arnold Henry , Camolotto Soledad , Tariq Rushmeen , Waters Anna , O’Toole Kayla , Snyder Eric L. 
Published: December 2024

ABSTRACTThe ability of cancer cells to alter their identity, known as lineage plasticity, is crucial for tumor progression and therapy resistance. In lung adenocarcinoma (LUAD), tumor progression is characterized by a gradual loss of lineage fidelity and the emergence of non-pulmonary identity programs. This can lead to hybrid-identity (hybrid-ID) states in which developmentally incompatible identity programs are co-activated within individual cells. However, the molecular mechanisms underlying these identity shifts remain incompletely understood. Here, we identify the gastrointestinal (GI) transcriptional regulator HNF4α as a critical driver of tumor growth and proliferation in KRAS-driven LUAD. In LUAD cells that express the lung lineage specifier NKX2-1, HNF4α can induce a GI/liver-like state by directly binding and activating its canonical targets. HNF4α also forms an aberrant protein complex with NKX2-1, which disrupts NKX2-1 localization and dampens pulmonary identity within hybrid-ID LUAD. Sustained signaling through the RAS/MEK pathway is critical for maintaining the hybrid-ID state. Moreover, RAS/MEK inhibition augments NKX2-1 chromatin binding at pulmonary-specific genes and induces resistance-associated pulmonary signatures. Finally, we demonstrate that HNF4α depletion enhances sensitivity to pharmacologic KRASG12Dinhibition. Collectively, our data show that co-expression of opposing lineage specifiers leads to a hybrid identity state that can drive tumor progression and dictate response to targeted therapy in LUAD.
HAPLODIPLOIDY ACCELERATES MITOGENOME EVOLUTION IN INSECTS
Authors: Pakrashi Avas , Hebert Paul DN 
Published: December 2024

AbstractRates of mitogenome evolution differ among animal lineages, variation which has been linked to life history, ecological traits, and potentially to breeding system. Insects are a good model for examining the latter impacts as, although most are diplodiploids (DD), some lineages reproduce by haplodiploidy (HD) or thelytoky. In this study, we ask if breeding system influences patterns of evolution in the mitogenome using the 658 bp barcode region of the cytochromecoxidase I (COI) gene as a sentinel. Specifically, we ask if the incidence of amino acid substitutions and indels is linked to breeding system. We investigated this matter by examining COI sequences from specimens assigned to 1332 BINs, a species proxy. Belonging to 513 families and 26 orders, these BINs included representatives of roughly half of all insect families. Most are DD, but ten lineages, varying in rank from tribe to order, are HD. Our analysis reveals that HD lineages show higher rates of amino acid substitution than DD. In addition, indels are frequent in HD lineages but are absent in DD taxa with one exception. Among DD, the Strepsiptera is an outlier; its COI shows very rapid amino acid evolution and frequent indels. The accelerated rates of mitogenome evolution in HD lineages suggest that this breeding system facilitates coevolution between the nuclear and mitochondrial genomes.
Prediabetes Phenotype Clusters in the Diabetes Prevention Program Study
Authors: Stroebel Benjamin M. , Gadgil Meghana , Lewis Kimberly , Longoria Kayla , Zhang Li , Flowers Elena 
Published: December 2024

