bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of conceptus proteins on endometrium and blood leukocytes of dairy cattle using transcriptome and meta-analysis
Authors: Isabel da Silva Maria , Ott Troy 
Published: April 2024

ABSTRACTThis study investigates the short and long-term effects of IFNT and PAG on the transcriptome of endometrium and blood leukocytes. Holstein heifers received intrauterine infusions of one of the following treatments: 20 mL of a 200 μg/mL bovine serum albumin solution (BSA; vehicle) from day 14 to 16 of the estrous cycle (BSA), vehicle + 10 μg/mL of IFNT from day 14 to 16 (IFNT3), vehicle + 10 μg/mL of IFNT from day 14 to 19 (IFNT6), and vehicle + 10 μg/mL of IFNT from day 14 to 16 followed by vehicle + 10 μg/mL of IFNT + 5 μg/mL of PAG from day 17 to 19 (IFNT+PAG). RNA-seq analysis was performed in endometrial biopsies and blood leukocytes collected after treatments. Acute IFNT signaling in the endometrium (IFNT3 vs BSA), induced differentially expressed genes (DEG) associated with interferon activation, immune response, inflammation, cell death, and inhibited vesicle transport and extracellular matrix remodeling. Prolonged IFNT signaling (IFNT6 vs IFNT3) altered gene expression related to cell invasion, retinoic acid signaling, and embryo implantation. In contrast, PAG induced numerous DEG in blood leukocytes but only 4 DEG in the endometrium. In blood leukocytes, PAG stimulated genes involved in development and TGFB signaling while inhibiting interferon signaling and cell migration. Overall, IFNT is a primary regulator of endometrial gene expression, while PAG predominantly affected the transcriptome of circulating immune cells during early pregnancy. Further research is essential to fully grasp the roles of identified DEG in both the endometrium and blood leukocytes.Graphic abstractMain findingsAcute IFNT signaling in the endometrium activates genes involved in inflammation while inhibiting vesicle transport in cells and ECM remodeling.Prolonged IFNT signaling in the endometrium regulates genes involved in cell invasion and retinoic acid signaling.PAG alter gene expression in blood leukocytes more than in endometrium and may stimulate leukocyte differentiation while inhibiting leukocyte extravasation.
Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis
Authors: Ziehr David R. , Li Fei , Mark Parnell K. , Krah Nathan M. , Leahy Kevin J. , Guillermier Christelle , Varon Jack , Baron Rebecca M. , Maron Bradley A. , Philp Nancy J. , Hariri Lida P. , Kim Edy Y. , Steinhauser Matthew L. , Knipe Rachel S. , Rutter Jared , Oldham William M. 
Published: April 2024

ABSTRACTMyofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. While glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how MCT1 and MCT4, key lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings reveal that inhibiting MCT1 or MCT4 reduces TGFβ-stimulated pulmonary myofibroblast differentiationin vitroand decreases bleomycin-induced pulmonary fibrosisin vivo. Through comprehensive metabolic analyses, including bioenergetics, stable isotope tracing, metabolomics, and imaging mass spectrometry in both cells and mice, we demonstrate that inhibiting lactate transport enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, a novel MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors for patients for whom limited therapeutic options currently exist.SUMMARYSmall molecule inhibitors of lactate transporters, including the novel MCT4 inhibitor VB253, reprogram fibroblast metabolism to prevent myofibroblast differentiation and decrease bleomycin-induced pulmonary fibrosis.
Intrinsically disordered membrane anchors of Rheb, RhoA and DiRas3 small GTPases: Molecular dynamics, membrane organization, and interactions
Authors: Hutchins Chase M. , Gorfe Alemayehu A. 
Published: April 2024

