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Edges and surfaces play indispensable roles in affecting the chemical-physical properties of materials, particularly in two-dimensional transition metal dichalcogenides (TMDCs) with reduced dimensionality. Herein, we report a novel edge/surface structure in multilayer 1T-TiSe2, i.e., the orthogonal (1 × 1) reconstruction, induced by the self-intercalation of Ti atoms into interlayer octahedral sites of the host TiSe2 at elevated temperature. Formation dynamics of the reconstructed edge/surface are captured at the atomic level by in situ scanning transmission electron microscopy (STEM) and further validated by density functional theory (DFT), which enables the proposal of the nucleation mechanism and two growth routes (zigzag and armchair). Via STEM-electron energy loss spectroscopy (STEM-EELS), a chemical shift of 0.6 eV in Ti L3,2 is observed in the reconstructed edge/surface, which is attributed to the change of the coordination number and lattice distortion. The present work provides insights to tailor the atomic/electronic structures and properties of 2D TMDC materials.
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BACKGROUND: Cardiovascular disease may be the main reason for stagnant growth in life expectancy in the United States since 2010. The American Heart Association recently released an updated algorithm for evaluating cardiovascular health (CVH)-Life's Essential 8 (LE8) score. We aimed to quantify the associations of CVH levels, estimated by the LE8 score, with life expectancy in a nationally representative sample of US adults. METHODS: We included 23 003 nonpregnant, noninstitutionalized participants aged 20 to 79 years who participated in the National Health and Nutrition Examination Survey from 2005 to 2018 and whose mortality was identified through linkage to the National Death Index through December 31, 2019. The overall CVH was evaluated by the LE8 score (range, 0-100), as well as the score for each component of diet, physical activity, tobacco/nicotine exposure, sleep duration, body mass index, non-high-density lipoprotein cholesterol, blood glucose, and blood pressure. Life table method was used to estimate life expectancy by levels of the CVH. RESULTS: During a median of 7.8 years of follow-up, 1359 total deaths occurred. The estimated life expectancy at age 50 years was 27.3 years (95% CI, 26.1-28.4), 32.9 years (95% CI, 32.3-33.4), and 36.2 years (95% CI, 34.2-38.2) in participants with low (LE8 score <50), moderate (50≤ LE8 score <80), and high (LE8 score ≥80) CVH, respectively. Equivalently, participants with high CVH had an average 8.9 (95% CI, 6.2-11.5) more years of life expectancy at age 50 years compared with those with low CVH. On average, 42.6% of the gained life expectancy at age 50 years from adhering to high CVH was attributable to reduced cardiovascular disease death. Similarly significant associations of CVH with life expectancy were observed in men and women, respectively. Similarly significant associations of CVH with life expectancy were observed in White participants and Black participants but not in Mexican participants. CONCLUSIONS: Adhering to a high CVH, defined as the LE8 score, is related to a considerably increased life expectancy in US adults, but more research needs to be done in other races and ethnicities (eg, Hispanic and Asian).
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Doenças Cardiovasculares , Masculino , Adulto , Humanos , Estados Unidos/epidemiologia , Feminino , Pessoa de Meia-Idade , Doenças Cardiovasculares/diagnóstico , Inquéritos Nutricionais , Dieta , Pressão Sanguínea , Nível de Saúde , Expectativa de Vida , Fatores de RiscoRESUMO
Spectrum-structure correlation is playing an increasingly crucial role in spectral analysis and has undergone significant development in recent decades. With the advancement of spectrometers, the high-throughput detection triggers the explosive growth of spectral data, and the research extension from small molecules to biomolecules accompanies massive chemical space. Facing the evolving landscape of spectrum-structure correlation, conventional chemometrics becomes ill-equipped, and deep learning assisted chemometrics rapidly emerges as a flourishing approach with superior ability of extracting latent features and making precise predictions. In this review, the molecular and spectral representations and fundamental knowledge of deep learning are first introduced. We then summarize the development of how deep learning assist to establish the correlation between spectrum and molecular structure in the recent 5 years, by empowering spectral prediction (i.e., forward structure-spectrum correlation) and further enabling library matching and de novo molecular generation (i.e., inverse spectrum-structure correlation). Finally, we highlight the most important open issues persisted with corresponding potential solutions. With the fast development of deep learning, it is expected to see ultimate solution of establishing spectrum-structure correlation soon, which would trigger substantial development of various disciplines.
