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Nature Communications Jul 2024The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental...
The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11 zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCF mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCF mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.
Topics: CCCTC-Binding Factor; Humans; Animals; Mice; Neurodevelopmental Disorders; Organoids; Mutation; GABAergic Neurons; Male; Chromatin; Female; Brain; Point Mutation; Human Embryonic Stem Cells
PubMed: 38951485
DOI: 10.1038/s41467-024-49684-1 -
Scientific Reports Jul 2024Meditation, yoga, guided imagery, and progressive relaxation are promoted as complementary approaches for health and wellbeing in the United States, but their uptake by...
Meditation, yoga, guided imagery, and progressive relaxation are promoted as complementary approaches for health and wellbeing in the United States, but their uptake by different sociodemographic groups is unclear. This study assessed the prevalence and 20 year trends in the use of these practices in US adults between 2002-2022. We examined practice use and associations with sociodemographic and health factors in a population-weighted analysis of n = 134,959 participants across 5 cycles of the National Health Interview Survey. The overall use of meditation (18.3%, 60.53 million), yoga (16.8%, 55.78 million) and guided imagery/progressive relaxation (6.7%, 22.22 million) increased significantly from 2002 to 2022. Growth was consistent across most sociodemographic and health strata, however users of 'Other' race (comprising 54% Indigenous Americans, Odds Ratios; ORs = 1.28-1.70) and users with moderate (ORs = 1.19-1.29) psychological distress were overrepresented across all practices, and those with severe psychological distress were overrepresented in meditation (OR = 1.33) and guided imagery/progressive relaxation (OR = 1.42). Meditation use has accelerated over time for 65 + year olds (OR = 4.22), people not accessing mental health care (OR = 1.39), and less educated (OR = 4.02) groups, potentially reflecting unmet health needs. Health professionals should consider the extensive use of complementary practices in service and treatment planning and consider their risks and benefits.
Topics: Humans; Meditation; Yoga; Male; Female; Adult; United States; Middle Aged; Prevalence; Aged; Young Adult; Adolescent; Relaxation Therapy; Imagery, Psychotherapy
PubMed: 38951149
DOI: 10.1038/s41598-024-64562-y -
Experimental & Molecular Medicine Jul 2024The amyloid cascade hypothesis suggests that amyloid beta (Aβ) contributes to initiating subsequent tau pathology in Alzheimer's disease (AD). However, the underlying...
The amyloid cascade hypothesis suggests that amyloid beta (Aβ) contributes to initiating subsequent tau pathology in Alzheimer's disease (AD). However, the underlying mechanisms through which Aβ contributes to tau uptake and propagation remain poorly understood. Here, we show that preexisting amyloid pathology accelerates the uptake of extracellular tau into neurons. Using quantitative proteomic analysis of endocytic vesicles, we reveal that Aβ induces the internalization of fibroblast growth factor receptor 3 (FGFR3). Extracellular tau binds to the extracellular domain of FGFR3 and is internalized by the FGFR3 ligand, fibroblast growth factor 2 (FGF2). Aβ accelerates FGF2 secretion from neurons, thereby inducing the internalization of tau-attached FGFR3. Knockdown of FGFR3 in the hippocampus reduces tau aggregation by decreasing tau uptake and improving memory function in AD model mice. These data suggest FGFR3 in neurons as a novel tau receptor and a key mediator of Aβ-induced tau uptake in AD.
PubMed: 38951140
DOI: 10.1038/s12276-024-01274-3 -
PLoS Genetics Jul 2024Lactococcus lactis is a lactic acid bacterium of major importance for food fermentation and biotechnological applications. The ability to manipulate its genome quickly...
Lactococcus lactis is a lactic acid bacterium of major importance for food fermentation and biotechnological applications. The ability to manipulate its genome quickly and easily through competence for DNA transformation would accelerate its general use as a platform for a variety of applications. Natural transformation in this species requires the activation of the master regulator ComX. However, the growth conditions that lead to spontaneous transformation, as well as the regulators that control ComX production, are unknown. Here, we identified the carbon source, nitrogen supply, and pH as key factors controlling competence development in this species. Notably, we showed that these conditions are sensed by three global regulators (i.e., CcpA, CodY, and CovR), which repress comX transcription directly. Furthermore, our systematic inactivation of known signaling systems suggests that classical pheromone-sensing regulators are not involved. Finally, we revealed that the ComX-degrading MecA-ClpCP machinery plays a predominant role based on the identification of a single amino-acid substitution in the adaptor protein MecA of a highly transformable strain. Contrasting with closely-related streptococci, the master competence regulator in L. lactis is regulated both proximally by general sensors and distantly by the Clp degradation machinery. This study not only highlights the diversity of regulatory networks for competence control in Gram-positive bacteria, but it also paves the way for the use of natural transformation as a tool to manipulate this biotechnologically important bacterium.