AbstractProtein structure has been well established to play a key role in determining function; however, intrinsically disordered proteins and regions (IDPs and IDRs) defy this paradigm. IDPs and IDRs exist as an ensemble of structures rather than a stable 3D structure yet play essential roles in many cell signaling processes. Nearly all Ras Superfamily GTPases are tethered to membranes by a lipid tail at the end of a flexible IDR. The sequence of these IDRs are key determinants of membrane localization, and interactions between the IDR and the membrane have been shown to affect signaling in RAS proteins through modulation of dynamic membrane organization. Here we utilized atomistic molecular dynamics simulations to study the membrane interactions, conformational dynamics, and lipid sorting of three IDRs from small GTPases Rheb, RhoA and DiRas3 in model membranes representing their physiological target membranes. We found that complementarity between lipidated IDR sequence and target membrane lipid composition is a determinant of conformational plasticity. We also show that electrostatic interactions between anionic lipids and basic residues on IDRs generate semi-stable conformational sub-states, and a lack of these residues leads to greater conformational diversity. Finally, we show that small GTPase IDRs with a polybasic domain alter local lipid composition by segregating anionic membrane lipids, and, in some cases, excluding other lipids from their immediate proximity in favor of anionic lipids.
Generation and validation of a D1 dopamine receptor Flpo knock-in mouse
Authors: Oppman Alexis M. , Paradee William J. , Narayanan Nandakumar S. , Kim Young-cho 
Published: April 2024

ABSTRACTBackgroundDopamine is a powerful neuromodulator of diverse brain functions, including movement, motivation, reward, and cognition. D1-type dopamine receptors (D1DRs) are the most prevalently expressed dopamine receptors in the brain. Neurons expressing D1DRs are heterogeneous and involve several subpopulations. Studying these neurons has been limited by current animal models, especially when considering their integration with conditional or intersectional genetic tools.New methodTo address this limitation, we developed a novel Drd1-P2A-Flpo (Drd1-Flpo) mouse line in which the Flpo gene was knocked in immediately after the Drd1 gene using CRISPR-Cas9. We validated the Drd1-Flpo line by confirming Flp expression and functionality specific to D1DR+ neurons.Comparison with existing methods: The Drd1-Flpo line is useful resource for studying subpopulation of D1DR+ neurons with intersectional genetic tools.ConclusionsWe demonstrated brain-wide GFP expression driven by Drd1-Flpo, suggesting that this mouse line may be useful for comprehensive anatomical and functional studies in many brain regions. The Drd1-Flpo model will advance the study of dopaminergic signaling by providing a new tool for investigating the diverse roles of D1DR+ neurons and their subpopulations in brain disease.Significance StatementThe roles of dopamine in the brain are mediated by dopamine receptors. D1-type dopamine receptors (D1DRs) and D1DR-expressing (D1DR+) neurons play important roles in various brain functions. We generated a Drd1-Flpo mouse line that expresses Flp recombinase in D1DR+ neurons. This novel Drd1-Flpo mouse facilitates investigation of specific roles of D1DR+ neurons in various brain areas including the striatum, frontal cortex, and cerebellum, and it provides an alternative to existing Drd1-Cre mice. In addition, the Drd1-Flpo mouse line provides a tool for intersectional genetic studies, when used with existing transgenic Cre lines. The Drd1-Flpo mouse line can help unravel the specific contributions of D1DR+ neuron subpopulations to brain function and dysfunction.
Combination of Haloperidol with UNC9994, β-arrestin-biased analog of Aripiprazole, ameliorates schizophrenia-related phenotypes induced by NMDAR deficit in mice
Authors: Lipina Tatiana V. , Wetsel William C , Caron Marc G. , Salahpour Ali , Ramsey Amy J. 
Published: April 2024