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BACKGROUND: Diabetes patients are at higher risk for mortality than the general population; however, little is known about whether the excess mortality risk associated with diabetes could be mitigated or nullified via controlling for risk factors. METHODS: We included 18,535 diabetes patients and 91,745 matched individuals without diabetes without baseline cancer or cardiovascular disease (CVD), followed up from 2006 to 2021. The main exposure was the number of optimized risk factors including glycated hemoglobin < 53 mmol/mole, systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg, no albuminuria, non-current smoking and low-density lipoprotein cholesterol (LDL-C) < 2.5 mmol/L. We used Cox proportional hazards models to explore the association of the degree of risk factor control with all-cause mortality, cancer mortality, CVD mortality and other mortality. RESULTS: Each additional risk factor control was associated with a 16, 10, 21 and 15% lower risk of all-cause mortality, cancer mortality, CVD mortality and other mortality, respectively. Optimal risk factors control (controlling 5 risk factors) was associated with a 50% (HR 0.50, 95% CI 0.41-0.62), 74% (HR 0.26, 95% CI 0.16-0.43) and 38% (HR 0.62, 95% CI 0.44-0.87) lower risk of all-cause mortality, CVD mortality and other mortality, respectively. Diabetes patients with 4, 3 and 5 or more controlled risk factors, respectively, showed no excess risk of all-cause mortality, cancer mortality and CVD mortality compared to matched non-diabetes patients. CONCLUSIONS: The results from this study indicate that optimal risk factor control may eliminate diabetes-related excess risk of all-cause mortality, CVD mortality and other mortality.
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Doenças Cardiovasculares , Diabetes Mellitus , Neoplasias , Humanos , Estudos de Coortes , Biobanco do Reino Unido , Bancos de Espécimes Biológicos , Fatores de RiscoRESUMO
BACKGROUND: Spinal cord injury (SCI) is characterized by extensive demyelination and inflammatory responses. Facilitating the clearance of lipid droplets (LDs) within microglia contributes to creating a microenvironment that favors neural recovery and provides essential materials for subsequent remyelination. Therefore, investigating MicroRNAs (miRNAs) that regulate lipid homeostasis after SCI and elucidating their potential mechanisms in promoting LDs clearance in microglia have become focal points of SCI research. METHODS: We established a subacute C5 hemicontusion SCI model in mice and performed transcriptomic sequencing on the injury epicenter to identify differentially expressed genes and associated pathways. Confocal imaging was employed to observe LDs accumulation. Multi-omics analyses were conducted to identify differentially expressed mRNA and miRNA post-SCI. Pathway enrichment analysis and protein-protein interaction network construction were performed using bioinformatics methods, revealing miR-223-Abca1 as a crucial miRNA-mRNA pair in lipid metabolism regulation. BV2 microglia cell lines overexpressing miR-223 were engineered, and immunofluorescence staining, western blot, and other techniques were employed to assess LDs accumulation, relevant targets, and inflammatory factor expression, confirming its role in regulating lipid homeostasis in microglia. RESULTS: Histopathological results of our hemicontusion SCI model confirmed LDs aggregation at the injury epicenter, predominantly within microglia. Our transcriptomic analysis during the subacute phase of SCI in mice implicated ATP-binding cassette transporter A1 (Abca1) as a pivotal gene in lipid homeostasis, cholesterol efflux and microglial activation. Integrative mRNA-miRNA multi-omics analysis highlighted the crucial role of miR-223 in the neuroinflammation process following SCI, potentially through the regulation of lipid metabolism via Abca1. In vitro experiments using BV2 cells overexpressing miR-223 demonstrated that elevated levels of miR-223 enhance ABCA1 expression in myelin debris and LPS-induced BV2 cells. This promotes myelin debris degradation and LDs clearance, and induces a shift toward an anti-inflammatory M2 phenotype. CONCLUSIONS: In summary, our study unveils the critical regulatory role of miR-223 in lipid homeostasis following SCI. The mechanism by which this occurs involves the upregulation of ABCA1 expression, which facilitates LDs clearance and myelin debris degradation, consequently alleviating the lipid burden, and inhibiting inflammatory polarization of microglia. These findings suggest that strategies to enhance miR-223 expression and target ABCA1, thereby augmenting LDs clearance, may emerge as appealing new clinical targets for SCI treatment.
