bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post-translational Modification of α-Synuclein Modifies Monomer Dynamics and Aggregation Kinetics
Authors: Gamage Kasun , Wang Binyou , Hard Eldon R , Van Thong , Galesic Ana , Phillips George R , Pratt Matthew , Lapidus Lisa J. 
Published: May 2024

AbstractThe intrinsically disordered protein α-Synuclein is identified as a major toxic aggregate in Parkinson’s as well as several other neurodegenerative diseases. Recent work on this protein has focused on the effects of posttranslational modifications on aggregation kinetics. Among these, O-GlcNAcylation of α-Synuclein has been observed to inhibit the aggregation propensity of the protein. Here we investigate the monomer dynamics of two O-GlcNAcylated α-Synucleins, α-Syn(gT72) and α-Syn(gS87) and correlate them with the aggregation kinetics. We find that, compared to the unmodified protein, glycosylation at T72 makes the protein less compact and more diffusive while glycosylation at S87 makes the protein more compact and less diffusive. Based on a model of the earliest steps in aggregation, we predict that T72 should aggregate slower than unmodified protein, which is confirmed by ThT fluorescence measurements. In contrast, S87 should aggregate faster, which is not mirrored in ThT kinetics of later fibril formation but does not rule out a higher rate of formation of small oligomers. Together, these results show that posttranslational modifications do not uniformly affect aggregation propensity.
Persistent effects of repeated adolescent and adult heroin vapor inhalation in female Wistar rats
Authors: Gutierrez Arnold , Taffe Michael A. 
Published: May 2024

AbstractAdolescent drug exposure has been associated with more severe mental health outcomes related to substance abuse and anxiety disorders. The aim of the present study was to contrast the long-term effects of repeated heroin vapor inhalation during adolescence with similar heroin exposure in adulthood. Groups of female Wistar rats underwent twice daily 30-minute sessions of heroin or propylene glycol (control) vapor inhalation from postnatal days (PND) 36-45 or PND 85-94, respectively. Nociception was assessed after vapor inhalation sessions and forty days later, for the Adolescent-Exposed and Adult-Exposed groups. Anxiety-like behavior was assessed with an elevated plus-maze (EPM) and spatial learning was assessed with a Barnes maze. Acute effects of naloxone (0.3 mg/kg, i.p.) and heroin (0.5 and 1.0 mg/kg, s.c.) on thermal nociception were determined on PND 140/189 and PND 149/198, respectively. Repeated heroin vapor inhalation produced anti-nociceptive tolerance across sessions in both adolescent and adult rats, with the adolescents exhibiting more complete tolerance. Heroin vapor inhalation produced anxiolytic effects, regardless of age of exposure. There were no effects of heroin on spatial learning. Naloxone produced acute hyperalgesia in all but the Adolescent-Exposed heroin group, and heroin anti-nociception was blunted in both heroin-exposed groups at the highest heroin dose. Repeated heroin vapor inhalation can produce lasting effects on nociception and anxiety-like behavior that persist for months after the exposure. Importantly, these findings suggest that adolescent exposure to heroin vapor produces specific effects on nociception that are not observed when exposure occurs in adulthood.
Digital Profiling of Tumor Extracellular Vesicle-associated RNAs Directly from Unprocessed Blood Plasma
Authors: Clarissa Elizabeth Maria , Kumar Sumit , Park Juhee , Karmacharya Mamata , Oh In-Jae , Kim Mi-Hyun , Ryu Jeong-Seon , Cho Yoon-Kyoung 
Published: May 2024

ABSTRACTTumor-derived extracellular vesicle (tEV)-associated RNAs hold promise as diagnostic biomarkers, but their clinical use is hindered by the rarity of tEVs among non-tumor EVs. Here, we present EV-CLIP, a highly sensitive droplet-based digital method for profiling EV RNA. EV-CLIP utilizes the fusion of EVs with charged liposomes (CLIPs) in a microfluidic chip. Optimized CLIP surface charge enables exceptional sensitivity and selectivity for EV-derived miRNAs and mRNAs. This approach streamlines detection with minimal plasma volume (20 µL) and eliminates the need for prior EV isolation or RNA preparation, preventing loss of EVs or RNA. In testing with 83 patient samples, EV-CLIP detected EGFR L858R and T790M mutations with high AUC values of 1.0000 and 0.9784, respectively. Its success in serial monitoring during chemotherapy highlights its potential for precise quantification of rare EV subpopulations, facilitating the exploration of single EV RNA content and enhancing understanding of diverse EV populations in various disease states.SUMMARYEV-CLIP: A highly sensitive digital method for tumor-derived EV RNA detection using undiluted blood plasma samples, promising for precise tumor management.
Exosomal miRNA-124 is involved in the immune regulation of cervical cancer by regulating CD45 alternative splicing
Authors: Liang Minxing , Yi Man , Yuan Yuyang , Chen Chengyi , Wang Qiyu , Lan Bo , Yang Jun , Li Xin , Yin Yue 
Published: May 2024

