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The endoplasmic reticulum, a key cellular organelle, regulates a wide variety of cellular activities. Endoplasmic reticulum autophagy, one of the quality control systems of the endoplasmic reticulum, plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover, remodeling, and proteostasis. In this review, we briefly describe the endoplasmic reticulum quality control system, and subsequently focus on the role of endoplasmic reticulum autophagy, emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements. We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases. In summary, this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders. This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.

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Due to the inherent characteristics of traditional graphite anode material, its lithium diffusion kinetic is significantly constrained, easily leading to a noticeable capacity degradation during rapid charge/discharge cycling. Although modifying the graphite by mixing the hard carbon can effectively enhance its fast-charging performance, yet the underlying mechanism of improvement effect and structure design of interface are still needed to further investigate. To address this research gap, hard carbon-coated graphite (HCCG) material has been designed and synthesized through simple interface engineering, which is aimed to explore and elucidate the optimization mechanisms on fast-charging performance from the graphite interface perspective. According to the electrochemical calculations, the HCCG anode exhibits significant enhancements. Specially, its reversible lithium content is increased by approximately 8 % at various states of charge, its exchange current density is tripled, and its Tafel slope is reduced to one-quarter of the original graphite. Therefore, the HCCG maintains an impressive 86.89 % capacity retention and a high capacity of 202.3 mAh g-1 after 1450 cycles at ultrahigh rate of 5C. These improvements indicate a substantial reduction in electrode polarization during fast charging, which is ascribed to the abundant lithium intercalation pathways and accommodation space provided by the intimate hard carbon coating layer. Moreover, as a "buffer layer," hard carbon coating can accommodate considerable amount of lithium deposited on the graphite surface, effectively mitigating the capacity loss caused by lithium deposition and maintaining effective electrochemical contact without delamination. This comprehensive analysis of hard carbon coating illustrates the improvement mechanism of fast-charging performance, which can offer valuable insights into the dynamic and structural optimization of graphite anode interfaces.

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Chronic HIV infection can dysregulate lipid/cholesterol metabolism in the peripheral system, contributing to the higher incidences of diabetes and atherosclerosis in HIV (+) individuals. Recently, accumulating evidence indicate that HIV proteins can also dysregulate lipid/cholesterol metabolism in the brain and such dysregulation could be linked with the pathogenesis of HIV-associated neurological disorders (HAND)/NeuroHIV. To further characterize the association between lipid/cholesterol metabolism and HAND, we employed HIV-inducible transactivator of transcription (iTAT) and control mice to compare their brain lipid profiles. Our results reveal that HIV-iTAT mice possess dysregulated lipid profiles and have increased numbers of lipid droplets (LDs) accumulation microglia (LDAM) in the brains. HIV protein TAT can upregulate LDs formation through enhancing the lipid/cholesterol synthesis in vitro. Mechanistically, HIV-TAT increases the expression of sterol regulatory element-binding protein 2 (SREBP2) through microRNA-124 downregulation. Cholesterol synthesis inhibition can block HIV-TAT-mediated NLRP3 inflammasome activation and microglial activation in vitro as well as mitigate aging-related behavioral impairment and memory deficiency in HIV-iTAT mice. Taken together, our results indicate an inherent role of lipid metabolism and LDAM in the pathogenesis of NeuroHIV (immunometabolism). These findings suggest that LDAM reversal through modulating lipid/cholesterol metabolism could be a novel therapeutic target for ameliorating NeuroHIV symptoms in chronic HIV (+) individuals.