PubMed: 38950059
DOI: 10.1371/journal.pgen.1011340 -
Methods in Molecular Biology (Clifton,... 2024Antimicrobial resistance (AMR) poses a serious threat to global health, potentially causing 10 million deaths per year globally by 2050. To tackle AMR, researchers from...
Antimicrobial resistance (AMR) poses a serious threat to global health, potentially causing 10 million deaths per year globally by 2050. To tackle AMR, researchers from all around the world have generated a selection of various formulated (viz. nanoparticulate, liposomal) therapeutic combinations to be evaluated for new antimicrobial drug discovery. To meet the urgent need for accelerating new antibacterial drug development, we need rapid but reliable whole-cell assay methods and models to test formulated therapeutic combinations against several pathogens in different in vitro conditions as models of actual infections.Over the past two decades, high-throughput spot-culture growth inhibition assay (HT-SPOTi) has been demonstrated to be a gold-standard drug susceptibility method for evaluating novel chemotherapeutic entities and existing drugs against various microbes of global concern. Our modified HT-SPOTi method serves the purpose of evaluating drug combinations against Gram-positive/negative microorganisms as well as acid-fast bacilli. The newly developed and modified HT-SPOTi assay builds upon the limitations of our previously published method to incorporate antimicrobial susceptibility testing with formulated therapeutic combinations. The modified HT-SPOTi is compared with a range of other antimicrobial susceptibility testing methods and validated using a library of existing antibiotics as well as formulated therapeutic combinations. The modified HT-SPOTi assay can serve as an efficient and reliable high-throughput drug screening platform to discover new potential antimicrobial molecules, including as part of therapeutic formulations.This chapter describes the generation of drug susceptibility profile for formulated therapeutic combinations using modified HT-SPOTi in a semi-automated system.
Topics: Microbial Sensitivity Tests; Anti-Bacterial Agents; High-Throughput Screening Assays; Humans; Bacteria
PubMed: 38949698
DOI: 10.1007/978-1-0716-3981-8_4 -
Chemistry, An Asian Journal Jul 2024Antimicrobial resistance (AMR) poses a serious threat to human health worldwide. It is now more challenging than ever to introduce a potent antibiotic to the market...
Antimicrobial resistance (AMR) poses a serious threat to human health worldwide. It is now more challenging than ever to introduce a potent antibiotic to the market considering rapid emergence of antimicrobial resistance, surpassing the rate of antibiotic drug discovery. Hence, new approaches need to be developed to accelerate the rate of drug discovery process and meet the demands for new antibiotics, while reducing the cost of their development. Machine learning holds immense promise of becoming a useful tool, especially since in the last two decades, exponential growth has occurred in computational power and biological big data analytics. Recent advancements in machine learning algorithms for drug discovery have provided significant clues for potential antibiotic classes. Apart from discovery of new scaffolds, machine learning protocols will significantly impact prediction of AMR patterns and drug metabolism. In this review, we outline power of machine learning in antibiotic drug discovery, metabolic fate, and AMR prediction to support researchers engaged and interested in this field.
PubMed: 38948939
DOI: 10.1002/asia.202400102 -
Evolutionary Applications Jul 2024A suite of plant traits is thought to make weed populations highly invasive, including vigorous growth and reproduction, superior competitive ability, and high dispersal...
A suite of plant traits is thought to make weed populations highly invasive, including vigorous growth and reproduction, superior competitive ability, and high dispersal ability. Using a breeding design and a common garden experiment, we tested whether such an "invasion syndrome" has evolved in an invasive range of , and whether the evolution is likely to be genetically constrained. We found an overall shift in invasive phenotypes between native North American and invasive Japanese populations. The invasive populations were taller and produced more leaves, suggesting a superior ability to exploit limited resources. The populations also produced more allelopathic compounds that can suppress competitor growth. Finally, invasive populations produced more seeds, which are smaller and are released from a greater height, indicating a potential for superior dispersal ability than the native populations. Quantitative genetics analyses found a large amount of additive genetic variation in most focal traits across native and invasive populations, with no systematic differences in its magnitude between the ranges. Genetic covariances among three traits representing invasion strategies (leaf mass, polyacetylene concentration and seed size) were small. The R metric, which measures the effect of genetic covariances on the rate of adaptation, indicated that the covariance neither constrains nor accelerates concerted evolution of these traits. The results suggest that the invasion syndrome in has evolved in the novel range due to ample additive genetic variation, and relatively free from genetic trade-offs.
PubMed: 38948541
DOI: 10.1111/eva.13734 -
PeerJ 2024Ischemic stroke (IS) is a disease with a high mortality and disability rate worldwide, and its incidence is increasing per year. Angiogenesis after IS improves blood...
β-asarone induces viability and angiogenesis and suppresses apoptosis of human vascular endothelial cells after ischemic stroke by upregulating vascular endothelial growth factor A.