AbstractObjectiveTo investigate the regulatory mechanism of miRNA-124 in tumor immune regulation of cervical cancer.MethodsPeripheral blood samples of cervical cancer patients and transient infection controls were collected to extract exosomal miR-124 and Stem-loop Q-PCR to detect the expression level of miR-124. QPCR, WB, and flow cytometry were used to detect the mRNA and protein expression of Th cell differentiation and function-related genes. Transfection, QPCR, and flow cytometry were used to detect the effects of miR-124 overexpression and silencing on the differentiation of Th immune memory cells. In vitro, cell-killing experiments were performed to detect the tumor-killing activity of TH immune memory cells co-cultured with the Hela cell line, and the downstream target genes of miR-124 were predicted and verified by luciferase. Multiplex PCR was used to detect the genotype of miR-124 SNP in peripheral blood DNA. QPCR and WB were used to detect the mRNA and protein expression and phosphorylation of miR-124 target gene GSK3-PSF-CD45 pathway, and GSK3 inhibitor was used to block the pathway.ResultsWe found that exosomal miRNA-124 was significantly downregulated in cervical cancer tissues and affected Th cell immune function and memory cell generation. The overexpression of miRNA-124 can directly target GSK3, phosphorylate the target gene, and inhibit the expression of GSK3, thereby increasing the expression of CD45, increasing the ability of Th immune cells to recognize and kill the HPV virus, and significantly inhibiting the proliferation and migration of cervical cancer cells.
A systematic review of laboratory investigations into the pathogenesis of avian influenza viruses in wild avifauna of North America
Authors: Gonnerman Matthew , Leyson Christina , Sullivan Jeffery D. , Pantin-Jackwood Mary J. , Spackman Erica , Mullinax Jennifer M. , Prosser Diann J. 
Published: May 2024

ABSTRACTThe lack of consolidated information regarding wild bird species’ response to avian influenza virus (AIV) infection is a challenge for conservation managers, researchers, and related sectors such as public health and commercial poultry. Such information could be used to model complex disease dynamics within communities, prioritize species for surveillance and conservation efforts, or identify species more likely to facilitate spillover into domestic animals or humans. Using two independent searches, we reviewed published literature for studies describing wild bird species experimentally infected with avian influenza to assess host species’ relative susceptibility to AIVs. Additionally, we summarized broad-scale parameters for elements such as shedding duration and minimum infectious dose that can be used in transmission modeling efforts. Our synthesis documented that waterfowl (i.e., Anatidae) comprise the vast majority of published AIV pathobiology studies, whereas gulls and passerines were less represented in research despite evidence that they also are susceptible and contribute to high pathogenicity avian influenza disease dynamics. This study represents the first comprehensive effort to compile available literature regarding the pathobiology of AIV’s in all wild birds in over a decade. This database provides an opportunity to critically examine and assess what is known and identify where further insight is needed.
STAT5B SH2 variants disrupt mammary enhancers and the stability of genetic programs during pregnancy
Authors: Lee Hye Kyung , Liu Chengyu , Hennighausen Lothar 
Published: May 2024