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Transportador 1 de Cassete de Ligação de ATP , Gotículas Lipídicas , Camundongos Endogâmicos C57BL , MicroRNAs , Microglia , Traumatismos da Medula Espinal , Regulação para Cima , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , MicroRNAs/metabolismo , MicroRNAs/genética , Microglia/metabolismo , Microglia/patologia , Animais , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Gotículas Lipídicas/metabolismo , Camundongos , Linhagem Celular , Masculino , Metabolismo dos Lipídeos/genéticaRESUMO
BACKGROUND AND AIMS: Alcohol-perturbed gut immune homeostasis is associated with the development of alcoholic liver disease (ALD). However, the role of intestinal dendritic cells (DCs) in ALD progression is still unknown. This study aimed to investigate the cellular and molecular mechanisms through which intestinal DCs respond to alcohol exposure and contribute to the pathogenesis of ALD. APPROACH AND RESULTS: After 8 weeks of alcohol consumption, the number of basic leucine zipper transcription factor ATF-like 3 ( Batf3 )-dependent conventional type 1 DCs (cDC1s) was dramatically decreased in the intestine but not the liver. cDC1 deficient Batf3 knockout mice along with wild-type mice were subjected to chronic-binge ethanol feeding to determine the role of intestinal cDC1s reduction in ALD. cDC1s deficiency exacerbated alcohol-induced gut barrier disruption, bacterial endotoxin translocation into the circulation, and liver injury. Adoptive transfer of cDC1s to alcohol-fed mice ameliorated alcohol-mediated gut barrier dysfunction and liver injury. Further studies revealed that intestinal cDC1s serve as a positive regulator of Akkermansia muciniphila ( A. muciniphila ). Oral administration of A. muciniphila markedly reversed alcoholic steatohepatitis in mice. Mechanistic studies revealed that cDC1s depletion exacerbated alcohol-downregulated intestinal antimicrobial peptides which play a crucial role in maintaining A. muciniphila abundance, by disrupting the IL-12-interferon gamma signaling pathway. Lastly, we identified that intestinal cDC1s were required for the protective role of Lactobacillus reuteri in alcoholic steatohepatitis. CONCLUSIONS: This study demonstrated that cDC1s protect alcohol-induced liver injury by maintaining A. muciniphila abundance in mice. Targeting cDC1s may serve as a promising therapeutic approach for treating ALD.
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Fígado Gorduroso Alcoólico , Hepatopatias Alcoólicas , Camundongos , Animais , Hepatopatias Alcoólicas/prevenção & controle , Hepatopatias Alcoólicas/patologia , Etanol , Verrucomicrobia , Células Dendríticas/metabolismo , Endotoxinas , Camundongos Endogâmicos C57BLRESUMO
Computing thermal transport from first-principles in UO_{2} is complicated due to the challenges associated with Mott physics. Here, we use irreducible derivative approaches to compute the cubic and quartic phonon interactions in UO_{2} from first principles, and we perform enhanced thermal transport computations by evaluating the phonon Green's function via self-consistent diagrammatic perturbation theory. Our predicted phonon lifetimes at T=600 K agree well with our inelastic neutron scattering measurements across the entire Brillouin zone, and our thermal conductivity predictions agree well with previous measurements. Both the changes due to thermal expansion and self-consistent contributions are nontrivial at high temperatures, though the effects tend to cancel, and interband transitions yield a substantial contribution.
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Renal fibrosis plays a key role in the pathogenesis of chronic kidney disease (CKD), in which the persistent high expression of transforming growth factor ß1 (TGF-ß1) and α-smooth muscle actin (α-SMA) contributes to the progression of CKD to renal failure. In order to improve the solubility, bioavailability, and targeting of tanshinone IIA (Tan IIA), a novel targeting material, aminoethyl anisamide-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphate ethanolamine (AEAA-PEG-DSPE, APD) modified Tan IIA liposomes (APD-Tan IIA-L) was constructed. An animal model of glomerulonephritis induced by doxorubicin in BALB/c mice was established. APD-Tan IIA-L significantly decreased blood urea nitrogen and serum creatinine (SCr), and the consequences of renal tissue oxidative stress indicators showed that APD-Tan IIA-L downregulated malondialdehyde, upregulated superoxide dismutase, catalase, and glutathione peroxidase. Masson's trichrome staining showed that the deposition of collagen in the APD-Tan IIA-L group decreased significantly. The pro-fibrotic factors (fibronectin, collagen I, TGF-ß1, and α-SMA) and epithelial-mesenchymal transition marker (N-cadherin) were significantly inhibited by APD-Tan IIA-L. By improving the microenvironment of fibrotic kidneys, APD-Tan IIA-L attenuated TGF-ß1-induced excessive proliferation of fibroblasts and alleviated oxidative stress damage to the kidney, providing a new strategy for the clinical treatment of renal fibrosis.