AbstractBackgroundGlutamatergic system dysfunction, particularly involving the N-methyl-D-aspartate receptor (NMDAR), contributes to a full spectrum of schizophrenia-like symptoms, including the cognitive and negative symptoms that are resistant to treatment with antipsychotic drugs (APDs). Aripiprazole, an atypical antipsychotic drug (APD), acts as a dopamine partial agonist and its combination with haloperidol (a typical APD) has been suggested as a potential strategy to improve schizophrenia symptoms. Recently, an analog of aripiprazole - UNC9994 was developed. UNC9994 does not affect D2R-mediated Gi/o protein signaling but acts as a partial agonist for D2R/β-arrestin interactions. Hence, our objective was to probe the effects of co-administrating haloperidol with UNC9994 in NMDAR mouse models of schizophrenia.MethodsNMDAR hypofunction was induced pharmacologically by acute injection of MK-801 (NMDAR pore blocker; 0.15 mg/kg) and genetically by knockdown of Grin1 gene expression in mice, which have a 90% reduction in NMDAR levels (Grin1-KD). After intraperitoneal injections of vehicle, haloperidol (0.15 mg/kg), UNC9994 (0.25 mg/kg) or their combination mice were tested in open field, Pre-Pulse inhibition (PPI), Y-maze and Puzzle box.ResultsOur findings indicate that low dose co-administration of UNC9994 and haloperidol reduces hyperactivity in MK-801-treated animals and in Grin1-KD mice. Furthermore, this dual administration effectively reverses PPI deficits, repetitive/rigid behavior in the Y-maze, and deficient executive function in the Puzzle box in both animal models.ConclusionsThe dual administration of haloperidol with UNC9994 at low doses represents a promising approach to ameliorate positive, negative, and cognitive symptoms of schizophrenia.Significance statementSchizophrenia is a devastating mental disorder and characterized by positive, negative, and cognitive symptoms. Cognitive and negative symptoms remain a focus of research dedicated to development of effective antipsychotic drugs (APDs). Aripiprazole, an atypical APD, acts as a dopamine partial agonist and its combination with haloperidol (a typical APD) has been suggested as a potential strategy to improve schizophrenia symptoms. An analog of aripiprazole - UNC9994 was recently developed, which does not affect D2R-mediated Gi/o protein signaling but acts as a partial agonist for D2R/β-arrestin interactions. Our pre-clinical findings on pharmacological (MK-801, 0.15 mg/kg) and genetic (Grin1-KD) mouse models of NMDAR deficiency showed that the dual administration of UNC9994 (0.25 mg/kg) with haloperidol (0.15 mg/kg) at low doses reduces hyperactivity, corrects prepulse inhibition (PPI) deficits, rigid behavior in the Y-maze, and deficient executive function in the Puzzle box. Further studies of the polypharmacy of UNC9994 with APDs is essential to facilitate translational studies in clinics.
Identification and Characterization of Compounds that Improve Plant Photosynthesis and Growth under Light Stress Conditions
Authors: Qu Yuchen , Sakoda Kazuma , Wakabayashi Yu , Nakajima Masatoshi , Asami Tadao , Terashima Ichiro , Yamori Wataru 
Published: April 2024

AbstractIn order to satisfy the food and fuel demands of a growing population, global food production needs to increase by more than 50% before 2050. However, various environmental stresses in the natural environment inhibit plant growth and result in reduced yields. This is primarily caused by decreases in photosynthetic capacity. Thus, there is an urgent need to develop new strategies to improve agricultural productivity and ensure food security. In this study, a novel chemical-screening system with 96 well plates and leaf disks of tobacco was used to identify several anthraquinone derivatives that could relieve high light stress from plants. Treatments with these chemicals induced greater photosynthetic capacity after high light stress conditions for 20–72 hours (h) in tobacco and better plant growth after exposure to light stress for 96 hours in Arabidopsis and lettuces. The photoprotective effect of anthraquinone derivatives is closely related to chemical induced oxidation of PSI. Furthermore, there were no negative effects on plant growth in chemically treated plants under non-stressful conditions. Taken together, this study shows that anthraquinone derivatives can confer high light stress tolerance in plants, resulting in improved plant photosynthesis and growth in environments with light stress.
Predicting gene expression responses to environment inArabidopsis thalianausing natural variation in DNA sequence
Authors: Takou Margarita , Bellis Emily S , Lasky Jesse R 
Published: April 2024