AbstractDuring pregnancy, mammary tissue undergoes expansion and differentiation, leading to lactation, a process regulated by the hormone prolactin through the JAK2-STAT5 pathway. STAT5 activation is key to successful lactation making the mammary gland an ideal experimental system to investigate the impact of human missense mutations on mammary tissue homeostasis. Here, we investigated the effects of two human variants in the STAT5B SH2 domain, which convert tyrosine 665 to either phenylalanine (Y665F) or histidine (Y665H), both shown to activate STAT5B in cell culture. We ported these mutations into the mouse genome and found distinct and divergent functions. HomozygousStat5bY665Hmice failed to form functional mammary tissue, leading to lactation failure, with impaired alveolar development and greatly reduced expression of key differentiation genes. STAT5BY665Hfailed to recognize mammary enhancers and impeded STAT5A binding. In contrast, mice carrying theStat5bY665Fmutation exhibited abnormal precocious development, accompanied by an early activation of the mammary transcription program and the induction of otherwise silent genetic programs. Physiological adaptation was observed inStat5bY665Hmice as continued exposure to pregnancy hormones led to lactation. In summary, our findings highlight that human STAT5B variants can modulate their response to cytokines and thereby impact mammary homeostasis and lactation.Graphical abstract
Activity-dependent FosB gene expression negatively regulates mast cell functions
Authors: Duque-Wilckens Natalia , Maradiaga Nidia , Szu-Ying Yeh , Joseph Dimitry , Srinavasan Vidhula , Thelen Kyan , Sotomayor Fabiola , Durga Kait , Nestler Eric , Moeser Adam J , Robison A.J. 
Published: May 2024

AbstractMast cells are innate immune cells that play a crucial role in numerous physiological processes across tissues by releasing pre-stored and newly synthesized mediators in response to stimuli, an activity largely driven by changes in gene expression. Given their widespread influence, dysfunction in mast cells can contribute to a variety of pathologies including allergies, long COVID, and autoimmune and neuroinflammatory disorders. Despite this, the specific transcriptional mechanisms that control mast cell mediator release remain poorly understood, significantly hindering the development of effective therapeutic strategies. We found that the two proteins encoded by the transcription factor FosB, FOSB and the highly stable variant ΔFOSB, are robustly expressed upon stimulation in both murine and human mast cell progenitors. Motivated by these findings, we generated a novel mouse model with targeted ablation of FosB gene expression specifically in mast cells (MCFosB-) by crossing a mast cell-specific Cre reporter line (Mcpt5-Cre) with a Cre-dependent floxed FosB mouse lines. We found that mast cell progenitors derived from MCFosB-mice, compared to wild types (WT), exhibit baseline increased histamine content and vesicle numbers. Additionally, they show enhanced calcium mobilization, degranulation, and histamine release following allergy-related IgE-mediated stimulation, along with heightened IL-6 release in response to infection-like LPS stimulation.In vivoexperiments with IgE- mediated and LPS challenges revealed that MCFosB-mice experience greater drops in body temperature, heightened activation of tissue-resident mast cells, and increased release of pro-inflammatory mediators compared to their WT counterparts. These findings suggest that FosB products play a crucial regulatory role in moderating stimulus-induced mast cell activation in response to both IgE and LPS stimuli. Lastly, by integrating CUT&RUN and RNAseq data, we identified several genes targeted by ΔFOSB that could mediate these observed effects, including Mir155hg, CLCF1, DUSP4, and Trib1. Together, this study provides the first evidence that FOSB/ΔFOSB modulate mast cell functions and provides a new possible target for therapeutic interventions aimed at ameliorating mast cell-related diseases.Graphical Abstract
Cross-species analyses reveal RORγt-expressing dendritic cells are a lineage of antigen presenting cells conserved across tissues
Authors: Narasimhan Hamsa , Richter Maria L. , Shakiba Ramin , Papaioannou Nikos E. , Stehle Christina , Ravi Rengarajan Kaushikk , Ulmert Isabel , Küntzel Vanessa , Stange Eva-Lena , Antonova Alina U. , Klein Ludger , Dudziak Diana , Colonna Marco , Torow Natalia , Hornef Mathias W. , Lahl Katharina , Romagnani Chiara , Colomé-Tatché Maria , Schraml Barbara U. 
Published: May 2024