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The intensification of human activities in the Yellow River Basin has significantly altered its ecosystems, challenging the sustainability of the region's ecosystem assets. This study constructs an ecosystem asset index for the period from 2001 to 2020, integrating it with human footprint maps to analyze the temporal and spatial dynamics of ecosystem assets and human activities within the basin, as well as their interrelationships. Our findings reveal significant improvement of ecosystem assets, mainly attributed to the conversion of farmland back into natural habitats, resulting in a 15,994 km2 increase in ecological land use. Notably, 45.88% of the basin has experienced concurrent growth in both human activities and ecosystem assets, with ecosystem assets expanding at a faster rate (22.61%) than human activities (17.25%). Areas with high-quality ecosystem assets are expanding, in contrast to areas with intense human activities, which are facing increased fragmentation. Despite a global escalation in threats from human activities to ecosystem assets, the local threat level within the Yellow River Basin has slightly diminished, indicating a trend towards stabilization. Results highlight the critical importance of integrating spatial and quality considerations into restoration efforts to enhance the overall condition of ecosystem assets, especially under increasing human pressures. Our work assesses the impact of human activities on the dynamics of ecosystem assets in the Yellow River Basin from 2001 to 2020, offering valuable insights for quality development in the region, may provide a scientific basis for general watershed ecological protection and sustainable management in a region heavily influenced by human activity but on a path to recovery.

Assuntos

Conservação dos Recursos Naturais , Ecossistema , Atividades Humanas , Rios , Humanos , Conservação dos Recursos Naturais/métodos , China , Monitoramento Ambiental/métodos

RESUMO

The application of silicon-based nanomaterials in fast-charging scenarios is hindered by volume expansion during lithiation and side reactions induced by surface effects. Constructing a robust encapsulation structure with high mechanical strength and conductivity is pivotal for optimizing the electrochemical performance of nanostructured silicon anodes. Herein, we propose a multifaceted hierarchical encapsulation structure featuring excellent mechanical strength and high conductivity by sequentially incorporating SiO x , hard carbon, and closed-pore carbon layers around silicon quantum dots, thereby enabling stable cycling at high current densities. In this structure, the ultra-thin SiO x layer strengthens the Si-C interface, while the outermost carbon matrix with closed pores functions both as a conductive network and a barrier against electrolyte intrusion. Notably, the synthesized material exhibits a specific capacity of 1506 mA h g-1 with 90.17% retention after 300 cycles at 1.0 A g-1. After 500 cycles at 5.0 A g-1, it retains 640.4 mA h g-1, over 70% of its initial capacity.

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IgG autoantibodies to heat shock protein 70 (HSP70) are found in many immune-mediated clinical syndromes, and their presence among patients with idiopathic pulmonary fibrosis (IPF) portends especially poor outcomes. However, pathological effects of IPF anti-HSP70 have not been studied extensively. IPF lung fibroblasts are apoptosis resistant, and this dysregulation contributes to the accumulation of fibroblasts that characterizes the disease. During stress, HSP70 protein is exported extracellularly, where it binds to cognate cell surface receptors that mediate a variety of functional effects, including apoptosis inhibition. We hypothesized anti-HSP70 could engage HSP70-receptor complexes on fibroblasts that alter their apoptosis susceptibility. We found HSP70 is ubiquitously expressed on primary human lung fibroblasts. Treatment with anti-HSP70 isolated from patients with IPF with acute exacerbations increased Bcl-2 expression in human lung fibroblasts and reduced their susceptibility to staurosporine-induced apoptosis. Chromatin immunoprecipitation assays showed Bcl-2 gene promoter regions are enriched with the active histone mark H4 lysine 16 acetylation, and this was increased in the autoantibody-treated fibroblasts. When H4 lysine 16 acetylation was decreased by knocking down its acetyltransferase, MOF (males absent on the first), the anti-HSP70 treatments failed to upregulate Bcl-2. This study describes a heretofore unknown, to our knowledge, pathogenic consequence of autoimmunity in which autoantibodies affect the epigenetic regulation of fibroblast apoptosis. In addition to IPF, this autoimmune process could also have relevance in other immunological syndromes characterized by anti-HSP70 autoimmunity. These findings lend credence to the importance of autoimmunity in IPF and illustrate pathways that could be targeted in innovative therapies for this morbid, medically refractory lung disease.

