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INTRODUCTION: We examined the associations of polygenic risk score (PRS) with Alzheimer's disease (AD) and plasma biomarkers in the Chinese population. METHODS: This population-based study used baseline data from MIND-China (2018; n = 4873) and follow-up data from dementia-free individuals (2014-2018; n = 2117). We measured AD-related plasma biomarkers in a subsample (n = 1256). Data were analyzed using logistic and Cox regression models. RESULTS: We developed PRS with (PRSAPOE) and without (PRSnon- APOE) apolipoprotein E (APOE) gene. In the longitudinal analysis, PRSAPOE was associated with a multivariable-adjusted hazards ratio of 1.91 (95% CI = 1.13-3.23) for AD. PRSAPOE in combination with demographics yielded discriminative (area under the curve [AUC]) and predictive(C-statistic) accuracy of 0.80 (95% confidence interval [CI] = 0.77-0.84) and 0.80 (0.77-0.82), respectively. PRSnon- APOE showed an association with AD risk similar to PRSAPOE. PRSAPOE, but not PRSnon- APOE, was associated with reduced plasma Aß42/Aß40 ratio and increased Neurofilament light chain (NfL) (p < 0.05). DISCUSSION: The PRS with and without APOE gene, in combination with demographics, shows good discriminative and predictive ability for AD. The AD-related pathologies underlie AD risk associated with PRSAPOE. HIGHLIGHTS: The PRSAPOE and PRSnon- APOE were associated with AD risk in the Chinese population. The PRSAPOE and PRSnon- APOE, in combination with demographics, showed good discriminative and predictive ability for AD. The AD-related pathologies underlie the AD risk associated with PRSAPOE but not PRSnon- APOE.
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INTRODUCTION: Evidence has emerged that cardiometabolic multimorbidity (CMM) is associated with dementia, but the underlying mechanisms are poorly understood. METHODS: This population-based study included 5704 older adults. Of these, data were available in 1439 persons for plasma amyloid-ß (Aß), total tau, and neurofilament light chain (NfL) and in 1809 persons for serum cytokines. We defined CMM following two common definitions used in previous studies. Data were analyzed using general linear, logistic, and mediation models. RESULTS: The presence of CMM was significantly associated with an increased likelihood of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) (p < 0.05). CMM was significantly associated with increased plasma Aß40, Aß42, and NfL, whereas CMM that included visceral obesity was associated with increased serum cytokines. The mediation analysis suggested that plasma NfL significantly mediated the association of CMM with AD. DISCUSSION: CMM is associated with dementia, AD, and VaD in older adults. The neurodegenerative pathway is involved in the association of CMM with AD. HIGHLIGHTS: The presence of CMM was associated with increased likelihoods of dementia, AD, and VaD in older adults. CMM was associated with increased AD-related plasma biomarkers and serum inflammatory cytokines. Neurodegenerative pathway was partly involved in the association of CMM with AD.
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Objectives: Cerebral small vessel disease (CSVD) visible on MRI can be asymptomatic. We sought to develop and validate a model for detecting CSVD in rural older adults. Methods: This study included 1,192 participants in the MRI sub-study within the Multidomain Interventions to Delay Dementia and Disability in Rural China. Total sample was randomly divided into training set and validation set. MRI markers of CSVD were assessed following the international criteria, and total CSVD burden was assessed on a scale from 0 to 4. Logistic regression analyses were used to screen risk factors and develop the diagnostic model. A nomogram was used to visualize the model. Model performance was assessed using the area under the receiver-operating characteristic curve (AUC), calibration plot, and decision curve analysis. Results: The model included age, high blood pressure, white blood cell count, neutrophil-to-lymphocyte ratio (NLR), and history of cerebral infarction. The AUC was 0.71 (95% CI, 0.67-0.76) in the training set and 0.69 (95% CI, 0.63-0.76) in the validation set. The model showed high coherence between predicted and observed probabilities in both the training and validation sets. The model had higher net benefits than the strategy assuming all participants either at high risk or low risk of CSVD for probability thresholds ranging 50-90% in the training set, and 65-98% in the validation set. Conclusion: A model that integrates routine clinical factors could detect CSVD in older adults, with good discrimination and calibration. The model has implication for clinical decision-making.