ABSTRACTObjectiveThe purpose of this study was to apply clustering methods to identify and characterize prediabetes phenotypes and their relationships with treatment arm and type 2 diabetes (T2D) outcomes in the Diabetes Prevention Program (DPP), and to compare the utility of additional clustering measures in phenotype characterization and T2D risk stratification.Research Design and MethodsThis was a secondary analysis of data from a subset of participants (n=994) from the previously completed Diabetes Prevention Program trial. Unsupervised k-means clustering analysis was applied to derive the optimal number of clusters of participants based on common clinical risk factors alone or common risk factors plus more comprehensive measures of glucose tolerance and body composition.ResultsFive clusters were derived from common clinical characteristics and the addition of comprehensive measures of glucose tolerance and body composition. Within each modeling approach, participants show significantly different levels of risk factors. The clinical only model showed higher accuracy for time to T2D, however the more comprehensive models further differentiated a metabolically health overweight phenotype. For both models, the greatest differentiation in determining time to T2D was in the metformin arm of the trial.ConclusionsData driven clustering of patients with prediabetes allows for identification of prediabetes phenotypes at greater risk for disease progression and responses to risk reduction interventions. Further investigation into phenotypic differences in treatment response could enable better personalization of prediabetes and T2D prevention and treatment choices.
Unraveling the Phenotype of Dormant Metastases Controlled by the Immune System
Authors: Chamorro Virginia , Algarra Ignacio , Sanz Verónica , Pulido María , Romero Irene , Chico Estefanía , Millán Marina , Escaño-Maestre María , Linares Isabel , García-Lora Ángel M. 
Published: December 2024

AbstractDuring the progression of cancer, metastatic cells frequently enter a dormant phase. The immune system plays a crucial role by restricting the growth of dormant metastases, although it cannot eradicate them. In our laboratory, we developed a preclinical mouse model of metastatic dormancy. Dormant spontaneous metastases are controlled by the immune system of wild-type mice. Depletion of the host immune system causes these metastases to awaken and progress. The elucidation of the phenotype, genes, miRNAs and immune cells involved in the phenomenon of metastatic dormancy may prove in the development of effective strategies for combating metastatic disease. Dormant Metastases are compared with Nude Metastases and Overt Metastases that have never been in dormancy. The findings of the study indicate that the dormant metastases exhibit a unique and differentiated phenotype. This is evidenced by their varied response to nutrient-restrictive conditions, chemotherapeutic agents, and cytokinesin vitro. Additionally, dormant metastases display a unique pattern of gene and miRNA expression. The microenvironment of dormant metastases shows an increase in certain immune cell subpopulations. Immune-controlled dormant metastases exhibit a unique phenotype that can be exploited to discover new biomarkers, as well as to develop therapies to eradicate them or control overt metastases.
Human-immune-system humanized-DRAGA mice are a valuable model to study novel immunotherapies for HIV-1
Authors: Pumtang-on Pongthorn , Goodarzi Negin , Davey Brianna C , Sevcik Emily N , Coleman-Fuller Natalie , Vezys Vaiva , Rao Mangala , Pampusch Mary S , Rendahl Aaron K , Casares Sofia A , Skinner Pamela J 
Published: December 2024

AbstractHumanized (h)DRAGA mice are a promisingin vivomodel for investigating immunotherapies for treating HIV infections. These mice are not only susceptible to HIV infection, but they also develop functional human immune cells, including T cells and B cells as well as follicular-like structures that mimic lymphoid B cell follicles, where HIV-producing cells concentrate during infection in a manner similar to that found in humans. This study evaluated the safety, tissue targeting, and efficacy of follicular-targeting HIV-specific chimeric antigen receptor (CAR)-T cells (CAR/CXCR5-T cells) in HIV-infected hDRAGA mice. Intravenously-infused CAR/CXCR5-T cells persisted in hDRAGA mice for the duration of the study, peaking six days post-infusion. This study indicated that CAR/CXCR5-T cell treatment is safe, with 100% survival rate of treated mice and no noticeable changes in pathology. Six days after infusion, CAR/CXCR5-T cells had accumulated in the follicle-like structures, with many appearing in direct contact with HIV-producing cells. However, CAR/CXCR5-T cell treatment did not appear to reduce viral loads compared to controls, perhaps because many of the engineered CAR/CXCR5-T cells were themselves infected with HIV, with some CAR/CXCR5-T cells showing evidence of HIV virion release. Future studies will investigate whether CAR/CXCR5-T cells engineered for resistance against HIV infection are effective in reducing viral loads. This study supports the approach of using the HIV-infected hDRAGA mouse model to test cellular immunotherapies for HIV, as the model recapitulates many aspects of HIV infection in human lymphoid follicles.