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BACKGROUND: Preoperative prediction of lymphovascular space invasion (LVSI) is crucial for improving the prognosis of patients with cervical cancer. PURPOSE: To evaluate the value of preoperative amide proton transfer (APT) imaging combined with serum CA125 levels for predicting LVSI in cervical cancer. MATERIAL AND METHODS: This retrospective study included 80 patients with cervical cancer who underwent preoperative magnetic resonance imaging, including APT imaging. Serum CA125 levels were measured using a fully automated immunoassay analyzer and chemiluminescence method. The presence of LVSI was determined based on the pathological results after surgery. RESULTS: Among the 40 patients who met the requirements, 29 had postoperative pathological confirmation of LVSI, while 11 did not. The areas under the receiver operating characteristic curves (AUC) of preoperative APT and CA125 levels predicting LVSI were 0.889 and 0.687, respectively. When the APT value was 2.9%, the corresponding Youden index was the highest (0.702), with a sensitivity of 79.3% and specificity of 90.9%. When the critical value of the preoperative serum CA15 level was 25.3 u/mL, the corresponding Youden index was the highest (0.508), with a sensitivity of 69.0% and a specificity of 81.8%. The sensitivity and specificity of preoperative APT imaging combined with serum CA125 in predicting LVSI were 82.7% and 100%, respectively, with a Youden's index of 0.828 and an AUC of 0.923. CONCLUSION: The combination of preoperative APT imaging and serum CA125 levels is valuable for predicting LVSI in cervical cancer. Diagnostic efficacy is highest when the APT value is >2.9% and the serum CA125 level is >25.3 u/mL.

Assuntos

Antígeno Ca-125 , Imageamento por Ressonância Magnética , Invasividade Neoplásica , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Antígeno Ca-125/sangue , Adulto , Imageamento por Ressonância Magnética/métodos , Idoso , Sensibilidade e Especificidade , Metástase Linfática/diagnóstico por imagem , Valor Preditivo dos Testes , Amidas , Prótons , Cuidados Pré-Operatórios/métodos , Biomarcadores Tumorais/sangue

RESUMO

Neurons rely heavily on high mitochondrial metabolism to provide sufficient energy for proper development. However, it remains unclear how neurons maintain high oxidative phosphorylation (OXPHOS) during development. Mitophagy plays a pivotal role in maintaining mitochondrial quality and quantity. We herein describe that G protein-coupled receptor 50 (GPR50) is a novel mitophagy receptor, which harbors the LC3-interacting region (LIR) and is required in mitophagy under stress conditions. Although it does not localize in mitochondria under normal culturing conditions, GPR50 is recruited to the depolarized mitochondrial membrane upon mitophagy stress, which marks the mitochondrial portion and recruits the assembling autophagosomes, eventually facilitating the mitochondrial fragments to be engulfed by the autophagosomes. Mutations Δ502-505 and T532A attenuate GPR50-mediated mitophagy by disrupting the binding of GPR50 to LC3 and the mitochondrial recruitment of GPR50. Deficiency of GPR50 causes the accumulation of damaged mitochondria and disrupts OXPHOS, resulting in insufficient ATP production and excessive ROS generation, eventually impairing neuronal development. GPR50-deficient mice exhibit impaired social recognition, which is rescued by prenatal treatment with mitoQ, a mitochondrially antioxidant. The present study identifies GPR50 as a novel mitophagy receptor that is required to maintain mitochondrial OXPHOS in developing neurons.