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Introduction: We sought to characterize cognitive profiles associated with enlarged perivascular spaces (EPVS) among Chinese older adults. Methods: This population-based study included 1191 dementia-free participants (age ≥60 years) in the MIND-China MRI Substudy (2018-2020). We visually evaluated EPVS in basal ganglia (BG) and centrum semiovale (CSO), white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and cortical superficial siderosis. We used a neuropsychological test battery to assess cognitive function. Data were analyzed using general linear models. Results: Greater BG-EPVS load was associated with lower z-scores in memory, verbal fluency, and global cognition (p < 0.05); these associations became non-significant when controlling for other cerebral small vessel disease (CSVD) markers (e.g., WMHs, lacunes, and mixed CMBs). Overall, CSO-EPVS load was not associated with cognitive z-scores (p > 0.05); among apolipoprotein E (APOE) -ε4 carriers, greater CSO-EPVS load was associated with lower verbal fluency z-score, even when controlling for other CSVD markers (p < 0.05). Discussion: The associations of BG-EPVS with poor cognitive function in older adults are largely attributable to other CSVD markers. HIGHLIGHTS: The association of enlarged perivascular spaces (EPVS) with cognitive function in older people is poorly defined.The association of basal ganglia (BG)-EPVS with poor cognition is attributed to other cerebral small vessel disease (CSVD) markers.In apolipoprotein E (APOE) ε4 carriers, a higher centrum semiovale (CSO)-EPVS load is associated with poorer verbal fluency.
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Dibutyl phthalate (DBP) is a widely-used plasticizer that is dispersed in various environments, causing significant pollution and health risks. The toxic mechanism of DBP has been discussed in recent years, while the susceptibility of mitochondrial DNA (mtDNA) to DBP exposure and the resulting damage remain unclear. In this study, maternal zebrafish were exposed to environmentally relevant concentration of DBP for 0, 2, 4, and 6 weeks. Results showed that DBP exposure impaired health status, leading to the reduced body length and weight, condition factor, hepatosomatic index, and gonadosomatic index. Furthermore, DBP exposure induced oxidative stress and ATP deficiency in the gill and liver in a time-dependent manner. The oxidized mtDNA (ox-mtDNA) levels in the D-loop and ND1 regions were assessed in different tissues, showing distinct response patterns. The high energy-consuming tissues such as heart, brain, gill, and liver exhibited elevated susceptibility to mitochondrial damage, with a rapid increase in ox-mtDNA levels in the short term. Conversely, in muscle, ovary, eggs, and offspring, ox-mtDNA gradually accumulated over the exposure period. Notably, the ox-mtDNA levels in the D-loop region of blood showed a prompt response to DBP exposure, making it convenient for evaluation. Additionally, decreased hatching rates, increased mortality, lipoperoxidation, and depressed swimming performance were observed in offspring following maternal DBP exposure, suggesting the inherited impairments of maternal mtDNA. These findings highlight the potential for ox-mtDNA to serve as a convenient biomarker for environmental contamination, aiding in ecological risk assessment and forewarning systems in aquatic environment.