AbstractThe evolution of gene expression responses are a critical component of adaptation to variable environments. Predicting how DNA sequence influences expression is challenging because the genotype to phenotype map is not well resolved forcisregulatory elements, transcription factor binding, regulatory interactions, and epigenetic features, not to mention how these factors respond to environment. We tested if flexible machine learning models could learn some of the underlyingcis-regulatory genotype to phenotype map. We tested this approach using cold-responsive transcriptome profiles in 5 diverseArabidopsis thalianaaccessions. We first tested for evidence thatcisregulation plays a role in environmental response, finding 14 and 15 motifs that were significantly enriched within the up- and down-stream regions of cold-responsive differentially regulated genes (DEGs). We next applied convolutional neural networks (CNNs), which learnde novo cis-regulatory motifs in DNA sequences to predict expression response to environment. We found that CNNs predicted differential expression with moderate accuracy, with evidence that predictions were hindered by biological complexity of regulation and the large potential regulatory code. Overall, DEGs between specific environments can be predicted based on variation incis-regulatory sequences, although more information needs to be incorporated and better models may be required.
Heparan sulfate regulates amphiregulin signaling towards reparative lung mesenchymal cells during influenza A infection
Authors: Loffredo Lucas F. , Surpur Anmol , Ringham Olivia R. , Li Fangda , de los Santos-Alexis Kenia , Arpaia Nicholas 
Published: April 2024

AbstractAmphiregulin (Areg), a growth factor produced by regulatory T (Treg) cells to facilitate tissue repair/regeneration, contains a heparan sulfate (HS) binding domain. How HS, a highly sulfated glycan subtype that alters growth factor signaling, influences Areg repair/regeneration functions is unclear. Here we report that inhibition of HS in various cell lines and primary lung mesenchymal cells (LMC) qualitatively alters downstream signaling and highlights the existence of HS-dependent vs. -independent Areg transcriptional signatures. Utilizing a panel of cell lines with targeted deletions in HS synthesis–related genes, we found that the presence of the glypican family of heparan sulfate proteoglycans is critical for Areg signaling and confirmed this dependency in primary LMC by siRNA-mediated knockdown. Furthermore, in the context of influenza A (IAV) infectionin vivo, we found that an Areg-responsive subset of reparative LMC upregulate glypican-4 and HS. Conditional deletion of HS primarily within this LMC subset resulted in reduced blood oxygen saturation following infection with IAV, with no changes in viral load. Finally, we found that co-culture of HS-knockout LMC with IAV-induced Treg cells results in reduced LMC responses. Collectively, this study reveals the essentiality of HS on a specific lung mesenchymal population as a mediator of Treg cell–derived Areg reparative signaling during IAV infection.
Epithelial IL-2 is critical for NK cell-mediated cancer immunosurveillance in mammary glands
Authors: Wang Lei , Maharjan Chandra K , Borcherding Nicholas , Master Rohan P , Mo Jiao , Tithi Tanzia Islam , Kim Myung-Chul , Carelock Madison E , Master Anuj P. , Gibson-Corley Katherine N. , Kolb Ryan H. , Smith Kendall A. , Zhang Weizhou 
Published: April 2024