Assuntos

Mitocôndrias , Mitofagia , Neurônios , Receptores Acoplados a Proteínas G , Animais , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Neurônios/metabolismo , Mitocôndrias/metabolismo , Camundongos , Humanos , Fosforilação Oxidativa , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Espécies Reativas de Oxigênio/metabolismo , Camundongos Knockout , Neurogênese

RESUMO

RESEARCH QUESTION: Does luteinizing hormone (LH) levels on human chorionic gonadotropin (HCG) trigger day (LHHCG) affect the clinical outcomes of patients with diminished ovarian reserve (DOR) undergoing gonadotropin-releasing hormone antagonist (GnRH-ant) protocol? METHODS: Retrospective analysis fresh embryo transfer cycles of DOR patients who underwent GnRH-ant protocol from August 2019 to June 2023. The participants were divided into different groups according to LHHCG level and age. The clinical data and outcomes were compared between groups. RESULTS: In patients with DOR, the HCG positive rate (59.3% versus 39.8%, P = 0.005), embryo implantation rate (34.5% versus 19.7%, P = 0.002), clinical pregnancy rate (49.2% versus 28.4%, P = 0.003), live birth rate (41.5% versus 22.7%, P = 0.005) in LHHCG < 2.58 IU/L group were significantly higher than LHHCG ≥ 2.58 IU/L group. There was no significant correlation between LHHCG level and clinical pregnancy in POSEIDON group 3. In POSEIDON group 4, the HCG positive rate (52.8% versus 27.0%, P = 0.015), embryo implantation rate (29.2% versus 13.3%, P = 0.023), clinical pregnancy rate (45.3% versus 18.9%, P = 0.010) in LHHCG < 3.14 IU/L group were significantly higher than LHHCG ≥ 3.14 IU/L group. Logistic regression analysis indicated that LHHCG level was an independent influencing factor for clinical pregnancy in POSEIDON group 4 patients (OR = 3.831, 95% CI: 1.379-10.643, P < 0.05). CONCLUSIONS: LHHCG level is an independent factor affecting pregnancy outcome of fresh embryo transfer in DOR patients undergoing GnRH-ant protocol, especially for advanced-aged women. LHHCG had a high predictive value for POSEIDON group 4 patients, and LHHCG ≥ 3.14 IU/L predicts poor pregnancy outcomes.

Assuntos

Gonadotropina Coriônica , Transferência Embrionária , Hormônio Liberador de Gonadotropina , Hormônio Luteinizante , Reserva Ovariana , Indução da Ovulação , Taxa de Gravidez , Humanos , Feminino , Gravidez , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hormônio Luteinizante/sangue , Gonadotropina Coriônica/administração & dosagem , Gonadotropina Coriônica/uso terapêutico , Adulto , Estudos Retrospectivos , Reserva Ovariana/efeitos dos fármacos , Reserva Ovariana/fisiologia , Indução da Ovulação/métodos , Transferência Embrionária/métodos , Fertilização in vitro/métodos , Antagonistas de Hormônios/uso terapêutico , Antagonistas de Hormônios/administração & dosagem , Resultado do Tratamento , Infertilidade Feminina/terapia , Infertilidade Feminina/sangue , Infertilidade Feminina/tratamento farmacológico , Resultado da Gravidez/epidemiologia

RESUMO

Layered silicon (L-Si) anodes are celebrated for their high theoretical capacity but face significant challenges regarding safety and material purity during preparation. This study addresses these challenges by employing NH4Cl-CaSi2 as the raw material in a gas-solid de-alloying process, which enhances both safety and purity compared to traditional methods. The L-Si anodes produced demonstrate outstanding electrochemical performance, delivering a high reversible lithium storage capacity of 1497.7 mA h g-1 at a current density of 0.5 A g-1, and exhibiting stable performance over 1200 charge-discharge cycles. In situ and ex situ characterizations reveal that electrolyte decomposition products effectively fill the voids within the electrode, while the gradual disintegration of the L-Si structure contributes to the formation of a dense, conductive network. This process enhances lithium ion transport and exploits the capacitive storage benefits of layered silicon.

