bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic upregulation of carotid body angiotensin signaling increases blood pressure
Authors: Zhu Fengli , Wang Zhuqing , Davis Kayla , McSwiggin Hayden , Zyuzin Jekaterina , Liu Jie , Yan Wei , Rehan Virender K. , Jendzjowsky Nicholas 
Published: May 2024

AbstractEpigenetic changes can be shaped by a wide array of environmental cues as well as maternal health and behaviors. One of the most detrimental behaviors to the developing fetus is nicotine exposure. Perinatal nicotine exposure remains a significant risk factor for cardiovascular health and in particular, hypertension. Increased basal carotid body activity and excitation are significant contributors to hypertension. This study investigated the epigenetic changes to carotid body activity induced by perinatal nicotine exposure resulting in carotid body-mediated hypertension. Using a rodent model of perinatal nicotine exposure, we show that angiotensin II type 1 receptor is upregulated in the carotid bodies of nicotine-exposed offspring. These changes were attributed to an upregulation of genetic promotion as DNA methylation of angiotensin II type 1 receptor occurred within intron regions, exemplifying an upregulation of genetic transcription for these genes. Nicotine increased angiotensin signalingin vitro. Carotid body reactivity to angiotensin was increased in perinatal nicotine-exposed offspring compared to control offspring. Further, carotid body denervation reduced arterial pressure as a result of suppressed efferent sympathetic activity in perinatal nicotine-exposed offspring. Our data demonstrate that perinatal nicotine exposure adversely affects carotid body afferent sensing, which augments efferent sympathetic activity to increase vasoconstrictor signaling and induce hypertension. Targeting angiotensin signaling in the carotid bodies may provide a way to alleviate hypertension acquired by adverse maternal uterine environments in general and perinatal nicotine exposure in particular.
Antibiotic use in early life subsequently impairs MAIT cell-mediated immunity
Authors: Sobel Adam L. , Melamed Jonathan , Haas Dominic , LeBlanc Gabrielle , Cirone Aiko , Constantinides Michael G. 
Published: May 2024

SummaryMucosal-associated invariant T (MAIT) cells are predominantly located in barrier tissues where they rapidly respond to pathogens and commensals by recognizing microbial derivatives of riboflavin synthesis. Early-life exposure to these metabolites imprints the abundance of MAIT cells within tissues, so we hypothesized that antibiotic use during this period may abrogate their development. We identified antibiotics that deplete riboflavin-synthesizing commensals and revealed an early period of susceptibility during which antibiotic administration impaired MAIT cell development. The reduction in MAIT cell abundance rendered mice more susceptible to pneumonia, while MAIT cell-deficient mice were unaffected by early-life antibiotics. Concomitant administration of a riboflavin-synthesizing commensal during antibiotic treatment was sufficient to restore MAIT cell development and immunity. Our work demonstrates that transient depletion of riboflavin-synthesizing commensals in early life can adversely affect responses to subsequent infections.
Application of Multiomics Approach to Investigate the Therapeutic Potentials of Stem Cell-derived Extracellular Vesicle Subpopulations for Alzheimer’s Disease
Authors: Abyadeh Morteza , Kaya Alaattin 
Published: May 2024