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Abietanos , Doxorrubicina , Fibrose , Glomerulonefrite , Rim , Lipossomos , Camundongos Endogâmicos BALB C , Animais , Camundongos , Lipossomos/química , Abietanos/farmacologia , Abietanos/química , Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Masculino , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/patologia , Fator de Crescimento Transformador beta1/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Modelos Animais de Doenças , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/induzido quimicamenteRESUMO
BACKGROUND: It is still unclear whether social support can moderate the high risk of depression and anxiety due to spontaneous miscarriage. OBJECTIVE: This study prospectively investigated the associations of spontaneous miscarriage with risks of depression and anxiety, and evaluated the interactions between spontaneous miscarriage and the degree of social support in relation to depression and anxiety risks. STUDY DESIGN: A total of 179,000 participants from the UK Biobank with pregnancy experience and without depression or anxiety at baseline were included. Spontaneous miscarriage was defined by self-report from participants at enrollment or by International Classification of Diseases codes. The degree of social support was defined as the number of social support factors including living with a spouse or partner, participation in social activities, and confiding. Cox proportional hazards models were used to evaluate the joint association of spontaneous miscarriage and social support with the risks of depression and anxiety. RESULTS: During a median follow-up of 12.3 years, 4939 depression incidents and 5742 anxiety incidents were documented. For participants with 1, 2, and ≥3 spontaneous miscarriages, hazard ratios (95% confidence intervals) for depression were 1.10 (1.02-1.19), 1.31 (1.14-1.50), and 1.40 (1.18-1.67), respectively (P trend <.001), compared with participants without a history of spontaneous miscarriage, after adjustment for covariates. For anxiety, the hazard ratios (95% confidence intervals) were 1.07 (1.00-1.15), 1.04 (0.90-1.19), and 1.21 (1.02-1.44), respectively (P trend=.01). Moreover, we found that the risk of depression associated with a combination of spontaneous miscarriage and low degree of social support in later life was greater than the sum of the risks associated with each individual factor, indicating significant interactions on an additive scale (P interaction=.03). CONCLUSION: Spontaneous miscarriage is associated with higher risks of depression and anxiety, and the risk of depression is further increased when there is also low degree of social support.
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AIM: Women with diabetes are at higher risk of cardiovascular diseases (CVD) than men with diabetes; however, the sex difference in the association between the degree of risk factor control and the risk of CVD in patients with diabetes is unclear. METHODS: In total, 17 260 participants diagnosed with diabetes from the UK Biobank were included and matched with 86 300 non-diabetes controls based on age, sex and assessment centre. The main exposure was the number of risk factors within the target range, including glycated haemoglobin level <53 mol/mol (7%), blood pressure <140/90 mm/Hg, low-density lipoprotein cholesterol <100 mg/dl, non-current smoking and absence of microalbuminuria. RESULTS: During a median follow-up of 13.3 years, a total of 3338 incident CVD cases, including 2807 ischaemic heart disease and 793 strokes, were documented. A more stringent control of risk factors was significantly associated with a lower risk of incident CVD, and such an association was significantly stronger in women than men. Compared with non-diabetes participants, the diabetes-related risk of CVD appeared to be eliminated if more than three risk factors were well controlled among women and men with diabetes. Moreover, clinical biomarkers (e.g. glycated haemoglobin and blood pressure) showed greater relative importance than other factors in women, whereas socio-economic and psychological factors (e.g. education and depression) exhibited similar relative importance to clinical biomarkers in men with diabetes. CONCLUSION: Our findings highlighted the importance of raising awareness of sex differences in the management of CVD risk factors among patients with diabetes.
