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Uncertainty about the future rises in recessions. But is uncertainty a source of business cycles or an endogenous response to them, and does the type of uncertainty matter? We propose a novel SVAR identification strategy to address these questions via inequality constraints on the structural shocks. We find that sharply higher macroeconomic uncertainty in recessions is often an endogenous response to output shocks, while uncertainty about financial markets is a likely source of output fluctuations.

In the paper, a novel magneto-electro-elastic model of bi-directional (2D) functionally graded materials (FGMs) beams is developed for investigating the nonlinear dynamics. It is shown that the asymmetric modes induced by the 2D FGMs may significantly affect the nonlinear dynamic responses, which is tremendously different from previous studies. Taking into account the geometric nonlinearity, the nonlinear equation of motion and associated boundary conditions for the beams are derived according to the Hamilton’s principle. The natural frequencies and numerical modes of the beams are calculated by the generalized differential quadrature method. The frequency responses of the nonlinear forced vibration are constructed based on the Galerkin technique incorporating with the incremental harmonic balance approach. The influences of the material distributions, length–thickness ratio, electric voltage, magnetic potential as well as boundary condition on the nonlinear resonant frequency and response amplitude are discussed in details. It is notable that increasing in the axial and thickness FG indexes, negative electric potential and positive magnetic potential can lead to decline the nonlinear resonance frequency and amplitude peak, which is usually applied to accurately design the multi-ferroic composite structures. Furthermore, the nonlinear characteristics of motion can be regulated by tuning/tailoring the 2D FG materials.

Emerging spatial technologies, including spatial transcriptomics and spatial epigenomics, are becoming powerful tools for profiling of cellular states in the tissue context 1 , 2 , 3 , 4 – 5 . However, current methods capture only one layer of omics information at a time, precluding the possibility of examining the mechanistic relationship across the central dogma of molecular biology. Here, we present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications (H3K27me3, H3K27ac or H3K4me3) and gene expression on the same tissue section at near-single-cell resolution. These were applied to embryonic and juvenile mouse brain, as well as adult human brain, to map how epigenetic mechanisms control transcriptional phenotype and cell dynamics in tissue. Although highly concordant tissue features were identified by either spatial epigenome or spatial transcriptome we also observed distinct patterns, suggesting their differential roles in defining cell states. Linking epigenome to transcriptome pixel by pixel allows the uncovering of new insights in spatial epigenetic priming, differentiation and gene regulation within the tissue architecture. These technologies are of great interest in life science and biomedical research. The authors present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications and gene expression on the same tissue section at near-single-cell resolution.

Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context 1 . The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping 2 – 5 , but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry 6 and microfluidic deterministic barcoding 5 . Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain regions. Applying spatial-ATAC-seq to tonsil tissue resolved the spatially distinct organization of immune cell types and states in lymphoid follicles and extrafollicular zones. This technology progresses spatial biology by enabling spatially resolved chromatin accessibility profiling to improve our understanding of cell identity, cell state and cell fate decision in relation to epigenetic underpinnings in development and disease. Spatial-ATAC-seq—spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing—delineated tissue-region-specific epigenetic landscapes in mouse embryos and identified gene regulators involved in the development of the central nervous system and the lymphoid tissue.

Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs) 1 , 2 , but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics 3 , 4 , cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism. Stress induces hair greying in mice through depletion of melanocyte stem cells, which is mediated by the activation of sympathetic nerves rather than through immune attack or adrenal stress hormones.