AbstractInterleukin 2 (IL-2) is the first identified cytokine and its interaction with receptors has been known to shape the immune responses in many lymphoid or non-lymphoid tissues for more than four decades. Active T cells are the primary cellular source for IL-2 production and epithelial cells have never been considered the major cellular source of IL-2 under physiological conditions. It is, however, tempting to speculate that epithelial cells could potentially express IL-2 that regulates the intricate interactions between epithelial cells and lymphocytes. Datamining our recently published single-cell RNAseq in the mouse mammary gland identified IL-2 expression in mammary epithelial cells, which is induced by prolactin via the STAT5 signaling pathway. Furthermore, epithelial IL-2 plays a crucial role in maintaining the physiological functions of natural killer (NK) cells within the mammary glands. IL-2 deletion in the mammary epithelial cells leads to a significant reduction in the number and function of NK cells, which in turn results in defective immunosurveillance, expansion of luminal epithelial cells, and tumor development. Interestingly, T cells in the mammary glands are not changed, indicating the specific regulation of NK cells by epithelial IL-2 production. In agreement, we also found that human epithelial cells express IL-2 and NK cells express the highest level of IL2RB among all the immune cells. Here, we provide the first evidence that epithelial cells produce IL-2, which is critical for maintaining the physiological functions of NK cells in immunosurveillance.
Management recommendations for Alpine protection forests: the importance of regeneration quality and initial stand composition
Authors: Schmid Ueli , Frehner Monika , Bugmann Harald 
Published: April 2024

AbstractThe protection of infrastructure against gravitational natural hazards is one of the most important ecosystem services (ES) of mountain forests in Alpine countries. For a continuous provision of this ES, forests need to have a high protective effect, e.g., high canopy cover and/or stem numbers, while being resistant to and resilient after disturbances by being well-structured and stable, having a species composition adapted to the local site conditions and sufficient regeneration, all on a relatively small spatial scale.While “natural” forests may fulfill these prerequisites without human intervention, management history and high levels of ungulate browsing have produced unsustainable stand structures in many protection forests that need to be improved by management. The general principles of protection forest management are well established, but there are no quantitative, science-based recommendations for management regimes, i.e., specific sequences of interventions, that ensure a continuous protective quality. Our goal was to derive such recommendations for different stand types across three elevational zones, from mixed forests of the upper montane to spruce forests of the subalpine zone.We used an updated version of the model ProForM to simulate stand development under different levels of ungulate browsing, testing a large number of management regimes that vary in the spatial aggregation of tree removal, the intensity and interval of the interventions. We investigated the influence of browsing pressure and management on the protective quality using Boosted Regression Trees and Beta regression.High levels of ungulate browsing had such a strong negative effect on the protective quality that it could not be improved through forest management. This underlines the need for maintaining ungulate densities in Alpine forests at levels that allow for the successful regeneration of all key tree species. In stands that are influenced less by browsing, the protective quality can be improved through management in many cases, with specific management recommendations differing mostly depending on the initial stand conditions and, to a lesser extent, on the elevational zone. Well-structured stands provide a high protective quality without management interventions during at least a century across all elevational zones. In young and in mature stands, we generally recommend management regimes with relatively long return intervals of 30 to 40 years and low intervention intensities of 10 to 20% basal area removal.
Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging
Authors: Poliezhaieva Tetiana , Pernas Pol Alonso , Espada Lilia , Bayar Melike , Li Yuting , Dönertaş Handan Melike , Ermolaeva Maria A. 
Published: April 2024

AbstractMitochondrial dysfunction is a prominent hallmark of aging contributing to the functional decline of metabolic plasticity in late life. While genetic distortions of mitochondrial integrity elicit premature aging, the mechanisms leading to “natural” aging of mitochondria are less clear. Here we initially used proteomics, genetics and functional tests in wild typeC. elegansand long-livedclk-1(qm30)andisp-1(qm150)mitochondrial mutants to identify molecular pathways that safeguard longevity amid persistent mitochondrial inefficiency. Strikingly, these analyses and subsequent transcriptomic and functional tests in the human system revealed aging-associated decline of phosphatidylcholine (PC) synthesis as a trigger of mitochondrial network disruption, which contributes to mitochondrial dysfunction during normal aging. Moreover, we found that ectopic boosting of PC levels via diet restores late life mitochondrial integrityin vivoand rescues metabolic plasticity in cell culture tests. Our work thus uncovered a novel natural driver of mitochondrial aging that is malleable by dietary interventions.