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Doenças Cardiovasculares , Diabetes Mellitus , Humanos , Feminino , Masculino , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/diagnóstico , Hemoglobinas Glicadas , Diabetes Mellitus/epidemiologia , Fatores de Risco , BiomarcadoresRESUMO
AIM: To investigate the extent to which joint risk factor control might attenuate the excess risk of chronic kidney disease (CKD) in participants with obesity. PATIENTS AND METHODS: We included a total of 97 538 participants who were obese at baseline and matched 97 538 normal weight control participants from the UK Biobank in the analysis. The degree of joint risk factor control was assessed based on six major CKD risk factors, including blood pressure, glycated haemoglobin, low-density lipoprotein cholesterol, albuminuria, smoking and physical activity. The Cox proportional hazards models were used to estimate associations between the degree of risk factor control and risk of CKD, following participants from their baseline assessment until the occurrence of CKD, death, or the end of the follow-up period. RESULTS: Among participants with obesity, joint risk factor control showed an association with a stepwise reduction of incident CKD risk. Each additional risk factor control corresponded to an 11% (hazard ratio: 0.89; 95% confidence interval: 0.86-0.91) reduced risk of CKD among participants with obesity, with the optimal controlling of all six risk factors associated with a 49% (hazard ratio: 0.51; 95% confidence interval: 0.43-0.61) decrease in risk of CKD. Furthermore, in individuals with obesity who jointly controlled all six risk factors, the excess risk of CKD associated with obesity was effectively neutralized compared with normal weight control subjects. Notably, the protective correlations between the degree of joint risk factor control and the incidence of CKD were more pronounced in men compared with women, in individuals with a lower healthy food score versus a higher score, and among diabetes medication users as opposed to non-users (pinteraction = 0.017, 0.033 and 0.014, respectively). CONCLUSION: The joint risk factor control is associated with an inverse association of CKD risk in an accumulative manner among individuals with obesity. Achieving ideal control over risk factors may effectively counterbalance the excessive risk of CKD typically associated with obesity.
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AIM: To prospectively assess the association of smoking timing with the risk of type 2 diabetes (T2D) and examine whether smoking amount or genetic susceptibility might modify the relationship. MATERIALS AND METHODS: A total of 294 815 participants without diabetes from the UK Biobank, including non-smokers and smokers with data on the time from waking to first cigarette, were included. Cox proportional hazards models were used to evaluate the association between smoking timing and the risk of incident T2D. RESULTS: During a median follow-up time of 12 years, a total of 9937 incident cases of T2D were documented. Compared with non-smokers, a shorter time from waking to first cigarette was significantly associated with a higher risk of incident T2D (P for trend < .001). In the fully adjusted model, the hazard ratios (HRs) (95% confidence interval) associated with smoking timing were 1.46 (1.17-1.81) for more than 2 hours, 1.51 (1.21-1.87) for 1-2 hours, 1.58 (1.34-1.85) for 30-60 minutes, 1.86 (1.57-2.21) for 5-15 minutes and 2.01 (1.60-2.54) for less than 5 minutes. We found that even among those who reported being light smokers, those with the shortest time from waking to first cigarette had a 105% higher risk of T2D with an HR of 2.05 (1.52-2.76), which was comparable with heavy smokers. The genetic risk score for T2D did not modify this association (P-interaction = .51). CONCLUSIONS: Our findings indicate that shorter time from waking to first cigarette is significantly associated with a higher risk of incident T2D.
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Diabetes Mellitus Tipo 2 , Predisposição Genética para Doença , Fumar , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos de Coortes , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiologia , Seguimentos , Incidência , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Fatores de Tempo , Biobanco do Reino Unido , Reino Unido/epidemiologiaRESUMO
BACKGROUND: The American Heart Association recently released a new cardiovascular health (CVH) metric, Life's Essential 8 (LE8), for health promotion. However, the association between levels of LE8 and the risk of cardiovascular disease (CVD) outcomes is not known from a large prospective cohort. We aim to analyze the relationship between CVH, indicated by LE8, and risks of coronary heart disease (CHD), stroke, and CVD. Moreover, we sought to test whether the genetic susceptibility to CHD or stroke could be modified by LE8. METHODS: A total of 137 794 participants free of CVD from the UK Biobank were included. CVH was scored using LE8 and categorized as low, moderate, and high. RESULTS: During a median of 10 years, 8595 CVD cases (6968 CHDs and 1948 strokes) were documented. A higher LE8 score was associated with remarkably lower risks of CHD, stroke, and CVD (P<0.001 for all). Comparing the high CVH to the low CVH, the hazard ratios (95% CI) were 0.34 (0.30-0.38) for CHD, 0.45 (0.37-0.54) for stroke, and 0.36 (0.33-0.40) for CVD. Moreover, the model with LE8 achieved higher accuracy and outperformed the model with Life's Simple 7 for CHD, stroke, and CVD (P<0.001 for all). The protective associations of the LE8 score with CVD outcomes were more pronounced among women (P interaction, <0.001 for CHD and 0.0013 for CVD, respectively) and among younger adults (P interaction, <0.001, 0.007, and <0.001 for CHD, stroke, and CVD, respectively). In addition, a significant interaction was found between the genetic risk of CHD and the LE8 score (P interaction, <0.001). The inverse association was stronger among those with a lower genetic risk of CHD. CONCLUSIONS: High level of CVH, defined by LE8, was associated with significantly lower risks of CHD, stroke, and CVD.