To investigate the mechanism by which CBX2 promotes oral squamous cell carcinoma (OSCC) by increasing CEP55/NF-κB/METTL3/SHP2 signaling, leading to metastasis, proliferation, and angiogenesis. We employed a comprehensive research approach. Through bioinformatics analysis (GSE153918 dataset), we identified differentially expressed genes (DEGs) and enriched pathways associated with OSCC and CBX2. Immunohistochemistry (IHC) was used to detect CBX2 expression in both tumor and peritumoral tissues from OSCC patients. Twenty-four BALB/c nude mice were divided into three groups and infected with or without CBX2-KD and/or METTL3-OE lentiviruses. Tumor volume and weight changes were observed in nude mice. IHC was performed to observe the protein expression of CBX2 and METTL3. The oral squamous cell carcinoma cell line SCC-25 was divided into six groups and subjected to CBX2 knockdown, NF-κB activation, METTL3 inhibition, METTL3 overexpression, and SHP2 inhibition. Western blot was used to observe the protein expression of CBX2, CEP55, p-NF-κB, METTL3, TGFβ1, p-SHP2, p-PI3K, Slug and Snail. Using Co-Immunoprecipitation (Co-IP) technology, we analyzed the interactions between endogenous CBX2 and CEP55, as well as the interactions between METTL3 and SHP2, and between METTL3 and TGFβ1, in cells. Wound healing, Transwell, and colony formation assays were conducted to observe the migration, invasion, and proliferation of tumor cells. Western blot was used to analyze the protein expression of VEGFA and H1F1α, and tube formation assays was performed to observe the effects on angiogenesis. Bioinformatic analysis revealed the critical role of the CBX2-NF-κB-METTL3-SHP2 pathway in oral squamous cell carcinoma. IHC results showed that CBX2 expression was lower in peritumoral tissues and higher in OSCC tissues. Tumor formation and IHC results in nude mice showed that CBX2 knockdown inhibited tumor growth, and METTL3 overexpression reversed this effect. Western blot results indicated that CBX2 knockdown, NF-κB activation, METTL3 inhibition, METTL3 overexpression, and SHP2 inhibition all upregulated or downregulated downstream signaling molecules. Co-IP experiments indicated that endogenous CBX2 and CEP55 physically interacted in SCC-25 cells, and METTL3 specifically interacted with SHP2 and TGFβ1. Wound healing, Transwell, and colony formation assays showed that CBX2 knockdown, NF-κB activation, METTL3 inhibition, METTL3 overexpression, and SHP2 inhibition all inhibited or promoted tumor cell migration, invasion, and proliferation. Western blot and tube formation assay results showed that CBX2 knockdown, NF-κB activation, METTL3 inhibition, METTL3 overexpression, and SHP2 inhibition all inhibited or promoted angiogenesis. CBX2 promoted oral squamous cell carcinoma via increasing CEP55/NF-κB/METTL3/SHP2 signaling, leading to metastasis, proliferation, and angiogenesis.

Objective In this study, we investigated the changes in peripheral blood inflammatory factors and intestinal flora in acquired immune deficiency syndrome (AIDS) and human immunodeficiency virus (HIV)-positive individuals (AIDS/HIV patients), and explored the relationships among intestinal flora, peripheral blood inflammatory factors, and CD4 + T lymphocytes. Methods Thirty blood and stool samples from an AIDS group and a control group were collected. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA), and the number of CD4 + T lymphocytes by a FACSCount automated instrument. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the messenger RNA (mRNA) levels of Bifidobacterium , Lactobacillus , Escherichia coli , Enterococcus faecalis , and Enterococcus faecium . Correlations among intestinal flora, inflammatory factor levels, and CD4 + T lymphocyte values were evaluated using the Spearman correlation coefficient. Results The levels of TNF-α and IL-6 in the AIDS group were higher than those in the control group, while the number of CD4 + T lymphocytes was lower. The amounts of Bifidobacterium and Lactobacillus in the AIDS group were significantly lower than those in control group, while the amounts of E. coli , E. faecalis , and E. faecium were much higher. The amounts of Bifidobacterium and Lactobacillus were negatively correlated with the content of TNF-α and IL-6 and the CD4 + T lymphocyte count, while those correlations were reversed for E. coli , E. faecalis , and E. faecium . Conclusions The intestinal microbiota of AIDS/HIV patients were disordered, and there was a correlation between the amount of intestinal flora and the number of CD4 + T lymphocytes and the levels of TNF-α and IL-6.

