Geroscience. 2023 Oct 2. doi: 10.1007/s11357-023-00927-x. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD) is an age-related disease, with loss of integrity of the blood-brain barrier (BBB) being an early feature. Cellular senescence is one of the reported nine hallmarks of aging. Here, we show for the first time the presence of senescent cells in the vasculature in AD patients and mouse models of AD. Senescent endothelial cells and pericytes are present in APP/PS1 transgenic mice but not in wild-type littermates at the time of amyloid deposition. In vitro, senescent endothelial cells display altered VE-cadherin expression and loss of cell junction formation and increased permeability. Consistent with this, senescent endothelial cells in APP/PS1 mice are present at areas of vascular leak that have decreased claudin-5 and VE-cadherin expression confirming BBB breakdown. Furthermore, single cell sequencing of endothelial cells from APP/PS1 transgenic mice confirms that adhesion molecule pathways are among the most highly altered pathways in these cells. At the pre-plaque stage, the vasculature shows significant signs of breakdown, with a general loss of VE-cadherin, leakage within the microcirculation, and obvious pericyte perturbation. Although senescent vascular cells were not directly observed at sites of vascular leak, senescent cells were close to the leak area. Thus, we would suggest in AD that there is a progressive induction of senescence in constituents of the neurovascular unit contributing to an increasing loss of vascular integrity. Targeting the vasculature early in AD, either with senolytics or with drugs that improve the integrity of the BBB may be valid therapeutic strategies.

PMID:37782439 | DOI:10.1007/s11357-023-00927-x

Elife. 2023 Oct 2;12:e85569. doi: 10.7554/eLife.85569. Online ahead of print.

ABSTRACT

In order to understand morphogenesis, it is necessary to know the material properties or forces shaping the living tissue. In spite of this need, very few in vivo measurements are currently available. Here, using the early Drosophila embryo as a model, we describe a novel cantilever-based technique which allows for the simultaneous quantification of applied force and tissue displacement in a living embryo. By analyzing data from a series of experiments in which embryonic epithelium is subjected to developmentally relevant perturbations, we conclude that the response to applied force is adiabatic and is dominated by elastic forces and geometric constraints, or system size effects. Crucially, computational modeling of the experimental data indicated that the apical surface of the epithelium must be softer than the basal surface, a result which we confirmed experimentally. Further, we used the combination of experimental data and comprehensive computational model to estimate the elastic modulus of the apical surface and set a lower bound on the elastic modulus of the basal surface. More generally, our investigations revealed important general features that we believe should be more widely addressed when quantitatively modeling tissue mechanics in any system. Specifically, different compartments of the same cell can have very different mechanical properties; when they do, they can contribute differently to different mechanical stimuli and cannot be merely averaged together. Additionally, tissue geometry can play a substantial role in mechanical response, and cannot be neglected.

PMID:37782009 | DOI:10.7554/eLife.85569

EMBO J. 2023 Oct 2:e114032. doi: 10.15252/embj.2023114032. Online ahead of print.

ABSTRACT

Bone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner. Notably, hypoxia-induced SREBP2 activation was only observed in an immature lineage of bone marrow-derived cells. Single-cell RNA-seq analysis revealed that SREBP2-mediated cholesterol biosynthesis was upregulated in HSCs and monocytes but not in macrophages in the hypoxic bone marrow niche. Moreover, inhibition of cholesterol biosynthesis impaired tumor growth through suppression of pro-tumorigenic immunity and angiogenesis. Thus, our findings indicate that Golgi-ER fusion regulates SREBP2-mediated metabolic alteration in lineage-specific BMDCs under hypoxia for tumor progression.

PMID:37781951 | DOI:10.15252/embj.2023114032

Mol Ther Oncolytics. 2023 Sep 13;31:100725. doi: 10.1016/j.omto.2023.09.001. eCollection 2023 Dec 19.