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Doenças Cardiovasculares , Doença das Coronárias , Acidente Vascular Cerebral , Adulto , Estados Unidos/epidemiologia , Humanos , Feminino , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos Prospectivos , Predisposição Genética para Doença , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Doença das Coronárias/epidemiologia , Doença das Coronárias/genéticaRESUMO
Facial palsy therapies based on cortical plasticity are in development, but facial synkinesis progress is limited. Studying neural plasticity characteristics, especially network organization and its constitutive elements (nodes/edges), is the key to overcome the bottleneck. We studied 55 participants (33 facial synkinesis patients, 22 healthy controls) with clinical assessments, functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI). We analyzed rich-club organization and metrics of structural brain networks (rich-club coefficients, strength, degree, density, and efficiency). Functional brain network metrics, including functional connectivity and its coupling with the structural network, were also computed. Patients displayed reduced strength and density of rich-club nodes and edges, as well as decreased global efficiency. All nodes exhibited decreased nodal efficiency in patients. Patients had significantly increased functional connectivity and decreased structural-functional coupling strength in rich-club nodes, rich-club edges, and feeder edges. Our study indicates that facial synkinesis patients have weakened structural connections but enhanced functional transmission from rich-club nodes. The loss of connections and efficiency in structural network may trigger compensatory increases in functional connectivity of rich-club nodes. Two potential biomarkers, rich-club edge density and structural-functional coupling strength, may serve as indicators of disease outcome. These findings provide valuable insights into synkinesis mechanisms and offer potential targets for cortical intervention.
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Imagem de Tensor de Difusão , Sincinesia , Humanos , Sincinesia/diagnóstico por imagem , Sincinesia/patologia , Encéfalo , Imageamento por Ressonância Magnética , Vias Neurais/diagnóstico por imagemRESUMO
BACKGROUND: Lipid droplet (LD)-laden microglia is a key pathological hallmark of multiple sclerosis. The recent discovery of this novel microglial subtype, lipid-droplet-accumulating microglia (LDAM), is notable for increased inflammatory factor secretion and diminished phagocytic capability. Lipophagy, the autophagy-mediated selective degradation of LDs, plays a critical role in this context. This study investigated the involvement of microRNAs (miRNAs) in lipophagy during demyelinating diseases, assessed their capacity to modulate LDAM subtypes, and elucidated the potential underlying mechanisms involved. METHODS: C57BL/6 mice were used for in vivo experiments. Two weeks post demyelination induction at cervical level 4 (C4), histological assessments and confocal imaging were performed to examine LD accumulation in microglia within the lesion site. Autophagic changes were observed using transmission electron microscopy. miRNA and mRNA multi-omics analyses identified differentially expressed miRNAs and mRNAs under demyelinating conditions and the related autophagy target genes. The role of miR-223 in lipophagy under these conditions was specifically explored. In vitro studies, including miR-223 upregulation in BV2 cells via lentiviral infection, validated the bioinformatics findings. Immunofluorescence staining was used to measure LD accumulation, autophagy levels, target gene expression, and inflammatory mediator levels to elucidate the mechanisms of action of miR-223 in LDAM. RESULTS: Oil Red O staining and confocal imaging revealed substantial LD accumulation in the demyelinated spinal cord. Transmission electron microscopy revealed increased numbers of autophagic vacuoles at the injury site. Multi-omics analysis revealed miR-223 as a crucial regulatory gene in lipophagy during demyelination. It was identified that cathepsin B (CTSB) targets miR-223 in autophagy to integrate miRNA, mRNA, and autophagy gene databases. In vitro, miR-223 upregulation suppressed CTSB expression in BV2 cells, augmented autophagy, alleviated LD accumulation, and decreased the expression of the inflammatory mediator IL-1ß. CONCLUSION: These findings indicate that miR-223 plays a pivotal role in lipophagy under demyelinating conditions. By inhibiting CTSB, miR-223 promotes selective LD degradation, thereby reducing the lipid burden and inflammatory phenotype in LDAM. This study broadens the understanding of the molecular mechanisms of lipophagy and proposes lipophagy induction as a potential therapeutic approach to mitigate inflammatory responses in demyelinating diseases.