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ADN Mitocondrial , Dibutil Ftalato , Estrés Oxidativo , Contaminantes Químicos del Agua , Pez Cebra , Animales , Contaminantes Químicos del Agua/toxicidad , Dibutil Ftalato/toxicidad , Femenino , ADN Mitocondrial/efectos de los fármacos , ADN Mitocondrial/genética , Estrés Oxidativo/efectos de los fármacos , Branquias/efectos de los fármacos , Branquias/metabolismo , Exposición Materna , Daño del ADN , Hígado/efectos de los fármacosRESUMEN
Ti-based Metal-organic frameworks (Ti-MOF) have been extensively investigated for producing hydrogen via solar water splitting, while their intrinsic activities are still retarded by the poor performance of photocarriers separation and utilization. Herein, a donor-acceptor (D-A) supramolecular photocatalyst is successfully constructed via encapsulating fullerene (C60) into MIL-125-NH2 and meanwhile depositing individual Pt atoms as cocatalyst. The as-prepared C60@MIL-125-NH2-Pt exhibits remarkable activity in photocatalytic water splitting, with a H2 formation rate of 1180 µmol g-1 h-1, which is â¼ 12 times higher than that of the pristine MIL-125-NH2. Further investigations indicate that the host-guest interactions between C60 and MIL-125-NH2 strengthen the built-in electric field, which greatly facilitates the separation and migration of photogenerated charge carriers. In addition, the cocatalyst of individual Pt atoms not only further promotes the separation and transport of carriers but also enhances the contact between water and the catalyst. All of these factors directly contribute to the superior activity of C60@MIL-125-NH2-Pt. This work provides a new perspective for constructing D-A supramolecular photocatalysts for enhanced charge separation and making full use of photoelectrons to realize efficient hydrogen production.
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In this study, high temperature thermotolerant nitrifying bacteria (TNB) and high temperature thermotolerant sulfide oxidizing bacteria (TSOB) were obtained from compost samples and inoculated into sewage sludge (SS) compost. The effects of inoculation on physical and chemical parameters, ammonia and hydrogen sulfide release, nitrogen form and sulfur compound content change and physical-chemical properties during nitrogen and sulfur conversion were studied. The results showed that inoculation of TNB and TSOB increased the temperature, pH, OM degradation, C/N ratio and germination index (GI) of compost. Compared with the control treatment (CK), the addition of inoculants reduced the release of NH3 and H2S, and transformed them into nitrogen and sulfur compounds, the hydrolysis of polymeric ferrous sulfate was promoted, resulting in relatively high content of sulfite and sulfate. At the same time, the physical and chemical properties of SS have a strong correlation with nitrogen and sulfur compounds.
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Compostaje , Nitrificación , Nitrógeno , Aguas del Alcantarillado , Azufre , Aguas del Alcantarillado/microbiología , Nitrógeno/metabolismo , Azufre/metabolismo , Compostaje/métodos , Oxidación-Reducción , Eliminación de Residuos Líquidos/métodos , Bacterias/metabolismoRESUMEN
The neuropathological mechanisms underlying the association between sleep duration and mild cognitive impairment remain poorly understood. This population-based study included 2032 dementia-free people (age ≥ 60 years; 55.1% women) derived from participants in the Multimodal Interventions to Delay Dementia and Disability in Rural China; of these, data were available in 841 participants for Alzheimer's plasma biomarkers (e.g. amyloid-ß, total tau and neurofilament light chain), 1044 for serum microvascular biomarkers (e.g. soluble adhesion molecules) and 834 for brain MRI biomarkers (e.g. whiter matter, grey matter, hippocampus, lacunes, enlarged perivascular spaces and white matter hyperintensity WMH). We used electrocardiogram-based cardiopulmonary coupling analysis to measure sleep duration, a neuropsychological test battery to assess cognitive function and the Petersen's criteria to define mild cognitive impairment. Data were analysed with multivariable logistic and general linear models. In the total sample (n = 2032), 510 participants were defined with mild cognitive impairment, including 438 with amnestic mild cognitive impairment and 72 with non-amnestic mild cognitive impairment. Long sleep duration (>8 versus 6-8â h) was significantly associated with increased likelihoods of mild cognitive impairment and non-amnestic mild cognitive impairment and lower scores in global cognition, verbal fluency, attention and executive function (Bonferroni-corrected P < 0.05). In the subsamples, long sleep duration was associated with higher plasma amyloid-ß40 and total tau, a lower amyloid-ß42/amyloid-ß40 ratio and smaller grey matter volume (Bonferroni-corrected P < 0.05). Sleep duration was not significantly associated with serum-soluble adhesion molecules, white matter hyperintensity volume, global enlarged perivascular spaces and lacunes (P > 0.05). Alzheimer's and neurodegenerative pathologies may represent common pathways linking long sleep duration with mild cognitive impairment and low cognition in older adults.