ABSTRACT

Immunotherapies have emerged as promising strategies for cancer treatment. However, existing immunotherapies have poor activity in high-grade serous ovarian cancer (HGSC) due to the immunosuppressive tumor microenvironment and the associated low tumoral CD8+ T cell (CTL) infiltration. Through multiple lines of evidence, including integrative analyses of human HGSC tumors, we have identified miR-146a as a master regulator of CTL infiltration in HGSC. Tumoral miR-146a expression is positively correlated with anti-cancer immune signatures in human HGSC tumors, and delivery of miR-146a to tumors resulted in significant reduction in tumor growth in both ID8-p53-/- and IG10 murine HGSC models. Increasing miR-146a expression in tumors improved anti-tumor immune responses by decreasing immune suppressive neutrophils and increasing CTL infiltration. Mechanistically, miR-146a targets IL-1 receptor-associated kinase 1 and tumor necrosis factor receptor-associated factor 6 adaptor molecules of the transcription factor nuclear factor κB signaling pathway in ID8-p53-/- cells and decreases production of the downstream neutrophil chemoattractant, C-X-C motif chemokine ligand 1. In addition to HGSC, tumoral miR-146a expression also correlates strongly with CTL infiltration in other cancer types including thyroid, prostate, breast, and adrenocortical cancers. Altogether, our findings highlight the ability of miR-146a to overcome immune suppression and improve CTL infiltration in tumors.

PMID:37781339 | PMC:PMC10539880 | DOI:10.1016/j.omto.2023.09.001

Front Physiol. 2023 Sep 15;14:1200119. doi: 10.3389/fphys.2023.1200119. eCollection 2023.

ABSTRACT

Lithium is commonly prescribed as a mood stabilizer in a variety of mental health conditions, yet its molecular mode of action is incompletely understood. Many cellular events associated with lithium appear tied to mitochondrial function. Further, recent evidence suggests that lithium bioactivities are isotope specific. Here we focus on lithium effects related to mitochondrial calcium handling. Lithium protected against calcium-induced permeability transition and decreased the calcium capacity of liver mitochondria at a clinically relevant concentration. In contrast, brain mitochondrial calcium capacity was increased by lithium. Surprisingly, 7Li acted more potently than 6Li on calcium capacity, yet 6Li was more effective at delaying permeability transition. The size distribution of amorphous calcium phosphate colloids formed in vitro was differentially affected by lithium isotopes, providing a mechanistic basis for the observed isotope specific effects on mitochondrial calcium handling. This work highlights a need to better understand how mitochondrial calcium stores are structurally regulated and provides key considerations for future formulations of lithium-based therapeutics.

PMID:37781224 | PMC:PMC10540846 | DOI:10.3389/fphys.2023.1200119

Int J Biol Sci. 2023 Aug 21;19(14):4427-4441. doi: 10.7150/ijbs.86608. eCollection 2023.

ABSTRACT

Diabetic kidney disease (DKD) is a global health issue that presents a complex pathogenesis and limited treatment options. To provide guidance for precise therapies, it is crucial to accurately identify the pathogenesis of DKD. Several studies have recognized that mitochondrial and endoplasmic reticulum (ER) dysfunction are key drivers of the pathogenesis of DKD. The mitochondria-associated ER membrane (MAM) is a dynamic membrane contact site (MSC) that connects the ER and mitochondria and is essential in maintaining the normal function of the two organelles. MAM is involved in various cellular processes, including lipid synthesis and transport, calcium homeostasis, mitochondrial fusion and fission, and ER stress. Meanwhile, recent studies confirm that MAM plays a significant role in the pathogenesis of DKD by regulating glucose metabolism, lipid metabolism, inflammation, ER stress, mitochondrial fission and fusion, and autophagy. Herein, this review aims to provide a comprehensive summary of the physiological function of MAMs and their impact on the progression of DKD. Subsequently, we discuss the trend of pharmaceutical studies that target MAM resident proteins for treating DKD. Furthermore, we also explore the future development prospects of MAM in DKD research, thereby providing a new perspective for basic studies and clinical treatment of DKD.

PMID:37781026 | PMC:PMC10535705 | DOI:10.7150/ijbs.86608

Front Cell Infect Microbiol. 2023 Sep 14;13:1281638. doi: 10.3389/fcimb.2023.1281638. eCollection 2023.

NO ABSTRACT

PMID:37780851 | PMC:PMC10539553 | DOI:10.3389/fcimb.2023.1281638

Front Plant Sci. 2023 Sep 13;14:1254107. doi: 10.3389/fpls.2023.1254107. eCollection 2023.

ABSTRACT

Xanthomonas arboricola pv. corylina (Xac; formerly Xanthomonas campestris pv. corylina) is the causal agent of the bacterial blight of hazelnuts, a devastating disease of trees in plant nurseries and young orchards. Currently, there are no PCR assays to distinguish Xac from all other pathovars of X. arboricola. A comparative genomics approach with publicly available genomes of Xac was used to identify unique sequences, conserved across the genomes of the pathogen. We identified a 2,440 bp genomic region that was unique to Xac and designed identification and detection systems for conventional PCR, qPCR (SYBR® Green and TaqMan™), and loop-mediated isothermal amplification (LAMP). All PCR assays performed on genomic DNA isolated from eight X. arboricola pathovars and closely related bacterial species confirmed the specificity of designed primers. These new multi-platform molecular diagnostic tools may be used by plant clinics and researchers to detect and identify Xac in pure cultures and hazelnut tissues rapidly and accurately.