AbstractConventional dendritic cells (cDCs) are potent antigen presenting cells (APCs) that exhibit tissue and age-specific diversity allowing them to direct situation-adapted immunity. Thereby they harbor great potential for being targeted in vaccination and cancer. Here, we resolve conflicting data about expression of retinoic acid receptor-related orphan receptor-γt (RORψt) in cDCs. We show that RORψt+DCs exist in murine lymphoid and non-lymphoid tissues across age. Fate mapping, functional assays and single cell multiomic profiling reveal these cells as ontogenetically and transcriptionally distinct from other well characterized cDC subtypes, as well as from RORψt+type 3 innate lymphocytes (ILC3s). We show that RORψt+DCs can migrate to lymph nodes and activate naïve CD4+T cells in response to inflammatory triggers. Comparative and cross-species transcriptomics revealed homologous populations in human spleen, lymph nodes and intestines. Further, integrated meta-analyses aligned RORψt+DCs identified here with other emerging populations of RORψt+APCs, including R-DC-like cells, Janus cells/extrathymic Aire expressing cells (eTACs) and subtypes of Thetis cells. While RORψt+APCs have primarily been linked to T cell tolerance, our work establishes RORψt+DCs as unique lineage of immune sentinel cells conserved across tissues and species that expands the functional repertoire of RORψt+APCs beyond promoting tolerance.One sentence summaryRORγt+DC exhibit versatile APC functions and are a distinct immune lineage conserved across age, tissues and species that entails Thetis cells, Janus cells/RORγt+eTACs and R-DC-like cells.
Transcriptional dissection of petty spurge (Euphorbia peplusL.) reproductive structures supports theEuphorbiacyathium as an inflorescence rather than a complete flower
Authors: Johnson Arielle Rose , Bao Ashley , Frank Margaret Hannah 
Published: May 2024

AbstractThe unique reproductive structure ofEuphorbiaspecies, the cyathium, has historically been considered an inflorescence despite its visual resemblance to a single complete flower. However, multiple other models have recently been proposed, including the idea that the cyathium is a flower or has some degree of floral identity. Enabled by the petty spurge (Euphorbia peplusL.) genome and guided by the ABCDE model of floral development, we dissected petty spurge cyathia and carried out a transcriptomic analysis of the different organs. We also constructed gene phylogenies and performed dN/dS analysis on select floral genes. The E class gene SEP3 was not upregulated in the involucre as compared with the cyathophyll, indicating that the cyathium is not a complete flower. The filiform structures show upregulation of B and E class genes and transcriptomic signatures of heterochromatin formation, consistent with the hypothesis that they are reduced flowers.E. peplushomologs for the inflorescence/floral meristem genes UFO and LFY and the B class genes AP3 and PI have highly diverged sequences relative to other Euphorbiaceae species, suggesting that these reproductive patterning genes may have evolved divergent functions. We propose a new model in which the evolution of the cyathium involves two innovations: 1. altering LFY function to influence the timing of floral meristem development to create a compact flower-like inflorescence, and 2. altering the B class genes so that no perianth is formed. Our new hypothesis includes testable predictions about protein interactions and gene sequence evolution.
Effects of parity and early pregnancy on peripheral blood leukocytes in dairy cattle
Authors: da Silva M. I. , Oli N. , Gambonini F. , Ott T. 
Published: May 2024

AbstractSubfertility remains a major problem in the dairy industry. Only 35-40% of high-yielding dairy cows and 55-65% of nonlactating heifers become pregnant after their first service. The immune system plays a critical role in the establishment of pregnancy. However, it can also create challenges for embryo survival and contribute to reduced fertility. We conducted 2 separate experiments to characterize changes in subsets of peripheral blood leukocytes (PBL) and their phenotype over the estrous cycle and early pregnancy in heifers and cows. We used flow cytometry and RT-qPCR to assess protein and mRNA expression of molecules important for immune function. We observed that monocytes and T cells were most affected by pregnancy status in heifers, whereas, CD8+lymphocytes and natural killer (NK) cells were most affected during early pregnancy in cows. Changes in immune parameters measured appeared to be greater in heifers than cows including changes in expression of numerous immune function molecules. To test the hypothesis, we conducted a third experiment to simultaneously analyze the immunological responses to pregnancy between cows and heifers. We observed that cows had greater expression of proinflammatory cytokines and molecules associated with leukocyte migration and phagocytosis compared to heifers. Moreover, animals that failed to become pregnant showed altered expression of anti-inflammatory molecules. Overall, these findings support the hypothesis that early pregnancy signaling alters the proportions and functions of peripheral blood immune cells and differences between cows and heifers may yield insight into the reduced fertility of mature lactating dairy cows.Interpretative summaryIn dairy farming, 35-40% of high-yielding cows and 55-65% of nonlactating heifers conceive after their initial service. The immune system plays a crucial role in protecting cows from diseases and facilitating pregnancy establishment. This study investigates immune adaptation in bovine pregnancy by analyzing changes in immune cell populations and the expression of immunoregulatory molecules in the blood of heifers and lactating cows during early pregnancy. The findings support the hypothesis that early pregnancy signaling alters the proportions and functions of peripheral blood immune cells, offering insights into reduced fertility in mature lactating dairy cows.
STOP1 dominates Arabidopsis tolerance to ammonium over NRT1.1/NPF6.3/CHL1
Authors: Hachiya Takushi , Sakai Mako , Nakagawa Tsuyoshi , Sakakibara Hitoshi 
Published: May 2024