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BACKGROUND: Individuals with autism spectrum disorder (ASD) have inhibitory control deficits. The combination of transcranial direct current stimulation (tDCS) and inhibitory control training produces good transfer effects and improves neuroplasticity. However, no studies have explored whether applying tDCS over the dlPFC improves inhibitory control and produces transfer effects in children with ASD. OBJECTIVE: To explore whether multisession tDCS could enhance inhibitory control training (response inhibition), near-transfer (interference control) and far-transfer effects (sustained attention; stability of attention) in children with ASD and the generalizability of training effects in daily life and the class, as reflected by behavioral performance and neural activity measured by functional near-infrared spectroscopy (fNIRS). METHODS: Twenty-eight autistic children were randomly assigned to either the true or sham tDCS group. The experimental group received bifrontal tDCS stimulation at 1.5 mA, administered for 15 min daily across eight consecutive days. tDCS was delivered during a computerized Go/No-go training task. Behavioral performance in terms of inhibitory control (Dog/Monkey and Day/Night Stroop tasks), sustained attention (Continuous Performance and Cancellation tests), prefrontal cortex (PFC) neural activity and inhibitory control and sustained attention in the class and at home were evaluated. RESULTS: Training (response inhibition) and transfer effects (interference control; sustained attention) were significantly greater after receiving tDCS during the Go/No-go training task than after receiving sham tDCS. Changes in oxyhemoglobin (HbO) concentrations in the dlPFC and FPA associated with consistent conditions in the Day/Night Stroop and Continuous Performance test were observed after applying tDCS during the inhibitory control training task. Notably, transfer effects can be generalized to classroom environments. CONCLUSION: Inhibitory control training combined with tDCS may be a promising, safe, and effective method for improving inhibitory control and sustained attention in children with ASD.
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Atención , Trastorno del Espectro Autista , Inhibición Psicológica , Espectroscopía Infrarroja Corta , Estimulación Transcraneal de Corriente Directa , Humanos , Estimulación Transcraneal de Corriente Directa/métodos , Masculino , Trastorno del Espectro Autista/terapia , Trastorno del Espectro Autista/fisiopatología , Espectroscopía Infrarroja Corta/métodos , Femenino , Niño , Atención/fisiología , Transferencia de Experiencia en Psicología/fisiología , Corteza Prefrontal/fisiología , Corteza Prefrontal/fisiopatologíaRESUMEN
Nanobubble (NB) technology has gained popularity in the environmental field owing to its distinctive characteristics and ecological safety. More recently, the application of NB technology in anaerobic digestion (AD) systems has been proven to promote substrate degradation and boost the production of biogas (H2 and/or CH4). This review presents the recent advancements in the application of NB technology in AD systems. Meanwhile, it also sheds light on the underlying mechanisms of NB technology that contribute to the enhanced biogas production from AD of organic solid wastes. Specifically, the working principles of the NB generator are first summarized, and then the structure of the NB generator is optimized to accommodate the demand for NB characteristics in the AD system. Subsequently, it delves into a detailed discussion of how the addition of nanobubble water (NBW) affects AD performance and the different factors that NB can potentially contribute. As a simple and environmentally friendly additive, NBW was commonly used in the AD process to enhance the fluidity and mass transfer characteristics of digestate. Additionally, NB has the potential to enhance the functionality of different types of microbial enzymes that play crucial roles in the AD process. This includes boosting extracellular hydrolase activities, optimizing coenzyme F420, and improving cellulase function. Finally, it is proposed that NBW has development potential for the pretreatment of substrate and inoculum, with future development being directed towards this aim.