Ischemic stroke (IS) is a disease with a high mortality and disability rate worldwide, and its incidence is increasing per year. Angiogenesis after IS improves blood supply to ischemic areas, accelerating neurological recovery. β-asarone has been reported to exhibit a significant protective effect against hypoxia injury. The ability of β-asarone to improve IS injury by inducing angiogenesis has not been distinctly clarified. The experimental rats were induced with middle cerebral artery occlusion (MCAO), and oxygen-glucose deprivation (OGD) model cells were constructed using human microvascular endothelial cell line (HMEC-1) cells. Cerebral infarction and pathological damage were first determined triphenyl tetrazolium chloride (TTC) and hematoxylin and eosin (H&E) staining. Then, cell viability, apoptosis, and angiogenesis were assessed by utilizing cell counting kit-8 (CCK-8), flow cytometry, spheroid-based angiogenesis, and tube formation assays in OGD HMEC-1 cells. Besides, angiogenesis and other related proteins were identified with western blot. The study confirms that β-asarone, like nimodipine, can ameliorate cerebral infarction and pathological damage. β-asarone can also upregulate vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) and induce phosphorylation of p38. Besides, the study proves that β-asarone can protect against IS injury by increasing the expression of VEGFA. experiments affirmed that β-asarone can induce viability and suppress apoptosis in OGD-mediated HMEC-1 cells and promote angiogenesis of OGD HMEC-1 cells by upregulating VEGFA. This establishes the potential for β-asarone to be a latent drug for IS therapy.
Topics: Allylbenzene Derivatives; Anisoles; Apoptosis; Ischemic Stroke; Humans; Vascular Endothelial Growth Factor A; Cell Survival; Animals; Up-Regulation; Rats; Endothelial Cells; Male; Cell Line; Rats, Sprague-Dawley; Neovascularization, Physiologic; Angiogenesis
PubMed: 38948219
DOI: 10.7717/peerj.17534 -
IScience Jun 2024Stem cell therapy for intrauterine adhesions (IUAs) has been widely used in clinical treatment. However, intravenous injection lacks sufficient targeting capabilities,...
Stem cell therapy for intrauterine adhesions (IUAs) has been widely used in clinical treatment. However, intravenous injection lacks sufficient targeting capabilities, while injection poses challenges in ensuring the effective survival of stem cells. Furthermore, the mechanism underlying the interaction between stem cells and endometrial cells remains poorly understood, and there is a lack of suitable models for studying these problems. Here, we designed an extracellular matrix (ECM)-adhesion mimic hydrogel for intrauterine administration, which was more effective than direct injection in treating IUAs. Additionally, we analyzed the epithelial-mesenchymal transition (EMT) and confirmed that the activation of endometrial epithelial stem cells is pivotal. Our findings demonstrated that umbilical cord mesenchymal stem cells (UC-MSCs) secrete WNT7A to activate endometrial epithelial stem cells, thereby accelerating regeneration of the endometrial epithelium. Concurrently, under transforming growth factor alpha (TGFA) stimulation secreted by the EMT epithelium, UC-MSCs upregulate E-cadherin while partially implanting into the endometrial epithelium.
PubMed: 38947517
DOI: 10.1016/j.isci.2024.109888 -
Research Square Jun 2024Background Epigenetic Age (EA) is an age estimate, developed using DNA methylation (DNAm) states of selected CpG sites across the genome. Although EA and chronological...
Background Epigenetic Age (EA) is an age estimate, developed using DNA methylation (DNAm) states of selected CpG sites across the genome. Although EA and chronological age are highly correlated, EA may not increase uniformly with time. Departures, known as epigenetic age acceleration (EAA), are common and have been linked to various traits and future disease risk. Limited by available data, most studies investigating these relationships have been cross-sectional - using a single EA measurement. However, the recent growth in longitudinal DNAm studies has led to analyses of associations with EA over time. These studies differ in (i) their choice of model; (ii) the primary outcome (EA vs. EAA); and (iii) in their use of chronological age or age-independent time variables to account for the temporal dynamic. We evaluated the robustness of each approach using simulations and tested our results in two real-world examples, using biological sex and birthweight as predictors of longitudinal EA. Results Our simulations showed most accurate effect sizes in a linear mixed model or generalized estimating equation, using chronological age as the time variable. The use of EA versus EAA as an outcome did not strongly impact estimates. Applying the optimal model in real-world data uncovered an accelerated EA rate in males and an advanced EA that decelerates over time in children with higher birthweight. Conclusion Our results can serve as a guide for forthcoming longitudinal EA studies, aiding in methodological decisions that may determine whether an association is accurately estimated, overestimated, or potentially overlooked.
PubMed: 38947070
DOI: 10.21203/rs.3.rs-4482915/v1