PMID:37780515 | PMC:PMC10535005 | DOI:10.3389/fpls.2023.1254107

Amyotroph Lateral Scler Frontotemporal Degener. 2023 Oct 1:1-15. doi: 10.1080/21678421.2023.2261979. Online ahead of print.

ABSTRACT

OBJECTIVE: Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD.

METHODS: By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage.

RESULTS: In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology.

CONCLUSIONS: Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.

PMID:37779364 | DOI:10.1080/21678421.2023.2261979

Behav Brain Sci. 2023 Oct 2;46:e239. doi: 10.1017/S0140525X23000791.

ABSTRACT

Communication barriers long-associated with ideographs, including combinatorial grapholinguistic complexity, computational encoding-decoding complexity, and technological rendering and deployment, become trivialized through advancements in interoperable smart mobile digital devices. Such technologies impart unprecedented extended-reality user hazards only mitigated by unprecedented colloquial and bureaucratic societal norms. Digital age norms thus influence natural ideographic language origins and evolution in ways novel to human history.

PMID:37779285 | DOI:10.1017/S0140525X23000791

Brief Bioinform. 2023 Sep 22;24(6):bbad343. doi: 10.1093/bib/bbad343.

ABSTRACT

Single-cell multiomics techniques have been widely applied to detect the key signature of cells. These methods have achieved a single-molecule resolution and can even reveal spatial localization. These emerging methods provide insights elucidating the features of genomic, epigenomic and transcriptomic heterogeneity in individual cells. However, they have given rise to new computational challenges in data processing. Here, we describe Single-cell Single-molecule multiple Omics Pipeline (ScSmOP), a universal pipeline for barcode-indexed single-cell single-molecule multiomics data analysis. Essentially, the C language is utilized in ScSmOP to set up spaced-seed hash table-based algorithms for barcode identification according to ligation-based barcoding data and synthesis-based barcoding data, followed by data mapping and deconvolution. We demonstrate high reproducibility of data processing between ScSmOP and published pipelines in comprehensive analyses of single-cell omics data (scRNA-seq, scATAC-seq, scARC-seq), single-molecule chromatin interaction data (ChIA-Drop, SPRITE, RD-SPRITE), single-cell single-molecule chromatin interaction data (scSPRITE) and spatial transcriptomic data from various cell types and species. Additionally, ScSmOP shows more rapid performance and is a versatile, efficient, easy-to-use and robust pipeline for single-cell single-molecule multiomics data analysis.

PMID:37779245 | DOI:10.1093/bib/bbad343

Int J Biol Macromol. 2023 Sep 29:127163. doi: 10.1016/j.ijbiomac.2023.127163. Online ahead of print.

ABSTRACT

Due to the multilayer structure of skin tissue, the fabrication of a 3-layer scaffold could result in planned dermal regeneration. Herein, polyurethane (PU) and polycaprolactone (PCL), as a function of their mechanical stability and collagen due to its arginine-glycine-aspartic acid sequences, zinc ions because of overcoming the common problems of biological factors were employed. The scaffolds' physical, mechanical, and biological properties were examined by SEM, FTIR, contact angle, mechanical tensile, bacteriocidal efficacy, and hemolysis. Also, after L-929 fibroblast seeding, their biological activity was determined by SEM, DAPI, and MTT assays. Then, the cell-seeded scaffolds were implanted in full-thickness wounds of rats and evaluated by wound closure, histological, and molecular techniques. The in vivo studies showed better wound closure with the composite scaffold containing zinc ions. While its dermal re-organization was retarded in the presence of zinc ions compared to the composite scaffold containing non-doped bioglass. Despite this, the doped composite scaffold indicated better observations with the histological evaluations than the nontreated and bare scaffold groups. Real-time PCR confirmed the higher expression of FGF2 and FGFR genes in rats treated with the zinc-doped composite scaffold. In conclusion, PU/PCL-collagen/PCL-collagen containing the doped or non-doped nanoparticles showed better potential to heal dermal injuries.

PMID:37778589 | DOI:10.1016/j.ijbiomac.2023.127163

Curr Opin Biotechnol. 2023 Sep 29;84:103004. doi: 10.1016/j.copbio.2023.103004. Online ahead of print.