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Biocombustibles , Eliminación de Residuos , Anaerobiosis , Eliminación de Residuos/métodos , Residuos Sólidos , Reactores BiológicosRESUMEN
BACKGROUND: We sought to examine the associations of the Lifestyle for Brain Health (LIBRA) index with cognitive function among rural Chinese older adults and to explore the potential role of cluster of differentiation 33 gene (CD33) in the associations. METHODS: This population-based cross-sectional study included 4914 dementia-free participants (age ≥60 years; 56.43 % women) in the 2018 baseline examination of MIND-China. The LIBRA index was generated from 11 factors. We used a neuropsychological test battery to assess episodic memory, verbal fluency, attention, executive function, and global cognition. The CD33(rs3865444) polymorphism was detected using multiple-polymerase chain reaction amplification. Data were analyzed using the general linear regression models. RESULTS: A higher LIBRA index was associated with multivariable-adjusted ß-coefficient (95 %CI) of -0.011(-0.020- -0.001) for global cognitive z-score, -0.020(-0.033- -0.006) for episodic memory, and -0.016(-0.029- -0.004) for verbal fluency. The CD33(rs3865444) was associated with a lower global cognitive z-score in the additive (CA vs. CC: ß-coefficient=0.042; 95 %CI=0.008-0.077), the dominant (CA+AA vs. CC: 0.040; 0.007-0.073), and the over-dominant (CA vs. CC+AA: 0.043; 0.009-0.077) models. Similar results were obtained for verbal fluency and attention. The CD33 gene showed statistical interactions with LIBRA index on cognitive function (Pinteraction<0.05) such that a higher LIBRA index was significantly associated with lower z-scores of global cognition and attention only among CD33 CC carriers (P < 0.05). CONCLUSIONS: This population-based study reveals for the first time that a higher LIBRA index is associated with worse cognitive performance in rural Chinese older adults and that CD33 gene could modify the association.
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Cognición , Estilo de Vida , Pruebas Neuropsicológicas , Población Rural , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Humanos , Femenino , Masculino , Anciano , Estudios Transversales , Cognición/fisiología , China/epidemiología , Población Rural/estadística & datos numéricos , Pruebas Neuropsicológicas/estadística & datos numéricos , Lectina 3 Similar a Ig de Unión al Ácido Siálico/genética , Persona de Mediana Edad , Pueblos del Este de AsiaRESUMEN
Plastics contaminations are found globally and fit the exposure profile of the planetary boundary threat. The plasticizer of dibutyl phthalate (DBP) leaching has occurred and poses a great threat to human health and the ecosystem for decades, and its toxic mechanism needs further comprehensive elucidation. In this study, environmentally relevant levels of DBP were used for exposure, and the developmental process, oxidative stress, mitochondrial ultrastructure and function, mitochondrial DNA (mtDNA) instability and release, and mtDNA-cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway with inflammatory responses were measured in zebrafish at early life stage. Results showed that DBP exposure caused developmental impairments of heart rate, hatching rate, body length, and mortality in zebrafish embryo. Additionally, the elevated oxidative stress damaged mitochondrial ultrastructure and function and induced oxidative damage to the mtDNA with mutations and instability of replication, transcription, and DNA methylation. The stressed mtDNA leaked into the cytosol and activated the cGAS-STING signaling pathway and inflammation, which were ameliorated by co-treatment with DBP and mitochondrial reactive oxygen species (ROS) scavenger, inhibitors of cGAS or STING. Furthermore, the larval results suggest that DBP-induced mitochondrial toxicity of energy disorder and inflammation were involved in the developmental defects of impaired swimming capability. These results enhance the interpretation of mtDNA stress-mediated health risk to environmental contaminants and contribute to the scrutiny of mitochondrial toxicants.