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Autofagia , Catepsina B , Doenças Desmielinizantes , Gotículas Lipídicas , Lisofosfatidilcolinas , Camundongos Endogâmicos C57BL , MicroRNAs , Microglia , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Microglia/metabolismo , Microglia/patologia , Camundongos , Gotículas Lipídicas/metabolismo , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Catepsina B/metabolismo , Catepsina B/genética , Lisofosfatidilcolinas/metabolismo , Modelos Animais de Doenças , Masculino , Regulação da Expressão Gênica , Linhagem CelularRESUMO
BACKGROUND: Obesity has been related to depression and adhering healthy lifestyle was beneficial to lower the risk of depression; however, little is known about the relationship between body composition and fat distribution with depression risk and the influence of body composition and fat distribution on the association of lifestyle and depression. Therefore, we aimed to investigate whether body composition and fat distribution were associated with the adverse events of depression and the relationship between lifestyle and depression. METHODS: We included 330,131 participants without depression at baseline in the UK Biobank (mean age, 56.9 years; 53.83% females). The assessment of depression was sourced from health outcomes across self-report, primary care, hospital inpatient data, and death data. Body composition was determined by bioelectrical impedance. Seven lifestyles (no current smoking, moderate alcohol consumption, regular physical activity, healthy diet, less sedentary behavior, healthy sleep pattern, and appropriate social connection) were used to generate a lifestyle score. RESULTS: During a median of 11.7 years of follow-up, 7576 incident depression occurred. All the body composition measures were positively associated with depression risk, with the Hazard ratios (HR) for the uppermost tertile (T3) versus the lowest tertile (T1) ranging from 1.26 (95% CI: 1.15-1.39) for trunk fat-free mass (TFFM) to 1.78 (1.62-1.97) for leg fat percentage (LFP). In addition, we found significant interactions between fat mass-related indices, especially leg fat mass (LFM) (p = 1.65 × 10-9), and lifestyle score on the risk of depression, for which the beneficial associations of a healthy lifestyle with the risk of depression were more evident among participants with low body fat measurement. CONCLUSIONS: High levels of body composition measures were associated with an increased depression risk. Adverse body composition measures may weaken the link between a healthy lifestyle and a reduced risk of depression.
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Bancos de Espécimes Biológicos , Biobanco do Reino Unido , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Estudos Prospectivos , Fatores de Risco , Depressão , Estilo de Vida , Composição Corporal , Estilo de Vida SaudávelRESUMO
Arsenic, a common metal-like substance, has been demonstrated to pose potential health hazards and induce behavioral changes in humans and rodents. However, the chronic neurotoxic effects of arsenic on aquatic animals are still not fully understood. This study aimed to investigate the effects of arsenic exposure on adult zebrafish by subjecting 3-month-old zebrafish to three different sodium arsenite water concentrations: 0⯵g/L (control group), 50⯵g/L, and 500⯵g/L, over a period of 30 days. To assess the risk associated with arsenic exposure in the aquatic environment, behavior analysis, transmission electron microscopy techniques, and quantitative real-time PCR were employed. The behavior of adult zebrafish was evaluated using six distinct tests: the mirror biting test, shoaling test, novel tank test, social preference test, social recognition test, and T maze. Following the behavioral tests, the brains of zebrafish were dissected and collected for ultrastructural examination and gene expression analysis. The results revealed that sodium arsenite exposure led to a significant reduction in aggression, cohesion, social ability, social cognition ability, learning, and memory capacity of zebrafish. Furthermore, ultrastructure and genes regulating behavior in the zebrafish brain were adversely affected by sodium arsenite exposure.
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Arsenic, a neurotoxic metalloid, poses significant health risks. However, ellagic acid, renowned for its antioxidant properties, has shown potential in neuroprotection. This study aimed to investigate the neuroprotective effects of ellagic acid against arsenic-induced neuronal ferroptosis and cognitive impairment and elucidate the underlying mechanisms. Using an arsenic-exposed Wistar rat model and an arsenic-induced HT22 cells model, we assessed cognitive ability, measured serum and brain arsenic levels, and evaluated pathological damage through histological analysis and transmission electron microscopy. Additionally, we examined oxidative stress and iron ion levels using GSH, MDA, ROS and tissue iron biochemical kits, and analyzed the expression of ferroptosis-related markers using western blot and qRT-PCR. Our results revealed that arsenic exposure increased both serum and brain arsenic levels, resulting in hippocampal pathological damage and subsequent decline in learning and memory abilities. Arsenic-induced neuronal ferroptosis was mediated by the inhibition of the xCT/GSH/GPX4/Nrf2 signaling axis and disruption of iron metabolism. Notably, ellagic acid intervention effectively reduced serum and brain arsenic levels, ameliorated neuronal damage, and improved oxidative stress, ferroptosis, and cognitive impairment. These beneficial effects were associated with the activation of the Nrf2/Keap1 signaling pathway, upregulation of GPX4 expression, and enhanced iron ion excretion. In conclusion, ellagic acid demonstrates promising neuroprotective effects against arsenic-induced neurotoxicity by mitigating neuronal ferroptosis and cognitive impairment.