AbstractAlzheimer’s disease (AD) presents a complex interplay of molecular alterations, yet understanding its pathogenesis remains a challenge. In this study, we delved into the intricate landscape of proteome and transcriptome changes in AD brains compared to healthy controls, examining 788 brain samples revealing common alterations at both protein and mRNA levels. Moreover, our analysis revealed distinct protein-level changes in aberrant energy metabolism pathways in AD brains that were not evident at the mRNA level. This suggests that the changes in protein expression could provide a deeper molecular representation of AD pathogenesis. Subsequently, using a comparative proteomic approach, we explored the therapeutic potential of mesenchymal stem cell-derived extracellular vehicles (EVs), isolated through various methods, in mitigating AD-associated changes at the protein level. Our analysis revealed a particular EV-subtype that can be utilized for compensating dysregulated mitochondrial proteostasis in the AD brain. By using network biology approaches, we further revealed the potential regulators of key therapeutic proteins. Overall, our study illuminates the significance of proteome alterations in AD pathogenesis and identifies the therapeutic promise of a specific EV subpopulation with reduced pro-inflammatory protein cargo and enriched proteins to target mitochondrial proteostasis.Graphical AbstractThe cross-comparison of transcriptomics and proteomics data from AD brain samples and MSCs-derived EVs uncovers the therapeutic potential of a subpopulation targeting mitochondrial proteostasis and inflammation.
Renal Proximal Tubule Cell-specific Megalin Deletion Does Not Affect Atherosclerosis But Induces Tubulointerstitial Nephritis in Mice Fed Western Diet
Authors: Amioka Naofumi , Franklin Michael K. , Kukida Masayoshi , Zhu Liyuan , Moorleghen Jessica J. , Howatt Deborah A. , Katsumata Yuriko , Mullick Adam E. , Yanagita Motoko , Martinez-Irizarry Michelle M. , Sandoval Ruben M. , Dunn Kenneth W. , Sawada Hisashi , Daugherty Alan , Lu Hong S. 
Published: May 2024

ABSTRACTBackgroundPharmacological inhibition of megalin (also known as low-density lipoprotein receptor-related protein 2: LRP2) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), the purpose of this study was to determine whether PTC-specific deletion of megalin reduces hypercholesterolemia-induced atherosclerosis in mice.MethodsFemaleLrp2f/f mice were bred with maleNdrg1-Cre ERT2+/0 mice to develop PTC-LRP2 +/+ and −/− littermates. To study atherosclerosis, all mice were bred to an LDL receptor −/− background and fed a Western diet to induce atherosclerosis.ResultsPTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor −/− mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 −/− mice fed the Western diet, but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 −/− mice in an LDL receptor +/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not hypercholesterolemia. In contrast, female PTC-LRP2 −/− mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished albumin accumulation in PTCs within 10 days of Western diet feeding. RNA sequencing analyses demonstrated the upregulation of inflammation-related pathways in kidney.ConclusionsPTC-specific megalin deletion does not affect atherosclerosis, but leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.
Temporal Single Cell Analysis of Leukemia Microenvironment Identifies Taurine-Taurine Transporter Axis as a Key Regulator of Myeloid Leukemia
Authors: Rodems Benjamin J. , Sharma Sonali , Baker Cameron D. , Kaszuba Christina M. , Ito Takashi , Liesveld Jane L. , Calvi Laura M. , Becker Michael W. , Jordan Craig T. , Ashton John M. , Bajaj Jeevisha 
Published: May 2024

ABSTRACTSignals from the microenvironment are known to be critical for development, sustaining adult stem cells, and for oncogenic progression. While candidate niche-driven signals that can promote cancer progression have been identified1–6, concerted efforts to comprehensively map microenvironmental ligands for cancer stem cell specific surface receptors have been lacking. Here, we use temporal single cell RNA-sequencing to identify molecular cues from the bone marrow stromal niche that engage leukemia stem cells (LSC) during oncogenic progression. We integrate these data with our RNA-seq analysis of human LSCs from distinct aggressive myeloid cancer subtypes and our CRISPR basedin vivoLSC dependency map7to develop a temporal receptor-ligand interactome essential for disease progression. These analyses identify the taurine transporter (TauT)-taurine axis as a critical dependency of myeloid malignancies. We show that taurine production is restricted to the osteolineage population during cancer initiation and expansion. Inhibiting taurine synthesis in osteolineage cells impairs LSC growth and survival. Our experiments with the TauT genetic loss of function murine model indicate that its loss significantly impairs the progression of aggressive myeloid leukemiasin vivoby downregulating glycolysis. Further, TauT inhibition using a small molecule strongly impairs the growth and survival of patient derived myeloid leukemia cells. Finally, we show that TauT inhibition can synergize with the clinically approved oxidative phosphorylation inhibitor venetoclax8, 9to block the growth of primary human leukemia cells. Given that aggressive myeloid leukemias continue to be refractory to current therapies and have poor prognosis, our work indicates targeting the taurine transporter may be of therapeutic significance. Collectively, our data establishes a temporal landscape of stromal signals during cancer progression and identifies taurine-taurine transporter signaling as an important new regulator of myeloid malignancies.
Novel Oral Adjuvant to Enhance Cytotoxic Memory-Like NK Cell Responses in an HIV Vaccine Platform
Authors: Alles Mario , Gunasena Manuja , Isckarus Christina , De Silva Ilmini , Board Sarah , Mulhern Will , Collins Patrick L. , Demberg Thorsten , Liyanage Namal P.M. 
Published: May 2024