ABSTRACT

Systems metabolic engineering, which integrates metabolic engineering with systems biology, synthetic biology, and evolutionary engineering, has revolutionized the sustainable production of fuels and materials through the creation of efficient microbial cell factories. Recent advancements in systems metabolic engineering targeting different biological components of the host cell have enabled the creation of highly productive microbial cell factories. This article provides a review of the recent tools and strategies used for enzyme-, genetic module-, pathway-, flux-, genome-, and cell-level engineering, supported by illustrative examples. Furthermore, we highlight recent trends in systems metabolic engineering, which involve the application of multiple tools discussed in this review. Finally, the paper addresses the challenges and perspectives of transitioning academic-level metabolic engineering studies to commercial-scale production.

PMID:37778304 | DOI:10.1016/j.copbio.2023.103004

Microbiome. 2023 Oct 2;11(1):219. doi: 10.1186/s40168-023-01651-6.

ABSTRACT

BACKGROUND: Goat is an important livestock worldwide, which plays an indispensable role in human life by providing meat, milk, fiber, and pelts. Despite recent significant advances in microbiome studies, a comprehensive survey on the goat microbiomes covering gastrointestinal tract (GIT) sites, developmental stages, feeding styles, and geographical factors is still unavailable. Here, we surveyed its multi-kingdom microbial communities using 497 samples from ten sites along the goat GIT.

RESULTS: We reconstructed a goat multi-kingdom microbiome catalog (GMMC) including 4004 bacterial, 71 archaeal, and 7204 viral genomes and annotated over 4,817,256 non-redundant protein-coding genes. We revealed patterns of feeding-driven microbial community dynamics along the goat GIT sites which were likely associated with gastrointestinal food digestion and absorption capabilities and disease risks, and identified an abundance of large intestine-enriched genera involved in plant fiber digestion. We quantified the effects of various factors affecting the distribution and abundance of methane-producing microbes including the GIT site, age, feeding style, and geography, and identified 68 virulent viruses targeting the methane producers via a comprehensive virus-bacterium/archaea interaction network.

CONCLUSIONS: Together, our GMMC catalog provides functional insights of the goat GIT microbiota through microbiome-host interactions and paves the way to microbial interventions for better goat and eco-environmental qualities. Video Abstract.

PMID:37779211 | DOI:10.1186/s40168-023-01651-6

J Nutr. 2023 Sep 30:S0022-3166(23)72539-X. doi: 10.1016/j.tjnut.2023.07.016. Online ahead of print.

ABSTRACT

Our ability to identify anemia and all its permutations demands an approach that integrates the key elements of a complex "ecology," which intertwines biology and mechanistic aspects of nutrients with both the health status and underlying factors-physical, economic, social, behavioral, demographic, and environmental. The complexity of anemia demands an ecologic approach that appreciates systems biology, translates sensitive and specific assessment methodologies and interventions, and ultimately improves clinical and public health outcomes. This series of technical papers on anemia by the U.S. Agency for International Development (USAID) Advancing Nutrition Anemia Task Force (ATF) is a first step in translating our ecologic approach to anemia with a view toward balancing research with its translation to effective programs, interventions, and policy. This introductory overview describes the components of our ecologic approach-linking the biology of anemia with its assessment and using the learning from that confluence to devise context-specific interventions. This introductory review briefly discusses the topics that underlie the biology and primary etiologies of anemia and presents a framework for public health assessment of anemia, leading to appropriate public health interventions. The other 3 manuscripts in the supplement provide the details of the arguments laid out in the introduction.

PMID:37778890 | DOI:10.1016/j.tjnut.2023.07.016

Cell Rep. 2023 Sep 30;42(10):113196. doi: 10.1016/j.celrep.2023.113196. Online ahead of print.

ABSTRACT

Maintaining healthy adipose tissue is crucial for metabolic health, requiring a deeper understanding of adipocyte development and response to high-calorie diets. This study highlights the importance of TET3 during white adipose tissue (WAT) development and expansion. Selective depletion of Tet3 in adipose precursor cells (APCs) reduces adipogenesis, protects against diet-induced adipose expansion, and enhances whole-body metabolism. Transcriptomic analysis of wild-type and Tet3 knockout (KO) APCs unveiled TET3 target genes, including Pparg and several genes linked to the extracellular matrix, pivotal for adipogenesis and remodeling. DNA methylation profiling and functional studies underscore the importance of DNA demethylation in gene regulation. Remarkably, targeted DNA demethylation at the Pparg promoter restored its transcription. In conclusion, TET3 significantly governs adipogenesis and diet-induced adipose expansion by regulating key target genes in APCs.