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ADN Mitocondrial , Dibutil Ftalato , Pez Cebra , Animales , ADN Mitocondrial/efectos de los fármacos , Dibutil Ftalato/toxicidad , Estrés Oxidativo/efectos de los fármacosRESUMEN
BACKGROUND: Lacunes are associated with cognitive impairment. We sought to identify strategic lacune locations associated with mild cognitive impairment (MCI) and subtypes of MCI among older adults, and further to examine the role of white matter hyperintensities and perivascular spaces in the association. METHODS: This population-based cross-sectional study included 1230 dementia-free participants in the brain magnetic resonance imaging substudy (2018-2020) in MIND-China (Multimodal Interventions to Delay Dementia and Disability in Rural China). Lacunes were visually identified in frontal lobe, parieto-occipital lobe, temporal lobe, insula, basal ganglia, thalamus, cerebellum, and brainstem. MCI, amnestic MCI (aMCI), and nonamnestic MCI (naMCI) were defined following the Petersen's criteria. Data were analyzed using logistic regression models. RESULTS: Of the 1230 participants (age, ≥60 years; mean age, 69.40; SD, 4.30 years; 58.5% women), lacunes were detected in 357 people and MCI was defined in 286 individuals, including 243 with aMCI and 43 with naMCI. Lacunes in the supratentorial area, internal capsula, putamen/pallidum, and insula was significantly associated with increased odds ratio of MCI (multivariable-adjusted odds ratio ranged 1.40-3.21; P<0.05) and aMCI (multivariable-adjusted odds ratio ranged 1.46-3.36; P<0.05), whereas lacunes in the infratentorial area and brainstem were significantly associated with naMCI (multivariable-adjusted odds ratio ranged 2.68-3.46; P<0.01). Furthermore, the associations of lacunes in insula and internal capsula with MCI and aMCI, as well as the associations of lacunes in infratentorial area and brainstem with naMCI were present independent of white matter hyperintensities volume and perivascular spaces number. CONCLUSIONS: Lacunes in the internal capsula, putamen/pallidum, insula, and brainstem may represent the strategic lacunes that are independently associated with MCI, aMCI, or naMCI in Chinese older adults. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1800017758.
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China has become one of the most serious countries suffering from biological invasions in the world. In the context of global climate change, invasive alien species (IAS) are likely to invade a wider area, posing greater ecological and economic threats in China. Western mosquitofish (Gambusia affinis), which is known as one of the 100 most invasive alien species, has distributed widely in southern China and is gradually spreading to the north, causing serious ecological damage and economic losses. However, its distribution in China is still unclear. Hence, there is an urgent need for a more convenient way to detect and monitor the distribution of G. affinis to put forward specific management. Therefore, we detected the distribution of G. affinis in China under current and future climate change by combing Maxent modeling prediction and eDNA verification, which is a more time-saving and reliable method to estimate the distribution of species. The Maxent modeling showed that G. affinis has a broad habitat suitability in China (especially in southern China) and would continue to spread in the future with ongoing climate change. However, eDNA monitoring showed that occurrences can already be detected in regions that Maxent still categorized as unsuitable. Besides temperature, precipitation and human influence were the most important environmental factors affecting the distribution of G. affinis in China. In addition, by environmental DNA analysis, we verified the presence of G. affinis predicted by Maxent in the Qinling Mountains where the presence of G. affinis had not been previously recorded.
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Ciprinodontiformes , ADN Ambiental , Animales , Humanos , Especies Introducidas , Ecosistema , ChinaRESUMEN
Dibutyl phthalate (DBP) contamination has raised global concern for decades, while its health risk with toxic mechanisms requires further elaboration. This study used zebrafish ZF4 cells to investigate the toxicity of ferroptosis with underlying mechanisms in response to DBP exposure. Results showed that DBP induced ferroptosis, characterized by accumulation of ferrous iron, lipid peroxidation, and decrease of glutathione peroxidase 4 levels in a time-dependent manner, subsequently reduced cell viability. Transcriptome analysis revealed that voltage-dependent anion-selective channel (VDAC) in mitochondrial outer membrane was upregulated in ferroptosis signaling pathways. Protecting mitochondria with a VDAC2 inhibitor or siRNAs attenuated the accumulation of mitochondrial superoxide and lipid peroxides, the opening of mitochondrial permeability transition pore (mPTP), and the overload of iron levels, suggesting VDAC2 oligomerization mediated the influx of iron into mitochondria that is predominant and responsible for mitochondria-dependent ferroptosis under DBP exposure. Furthermore, the pivotal role of activating transcription factor 4 (ATF4) was identified in the transcriptional regulation of vdac2 by ChIP assay. And the intervention of atf4b inhibited DBP-induced VDAC2 upregulation and oligomerization. Taken together, this study reveals that ATF4-VDAC2 signaling pathway is involved in the DBP-induced ferroptosis in zebrafish ZF4 cells, contributing to the in-depth understanding of biotoxicity and the ecological risk assessment of phthalates.