RESUMO
Fluoride exposure has been implicated as a potential risk factor for hypertension, but the underlying mechanisms remain unclear. This study investigated the role of the RhoA/ROCK signaling pathway in fluoride-induced hypertension. Male Wistar rats were divided into different groups and exposed to varying concentrations of sodium fluoride (NaF) or sodium chloride (NaCl) via drinking water. The rats' blood pressure was measured, and their aortic tissue was utilized for high-throughput sequencing analysis. Additionally, rat and A7r5 cell models were established using NaF and/or Fasudil. The study evaluated the effects of fluoride exposure on blood pressure, pathological changes in the aorta, as well as the protein/mRNA expression levels of phenotypic transformation indicators (a-SMA, calp, OPN) in vascular smooth muscle cells (VSMCs), along with the RhoA/ROCK signaling pathway (RhoA, ROCK1, ROCK2, MLC/p-MLC). The results demonstrated that fluoride exposure in rats led to increased blood pressure. High-throughput sequencing analysis revealed differential gene expression associated with vascular smooth muscle contraction, with the RhoA/ROCK signaling pathway emerging as a key regulator. Pathological changes in the rat aorta, such as elastic membrane rupture and collagen fiber deposition, were observed following NaF exposure. However, fasudil, a ROCK inhibitor, mitigated these pathological changes. Both in vitro and in vivo models confirmed the activation of the RhoA/ROCK signaling pathway and the phenotypic transformation of VSMCs from a contractile to a synthetic state upon fluoride exposure. Fasudil effectively inhibited the activities of ROCK1 and ROCK2 and attenuated the phenotypic transformation of VSMCs. In conclusion, fluoride has the potential to induce hypertension through the activation of the RhoA/ROCK signaling pathway and phenotypic changes in vascular smooth muscle cells. These results provide new insights into the mechanism of fluoride-induced hypertension.
Assuntos
Hipertensão , Músculo Liso Vascular , Ratos Wistar , Transdução de Sinais , Quinases Associadas a rho , Animais , Quinases Associadas a rho/metabolismo , Masculino , Hipertensão/induzido quimicamente , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteína rhoA de Ligação ao GTP/metabolismo , Fluoreto de Sódio/toxicidade , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Fenótipo , Pressão Sanguínea/efeitos dos fármacos , Fluoretos/toxicidade , Proteínas rho de Ligação ao GTPRESUMO
AIMS: To investigate the prospective associations of the loneliness and social isolation scales with cardiovascular disease (CVD) risk in diabetes patients and compare the relative importance of loneliness and social isolation with traditional risk factors. Also, the interactions of loneliness or isolation with the degree of risk factor control in relation to CVD risk were evaluated. METHODS AND RESULTS: A total of 18 509 participants diagnosed with diabetes from the UK Biobank were included. A two-item scale and a three-item scale were used to assess loneliness and isolation levels, respectively. The degree of risk factor control was defined as numbers of glycated hemoglobin (HbA1c), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), smoking, and kidney condition controlled within the target range. During a mean follow-up of 10.7 years, 3247 total CVD incidents were documented, including 2771 coronary heart disease and 701 strokes. In the fully adjusted model, compared with participants with the lowest loneliness score (zero), hazard ratios (95% confidence interval) for CVD were 1.11 (1.02 and 1.20) and 1.26 (1.11 and 1.42) for participants with a loneliness scale of 1 and 2, respectively (P-trend < 0.001). No significant associations were observed for social isolation. Loneliness ranked higher in relative strength for predicting CVD than the lifestyle risk factors in diabetes patients. A significant additive interaction between loneliness and the degree of risk factor control on the risk of CVD was observed (P for additive interaction = 0.005). CONCLUSION: Among diabetes patients, loneliness, but not social isolation scale, is associated with a higher risk of CVD and shows an additive interaction with the degree of risk factor control.