AbstractAntibody-dependent cell-mediated cytotoxicity, mediated by natural killer (NK) cells and antibodies, emerged as a secondary correlate of protection in the RV144 HIV vaccine clinical trial, the only vaccine thus far demonstrating some efficacy in human. Therefore, leveraging NK cells with enhanced cytotoxic effector responses may bolster vaccine induced protection against HIV. Here, we investigated the effect of orally administering indole-3-carbinol (I3C), an aryl hydrocarbon receptor (AHR) agonist, as an adjuvant to an RV144-like vaccine platform in a mouse model. We demonstrate the expansion of KLRG1-expressing NK cells induced by the vaccine together with I3C. This NK cell subset exhibited enhanced vaccine antigen-specific cytotoxic memory-like features. Our study underscores the potential of incorporating I3C as an oral adjuvant to HIV vaccine platforms to enhance antigen-specific (memory-like) cytotoxicity of NK cells against HIV-infected cells. This approach may contribute to enhancing the protective efficacy of HIV preventive vaccines against HIV acquisition.
Spatiotemporal control of subcellular O-GlcNAc signaling using Opto-OGT
Authors: Ong Qunxiang , Lim Rachel , Goh Cameron , Liao Yilie , Chan Sher En , Lim Crystal , Kam Valerie , Yap Jerome , Tseng Tiffany , Desrouleaux Reina , Wang Loo Chien , Ler Siok Ghee , Lim Siew Lan , Kim Sunyee , Sobota Radoslaw M , Bennett Anton M. , Han Weiping , Yang Xiaoyong 
Published: May 2024

AbstractThe posttranslational modification of intracellular proteins through O-linked β-N-acetylglucosamine (O-GlcNAc) is a conserved regulatory mechanism in multicellular organisms. Catalyzed by O-GlcNAc transferase (OGT), this dynamic modification plays an essential role in signal transduction, gene expression, organelle function, and systemic physiology. Here we present Opto-OGT, an optogenetic probe that allows for precise spatiotemporal control of OGT activity through light stimulation. By fusing a photosensitive cryptochrome protein to OGT, Opto-OGT can be robustly and reversibly activated with high temporal resolution by blue light and exhibits minimal background activity without illumination. Transient activation of Opto-OGT results in mTORC activation and AMPK suppression which recapitulate nutrient-sensing signaling. Furthermore, Opto-OGT can be customized to be localized at specific subcellular sites. By targeting OGT to the plasma membrane, we demonstrate downregulation of site-specific AKT phosphorylation and signaling outputs in response to insulin stimulation. Thus, Opto-OGT is a powerful tool to define the role of O-GlcNAcylation in cell signaling and physiology.
The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38
Authors: Tan Sijie , Dengler Alisa Susan , Darawsheh Rami Zahi , Kory Nora 
Published: May 2024