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Ferroptosis , Pez Cebra , Animales , Dibutil Ftalato/toxicidad , Dibutil Ftalato/metabolismo , Mitocondrias/metabolismo , Hierro/metabolismoRESUMEN
Recent advancements in the field of endothelial markers of lymphatic vessels and lymphangiogenic factors have shed light on the association between several ocular diseases and ocular nascent lymphatic vessels. The immune privilege of corneal tissue typically limits the formation of lymphatic vessels in a healthy eye. However, vessels in the eyes can potentially undergo lymphangiogenesis and be conditionally activated. It is evident that nascent lymphatic vessels in the eyes contribute to various ocular pathologies. Conversely, lymphatic vessels are present in the corneal limbus, ciliary body, lacrimal glands, optic nerve sheaths, and extraocular muscles, while a lymphatic vasculature-like system exists in the choroid, that can potentially cause several ocular pathologies. Moreover, numerous studies indicate that many ocular diseases can influence or activate nascent lymphatic vessels, ultimately affecting patient prognosis. By understanding the mechanisms underlying the onset, development, and regression of ocular nascent lymphatic vessels, as well as exploring related research on ocular diseases, this article aims to offer novel perspectives for the treatment of such conditions.
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Small cell lung cancer (SCLC) is an aggressive and lethal malignancy. Achaete-scute homolog 1 (ASCL1) is essential for the initiation of SCLC in mice and the development of pulmonary neuroendocrine cells (PNEC), which are the major cells of origin for SCLC. However, the regulatory mechanism of ASCL1 in SCLC remains elusive. Here, we found that ASCL1 expression gradually increases as the tumors grow in a mouse SCLC model, and is regulated by the cell cycle. Mechanistically, CDK2-CyclinA2 complex phosphorylates ASCL1, which results in increased proteasome-mediated ASCL1 protein degradation by E3 ubiquitin ligase HUWE1 during mitosis. TCF3 promotes the multisite phosphorylation of ASCL1 through the CDK2-CyclinA2 complex and the interaction between ASCL1 and TCF3 protects ASCL1 from degradation. The dissociation of TCF3 from ASCL1 during mitosis accelerates the degradation of ASCL1. In addition, chemotherapy drugs greatly reduce the transcription of ASCL1 in SCLC cells. Depletion of ASCL1 sensitizes SCLC cells to chemotherapy drugs. Together, our study demonstrates that ASCL1 is a cell-cycle-regulated protein and provides a theoretical basis for applying cell-cycle-related antitumor drugs in SCLC treatment. Implications:Our study revealed a novel regulatory mechanism of ASCL1 by cell cycle and chemotherapy drugs in SCLC. Treating patients with SCLC with a combination of ASCL1-targeting therapy and chemotherapy drugs could potentially be beneficial.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Ciclo Celular , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Animales , Humanos , Ratones , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
BACKGROUND: The neural cells in the brains of patients with Parkinson's disease (PWP) display aberrant synchronized oscillatory activity within the beta frequency range. Additionally, enhanced gamma oscillations may serve as a compensatory mechanism for motor inhibition mediated by beta activity and also reinstate plasticity in the primary motor cortex affected by Parkinson's disease. Transcranial alternating current stimulation (tACS) can synchronize endogenous oscillations with exogenous rhythms, thereby modulating cortical activity. The objective of this study is to investigate whether the addition of tACS to multidisciplinary intensive rehabilitation treatment (MIRT) can improve symptoms of PWP so as to enhance the quality of life in individuals with Parkinson's disease based on the central-peripheral-central theory. METHODS: The present study was a randomized, double-blind trial that enrolled 60 individuals with Parkinson's disease aged between 45 and 70 years, who had Hoehn-Yahr scale scores ranging from 1 to 3. Participants were randomly assigned in a 1:1 ratio to either the tACS + MIRT group or the sham-tACS + MIRT group. The trial consisted of a two-week double-blind treatment period followed by a 24-week follow-up period, resulting in a total duration of twenty-six weeks. The primary outcome measured the change in PDQ-39 scores from baseline (T0) to 4 weeks (T2), 12 weeks (T3), and 24 weeks (T4) after completion of the intervention. The secondary outcome assessed changes in MDS-UPDRS III scores at T0, the end of intervention (T1), T2, T3, and T4. Additional clinical assessments and mechanistic studies were conducted as tertiary outcomes. DISCUSSION: The objective of this study is to demonstrate that tACS can enhance overall functionality and improve quality of life in PWP, based on the framework of MIRT. Additionally, it seeks to establish a potential correlation between these therapeutic effects and neuroplasticity alterations in relevant brain regions. The efficacy of tACS will be assessed during the follow-up period in order to optimize neuroplasticity and enhance its potential impact on rehabilitation efficiency for PWP. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300071969. Registered on 30 May 2023.