PMID:37777963 | DOI:10.1016/j.celrep.2023.113196

Sci Rep. 2023 Sep 30;13(1):16451. doi: 10.1038/s41598-023-43825-0.

ABSTRACT

Multiplex PCR is an increasingly popular method for identifying species, investigating environmental diversity, and conducting phylogenetic analysis. The complexity and increasing availability of diverse templates necessitate a highly automated approach to design degenerate primer pairs for specific targets with multiple sequences. Existing tools for degenerate primer design suffer from poor maintenance, semi-automation, low adaptability, and low tolerance for gaps. We developed PMPrimer, a Python-based tool for automated design and evaluation of multiplex PCR primer pairs for specific targets using diverse templates. PMPrimer automatically designs optimal multiplex PCR primer pairs using a statistical-based template filter; performs multiple sequence alignment, conserved region identification, and primer design; and evaluates the primers based on template coverage, taxon specificity, and target specificity. PMPrimer identifies conserved regions using Shannon's entropy method, tolerates gaps using a haplotype-based method, and evaluates multiplex PCR primer pairs based on template coverage and taxon specificity. We tested PMPrimer using datasets with diverse levels of conservation, sizes, and applications, including tuf genes of Staphylococci, hsp65 genes of Mycobacteriaceae, and 16S ribosomal RNA genes of Archaea. PMPrimer showed outstanding performance compared with existing tools and experimental validated primers. PMPrimer is available as a Python package at https://github.com/AGIScuipeng/PMPrimer .

PMID:37777580 | DOI:10.1038/s41598-023-43825-0

Nat Commun. 2023 Sep 30;14(1):6109. doi: 10.1038/s41467-023-41683-y.

ABSTRACT

The influence of aging on intestinal stem cells and their niche can explain underlying causes for perturbation in their function observed during aging. Molecular mechanisms for such a decrease in the functionality of intestinal stem cells during aging remain largely undetermined. Using transcriptome-wide approaches, our study demonstrates that aging intestinal stem cells strongly upregulate antigen presenting pathway genes and over-express secretory lineage marker genes resulting in lineage skewed differentiation into the secretory lineage and strong upregulation of MHC class II antigens in the aged intestinal epithelium. Mechanistically, we identified an increase in proinflammatory cells in the lamina propria as the main source of elevated interferon gamma (IFNγ) in the aged intestine, that leads to the induction of Stat1 activity in intestinal stem cells thus priming the aberrant differentiation and elevated antigen presentation in epithelial cells. Of note, systemic inhibition of IFNγ-signaling completely reverses these aging phenotypes and reinstalls regenerative capacity of the aged intestinal epithelium.

PMID:37777550 | DOI:10.1038/s41467-023-41683-y

J Adv Res. 2023 Oct;52:1. doi: 10.1016/j.jare.2023.09.006.

NO ABSTRACT

PMID:37777321 | DOI:10.1016/j.jare.2023.09.006

Curr Biol. 2023 Sep 22:S0960-9822(23)01231-9. doi: 10.1016/j.cub.2023.09.015. Online ahead of print.

ABSTRACT

Animals with enhanced dim-light sensitivity are at higher risk of light-induced retinal degeneration when exposed to bright light conditions.1,2,3,4 This trade-off is mediated by the rod photoreceptor sensory protein, rhodopsin (RHO), and its toxic vitamin A chromophore by-product, all-trans retinal.5,6,7,8 Rod arrestin (Arr-1) binds to RHO and promotes sequestration of excess all-trans retinal,9,10 which has recently been suggested as a protective mechanism against photoreceptor cell death.2,11 We investigated Arr-1 evolution in animals at high risk of retinal damage due to periodic bright-light exposure of rod-dominated retinas. Here, we find the convergent evolution of enhanced Arr-1/RHO all-trans-retinal sequestration in owls and deep-diving whales. Statistical analyses reveal a parallel acceleration of Arr-1 evolutionary rates in these lineages, which is associated with the introduction of a rare Arr-1 mutation (Q69R) into the RHO-Arr-1 binding interface. Using in vitro assays, we find that this single mutation significantly enhances RHO-all-trans-retinal sequestration by ∼30%. This functional convergence across 300 million years of evolutionary divergence suggests that Arr-1 and RHO may play an underappreciated role in the photoprotection of the eye, with potentially vast clinical significance.

PMID:37776863 | DOI:10.1016/j.cub.2023.09.015