ABSTRACTMitochondrial transporters facilitate the exchange of diverse metabolic intermediates across the inner mitochondrial membrane, ensuring an adequate supply of substrates and cofactors to support redox and biosynthetic reactions within the mitochondrial matrix. However, the regulatory mechanisms governing the abundance of these transporters, crucial for maintaining metabolic compartmentalization and mitochondrial functions, remain poorly defined. Through analysis of protein half-life data and mRNA-protein correlations, we identified SLC25A38, a mitochondrial glycine transporter, as a short- lived protein with a half-life of 4 hours under steady-state conditions. Pharmacological inhibition and genetic depletion of various cellular proteolytic systems revealed that SLC25A38 is rapidly degraded by the iAAA-mitochondrial protease YME1L1. Depolarization of the mitochondrial membrane potential induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrozone prevented the degradation of SLC25A38. This dual regulation of SLC25A38 abundance by YME1L1 and mitochondrial membrane potential suggests a link between SLC25A38 turnover, the integrity of the inner mitochondrial membrane, and electron transport chain function. These findings open avenues for investigating whether mitochondrial glycine import coordinates with mitochondrial bioenergetics.
Specific Mitotic Events Drive Cytoskeletal Remodeling Required for Left-Right Organizer Development
Authors: Wu Yan , Lan Yiling , Ononiwu Favour , Poole Abigail , Rasmussen Kirsten , Da Silva Jonah , Shamil Abdalla Wael , Jao Li-En , Hehnly Heidi 
Published: May 2024

SummaryCellular proliferation is vital for tissue development, including the Left-Right Organizer (LRO), a transient organ critical for establishing the vertebrate LR body plan. This study investigates cell redistribution and the role of specific progenitor cells in LRO formation, focusing on cell lineage and behavior. Using zebrafish as a model, we mapped all mitotic events in Kupffer’s Vesicle (KV), revealing an FGF-dependent, anteriorly enriched mitotic pattern. With a KV-specific fluorescent microtubule (MT) line, we observed that mitotic spindles align along the KV’s longest axis until the rosette stage, spindles that form after spin, and are excluded from KV. Early aligned spindles assemble cytokinetic bridges that point MT bundles toward a tight junction where a rosette will initially form. Post-abscission, repurposed MT bundles remain targeted at the rosette center, facilitating actin recruitment. Additional cells, both cytokinetic and non-cytokinetic, are incorporated into the rosette, repurposing or assembling MT bundles before actin recruitment. These findings show that initial divisions are crucial for rosette assembly, MT patterning, and actin remodeling during KV development.
Proving a negative; estimating species ‘Confidence in Absence for Decision-Making’ (CIADM) using environmental DNA monitoring
Authors: Griffiths Nathan P. , Hänfling Bernd , Cattaneo Marco , Wright Rosalind M. , Macarthur James A. , Peixoto Sara , Bolland Jonathan D. 
Published: May 2024

AbstractPolicy-driven decision-making is an important aspect of environmental management globally, often focused on protecting priority species. However, declining trends in freshwater biodiversity have resulted in a lack of up-to-date knowledge regarding the distribution of rare and elusive species. Furthermore, when dealing with priority species, it is sometimes more important to provide a confident assessment of absence, than merely confirm their presence. Without such confident assessments, resource intensive management plans may be misplaced, and not adequately targeted to conserve important remaining populations.Here, we present a framework to estimate confidence in absence, referred to as “Confidence in Absence for Decision-Making” (CIADM), based on single-visit environmental DNA metabarcoding data obtained from water samples. It uses a case study of European eel presence / absence upstream of 44 water pumping stations, given their critically endangered status and the legislative drivers for remediation (EC Eel Regulation 1100/2007, Eels (England and Wales) Regulation 2009). Through a high degree of biological (sample) and technical (PCR) replication, we retrospectively assigned ‘confidence in absence’ values and proposed various strategies to achieve the required confidence levels in future surveys.Our findings indicate that 17 out of 44 pumping stations tested positive for eel, and we were able to assign a >99% confidence level that the remaining 27 sites were negative for eel DNA at the time of sampling. Increasing both biological and technical replication increased ‘confidence in absence’ values. For example, using three PCR replicates per sample, required four replicate biological samples to achieve >95% and six to achieve >99% confidence in eel absence given non-detection. However, we estimate that by using seven PCR replicates per sample a >99% confidence in eel absence following non-detection could be achieved with only three replicate biological samples. Furthermore, we found that eel positive sites had significantly higher species richness, and fish communities differed between eel positive and eel negative sites.This study highlights the importance of optimising workflow specific replication, and provides an adaptable framework to produce confidence estimations of priority species absence given non-detection.
Metagenomics to Metabolomics: Integrating Genomic Insights for Mulberry Crop Protection and Enhancement
Authors: Niranjan Vidya , Lavanya C , Pooja H V , Bhat Shreya Satyanarayan , Kulkarni Spoorthi R 
Published: May 2024