AbstractThe Arabidopsis nitrate transceptor NITRATE TRANSPORTER 1.1 (NRT1.1/NPF6.3/CHL1) plays significant roles even in the absence of nitrate. The loss-of-function of NRT1.1 alleviates growth suppression and chlorosis under toxic levels of ammonium as the sole nitrogen source. Recently, we reported that acidic stress-inducible genes are downregulated byNRT1.1deficiency under ammonium toxicity conditions, implying that NRT1.1 may exacerbate ammonium-dependent acidic stress. The transcription factor SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) enhances Arabidopsis tolerance to ammonium and acidic stresses. Furthermore, STOP1 directly activatesNRT1.1transcription. These previous findings prompted us to analyze the association between NRT1.1 and STOP1 on ammonium tolerance. Here, we show that ammonium-inducible STOP1 plays a dominant role over NRT1.1 in ammonium tolerance and expression of direct target genes of STOP1. We present a novel scheme in which NRT1.1 and STOP1 jointly regulate common target(s) associated with ammonium tolerance.
Deep learning based predictive modeling to screen natural compounds against TNF-alpha for the potential management of Rheumatoid Arthritis: Virtual screening to comprehensive in silico investigation
Authors: Nabi Tasnia , Riyed Tanver Hasan , Ornob Akid 
Published: May 2024

AbstractRheumatoid arthritis (RA) affects an estimated 0.1% to 2.0% of the world’s population, leading to a substantial impact on global health. The adverse effects and toxicity associated with conventional RA treatment pathways underscore the critical need to seek potential new therapeutic candidates, particularly those of natural sources that can treat the condition with minimal side effects. To address this challenge, this study employed a deep-learning (DL) based approach to conduct a virtual assessment of natural compounds against the Tumor Necrosis Factor-alpha (TNF-α) protein. TNF-α stands out as the primary pro-inflammatory cytokine, crucial in the development of RA. Our predictive model demonstrated appreciable performance, achieving MSE of 0.6, MAPE of 10%, and MAE of 0.5. The model was then deployed to screen a comprehensive set of 2563 natural compounds obtained from the Selleckchem database. Utilizing their predicted bioactivity (pIC50), the top 128 compounds were identified. Among them, 68 compounds were taken for further analysis based on drug-likeness analysis. Subsequently, selected compounds underwent additional evaluation using molecular docking (< − 8.7 kcal/mol) and ADMET resulting in four compounds posing nominal toxicity, which were finally subjected to MD simulation for 200 ns. Later on, the stability of complexes was assessed via analysis encompassing RMSD, RMSF, Rg, H-Bonds, SASA, and Essential Dynamics. Ultimately, based on the total binding free energy estimated using the MM/GBSA method, Imperialine, Veratramine, and Gelsemine are proven to be potential natural inhibitors of TNF-α.
Inferring intrinsic population growth rates andper capitainteractions from ecological time-series
Authors: Nguyen Phuong L. , Pomati Francesco , Rohr Rudolf P. 
Published: May 2024

AbstractKnowledge about theper capitainteractions between organisms and their intrinsic growth rates, and how these vary over environmental gradients, allows understanding and predicting species coexistence and community dynamics. Estimating these crucial ecological parameters requires tedious experimental work, with isolation of organisms from their natural context. Here, we provide a novel approach for inferring these key parameters from time-series data by using weighted multivariate regression on theper capitagrowth rates of populations. Beyond the validation of our approach on synthetic data, we reveal from experimental data an expected allocative trade-off between grazing resistance and rapid growth in algae. Application of observational data suggests facilitation between cyanobacteria and chrysophyte, indicating a possible explanation for cyanobacteria bloom. Our approach offers a way forward for inferringper capitainteractions and intrinsic growth rates directly from natural communities, providing realism, mechanistic understanding of eco-evolutionary dynamics, and key parameters to develop predictive models.