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Enfermedad de Parkinson , Estimulación Transcraneal de Corriente Directa , Humanos , Persona de Mediana Edad , Anciano , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/complicaciones , Estimulación Transcraneal de Corriente Directa/efectos adversos , Estimulación Transcraneal de Corriente Directa/métodos , Calidad de Vida , Terapia por Ejercicio/métodos , Método Doble Ciego , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVE: To investigate the prevalence and associated factors of excessive daytime sleepiness (EDS) among rural-dwelling Chinese older adults. METHODS: We collected data on demographic, epidemiological, and clinical factors via in-person interviews and clinical examinations following a structured questionnaire. The 15-item Geriatric Depression Scale (GDS-15) was used to assess depressive symptoms, the Berlin questionnaire (BQ) to assess obstructive sleep apnea (OSA) risk; and the Epworth Sleepiness Scale (ESS) to assess sleep characteristics. EDS was defined as the total ESS score > 10. RESULTS: This population-based study engaged 4845 participants (age ≥ 65 years, 57.3% female) in the 2018 examination of the Multimodal Interventions to Delay Dementia and Disability in Rural China. The prevalence of EDS was 9.3% in the total sample, 8.3% in females, and 10.6% in males, and the prevalence decreased with advanced age. Logistic regression analysis revealed that EDS was significantly associated with age (multivariable-adjusted odds ratio [OR] = 0.97; 95% confidence interval [CI] 0.95-0.99), female sex (0.53; 0.36-0.77), hypertension (0.68; 0.54-0.85), depressive symptoms (2.68; 2.07-3.46), high OSA risk (2.11; 1.69-2.63), and poor sleep quality (2.12; 1.60-2.82). CONCLUSION: EDS affects nearly one-tenth of rural older adults in China. Older age, female sex, and hypertension were associated with a decreased likelihood of EDS, while depressive symptoms, high OSA risk, and poor sleep quality were correlated with an elevated likelihood of EDS.
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Trastornos de Somnolencia Excesiva , Población Rural , Humanos , Femenino , Masculino , Anciano , Trastornos de Somnolencia Excesiva/epidemiología , Trastornos de Somnolencia Excesiva/diagnóstico , China/epidemiología , Población Rural/estadística & datos numéricos , Prevalencia , Factores de Riesgo , Anciano de 80 o más Años , Apnea Obstructiva del Sueño/epidemiología , Apnea Obstructiva del Sueño/diagnóstico , Estudios TransversalesRESUMEN
For paired binary data, the hybrid method and the score method are often recommended for use to calculate the confidence interval for risk difference. These asymptotic intervals do not control the coverage probability. We propose to develop a new score interval with continuity correction to further improve the performance of the existing intervals. The traditional correction value may be too large which leads to a wide interval. For that reason, we propose three different correction values to identify the optimal correction interval with balanced coverage probability and interval width. From simulation studies, we find that a small correction value for the score interval has good performance. In addition, we derive the non-iterative solutions for the developed continuity correction score intervals.