ABSTRACTIndian Mulberry (Morus indica) is vital in sericulture, with their leaves serving as the primary food source for silkworms. The soil microbiome surrounding mulberry trees plays a pivotal role in nutrient cycling and ecosystem functioning. This study utilizes metagenomic analysis to explore the taxonomic diversity and functional potential of microbial communities in mulberry soil, particularly focusing on the rhizosphere. Key bacterial species such asPseudomonas, Frankia, Azosipirulumare identified, highlighting their importance in mulberry health and disease dynamics. The abundance distribution of these bacterial populations reveals significant trends, offering insights into mulberry agroecosystem microbial ecology. Understanding garden soil-derived microbial consortia provides a foundation for exploring their role in nutrient cycling and plant health. The study reveals the intricate web of interactions between mulberry and their surrounding soil microbiota and identification of metabolites. Leveraging high-throughput sequencing and bioinformatics, the research identifies potential metabolites as biofertilizers and biopesticides, aiming to improve agricultural sustainability. The findings underscore the critical role of soil microbes in maintaining soil fertility, supporting plant health, and enhancing ecosystem resilience. Despite limitations and gaps, the study contributes to advancing eco-friendly agricultural practices and promoting soil health in mulberry cultivation. Ultimately, the research transcends the laboratory, resonating with stakeholders as it unravels the genetic blueprints of soil life and sows’ seeds of sustainable progress.
Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2
Authors: Bashore Frances M. , Min Sophia M. , Chen Xiangrong , Howell Stefanie , Rinderle Caroline H. , Morel Gabriel , Silvaroli Josie A. , Wells Carrow I. , Bunnell Bruce A. , Drewry David H. , Pabla Navjot S. , Ultanir Sila K. , Bullock Alex N. , Axtman Alison D. 
Published: May 2024

ABSTRACTAcylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound9was selected as a CDKL2 chemical probe based on its potent inhibition of CDKL2 enzymatic activity, engagement of CDKL2 in cells, and excellent kinome-wide selectivity, especially when used in cells. Compound16was designed as a negative control to be used alongside compound9in experiments to interrogate CDKL2-mediated biology. A solved co-crystal structure of compound9bound to CDKL2 highlighted key interactions it makes within its ATP-binding site. Inhibition of downstream phosphorylation of EB2, a CDKL2 substrate, in rat primary neurons provided evidence that engagement of CDKL2 by compound9in cells resulted in inhibition of its activity. When used at relevant concentrations, compound9does not impact the viability of rat primary neurons or certain breast cancer cells nor elicit consistent changes in the expression of proteins involved in epithelial–mesenchymal transition.
The yolk sac vasculature in early avian embryo provides a novel model for the analysis of cancer extravasation
Authors: Morita Mizuki , Fujii Ryo , Ryuno Asuka , Morimoto Manami , Inoko Akihito , Inoue Takahiro , Ikenouchi Junichi , Atsuta Yuji , Hayashi Yoshiki , Teramoto Takayuki , Saito Daisuke 
Published: May 2024

SUMMARYHematogenous metastasis, a key trait of cancer cells, involves a complex sequence of cell migration steps, including intravasation, circulation, arrest in capillary vessels, and extravasation. Among these steps, extravasation is challenging to image in amniotes like humans and mice due to its unpredictable timing and location, limiting our understanding of cellular and molecular mechanisms through imaging. Establishing a new cancer carrier model with high-resolution imaging capabilities in amniotes is crucial. In this study, we investigated the yolk sac vasculature (YSV) of early avian embryos (chickens and quail) as a new model for studying extravasation, offering excellent imaging capabilities. We examined the YSV structure and attempted fluorescent labeling to enhance visibility. We then injected mCherry-labeled HT-1080 cells into YSV and observed their behavior, revealing distinct morphologies and extravasation dynamics. Our findings suggest that the YSV model holds promise as a novel cancer carrier model for elucidating cellular and molecular mechanisms through imaging-based approaches.