Chronic, sustained exposure to stressors can profoundly affect tissue homeostasis, although the mechanisms by which these changes occur are largely unknown. Here we report that the stress hormone corticosterone—which is derived from the adrenal gland and is the rodent equivalent of cortisol in humans—regulates hair follicle stem cell (HFSC) quiescence and hair growth in mice. In the absence of systemic corticosterone, HFSCs enter substantially more rounds of the regeneration cycle throughout life. Conversely, under chronic stress, increased levels of corticosterone prolong HFSC quiescence and maintain hair follicles in an extended resting phase. Mechanistically, corticosterone acts on the dermal papillae to suppress the expression of Gas6 , a gene that encodes the secreted factor growth arrest specific 6. Restoring Gas6 expression overcomes the stress-induced inhibition of HFSC activation and hair growth. Our work identifies corticosterone as a systemic inhibitor of HFSC activity through its effect on the niche, and demonstrates that the removal of such inhibition drives HFSCs into frequent regeneration cycles, with no observable defects in the long-term. Stress inhibits  hair growth in mice through the release of the stress hormone corticosterone from the adrenal glands, which inhibits the activation of hair follicle stem cells by suppressing the expression of a secreted factor, GAS6, from the dermal niche.

The NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome-mediated inflammatory responses are critically involved in the progression of atherosclerosis (AS), which is the essential cause for cardiovascular diseases. Melatonin has anti-inflammatory properties. However, little is known about the potential effects of melatonin in the pathological process of AS. Herein, we demonstrate that melatonin suppressed prolonged NLRP3 inflammasome activation in atherosclerotic lesions by reactive oxygen species (ROS) scavenging via mitophagy in macrophages. The atherosclerotic mouse model was induced with a high-fat diet using ApoE−/− mice. Melatonin treatment markedly attenuated AS plaque size and vulnerability. Furthermore, melatonin decreased NLRP3 inflammasome activation and the consequent IL-1β secretion within atherosclerotic lesions. Despite the unchanged protein expression, the silent information regulator 3 (Sirt3) activity was elevated in the atherosclerotic lesions in melatonin-treated mice. In ox-LDL-treated macrophages, melatonin attenuated the NLRP3 inflammasome activation and the inflammatory factors secretion, while this protective effect was abolished by either Sirt3 silence or autophagy inhibitor 3-MA. Mitochondrial ROS (mitoROS), which was a recognized inducer for NLRP3 inflammasome, was attenuated by melatonin through the induction of mitophagy. Both Sirt3-siRNA and autophagy inhibitor 3-MA partially abolished the beneficial effects of melatonin on mitoROS clearance and NLRP3 inflammasome activation, indicating the crucial role of Sirt3-mediated mitophagy. Furthermore, we demonstrated that melatonin protected against AS via the Sirt3/FOXO3a/Parkin signaling pathway. In conclusion, the current study demonstrated that melatonin prevented atherosclerotic progression, at least in part, via inducing mitophagy and attenuating NLRP3 inflammasome activation, which was mediated by the Sirt3/FOXO3a/Parkin signaling pathway. Collectively, our study provides insight into melatonin as a new target for therapeutic intervention for AS.

Globally, gastric cancer (GC) is one of the most common types of cancer and the third leading cause of cancer-related death. In China, gastric and liver cancers have the highest mortality rates. Melatonin, also known as N-acetyl-5-methoxytryptamine, is a hormone that is produced by the pineal gland in animals and regulates sleep and wakefulness. Melatonin has been shown to inhibit various carcinomas, including GC. There are many different hypotheses to explain the anticancer effects of melatonin, including stimulation of apoptosis, inhibition of cell growth, regulation of anticancer immunity, induction of free-radical scavenging, and the competitive inhibition of estrogen. However, the underlying mechanism by which these effects are elicited remains elusive. The aim of the present study was to investigate the effects of melatonin on human GC cells and determine the underlying molecular mechanism. We treated SGC-7901 GC cells with melatonin and analyzed the resulting protein changes using protein chip technology. Several proteins related to cell apoptosis and proliferation were identified and further tested in SGC-7901 GC cells. We found that melatonin induced cell cycle arrest and the downregulation of CDC25A, phospho-CDC25A (at Ser75), p21 (p21Cip1/p21Waf1) and phospho-p21 (at Thr145). Melatonin also induced upregulation of Bax, downregulation of Bcl-xL, an increase in cleaved caspase-9 level and activation of caspase-3, which confirmed the involvement of the mitochondria in melatonin-induced apoptosis. Upstream regulators of the above proteins, MDM2, phospho-MDM2 (at Ser166) and AKT, phospho-AKT (at Thr308) were all attenuated by melatonin, which led to an increase in p53. The present study demonstrated that the oncostatic effects of melatonin on SGC-7901 GC cells are mediated via the blockade of the AKT/MDM2 intracellular pathway.