RESUMO

We show that next generation Cosmic Microwave Background (CMB) experiments will be capable of the first ever measurement of the inflaton coupling to other particles, opening a new window to probe the connection between cosmic inflation and particle physics. This sensitivity is based on the impact that the reheating phase after cosmic inflation has on the redshifting of cosmic perturbations. For our analysis we introduce a simple analytic method to estimate the sensitivity of future CMB observations to the reheating temperature and the inflaton coupling. Applying our method to LiteBIRD and CMB-S4 we find that, within a given model of inflation, these missions have the potential to impose both an upper and a lower bound on the inflaton coupling. Further improvement can be achieved if CMB data are combined with optical and 21 cm surveys. Our results demonstrate the potential of future observations to constrain microphysical parameters that can provide an important clue to understand how a given model of inflation may be embedded in a more fundamental theory of nature.

RESUMO

Perovskite light-emitting diodes (PeLEDs) have garnered significant attention due to their outstanding optoelectronic properties. However, investigating carrier transport and recombination behavior during device operation poses persistent challenges. In this study, we explore the impact of additive and interface engineering on device performance using transient electroluminescence (TREL). Polyethylene glycol (PEG) induces the formation of square-faceted nanocrystals with a homogeneous size distribution and extended fluorescence lifetime. Consequently, these PeLEDs exhibit remarkable stability. Additionally, employing an electron transport layer of 2,4,6-tris[3-(diphenylphosphino)phenyl]-1,3,5-triazine (PO-T2T), which has a better match to the energy bands of the perovskite layer and a higher carrier mobility, allows for lower turn-on voltage and faster response but also suffers from a short decay time and poor stability. Moreover, low-temperature TREL characterization shows that the carrier mobility is also significantly suppressed with decreasing temperature, which reduces the transient response speed.

RESUMO

This practice guideline focuses on the cognitive assessment for mild cognitive impairment in the Guangdong-Hong Kong-Macao Greater Bay Area. To achieve the standardization and normalization of its clinical practice and generate individualized intervention, the National Core Cognitive Center of the Second Affiliated Hospital of Guangzhou Medical University, the Cognitive Disorders Branch of Chinese Geriatic Society, the Dementia Group of Neurology Branch of Guangdong Medical Association and specialists from Hong Kong and Macao developed guidelines based on China's actual conditions and efficiency, economic cost and accuracy. The article addresses the significance, background, and the process of the assessment and follow-up to realize the promotion and dissemination of cognitive assessment.

RESUMO

OBJECTIVES: This study explored the characteristics of muscle stiffness of lower gastrocnemius in resting and exercise states in patients with postural instability gait difficulty (PIGD) and tremor dominant (TD) Parkinson's disease patients using shear wave elastography (SWE). DATA AND METHODS: 75 PD patients from the Department of Parkinson's Disease Center in the Hospital from September 2021 to December 2022 were prospectively included, including 44 patients with PIGD and 31 with TD. In the same period, 40 healthy subjects matching gender and age were included as the control group. SWE was used to detect Young's modulus of both sides (right and left, R- and L-) of the lateral head of the gastrocnemius in resting (YM1) and exerciser states (YM2) in all participants and the absolute difference Young's modulus between resting and exercise state (ΔYM) was calculated. RESULTS: R-YM2 and R-ΔYM were the highest in the normal controls, followed by the TD group, and lowest in the PIGD group. There were no differences in L-YM2 and L-ΔYM between the PIGD group and the TD group (all p > 0.05), but they were lower than those in the normal control group (all p < 0.05). In addition, R-YM2 and R-ΔYM were negatively correlated with disease duration and UPDRS III scores in the PIGD group (all p < 0.05). R-ΔYM has the highest value in the differential diagnosis of PIGD and TD patients. The area under the receiver operating characteristic curve (ROC) curve is 0.812 (95%CI, 0.730-0.893), and the diagnostic threshold is 120.5 Kpa with a sensitivity of 63.6%, a specificity of 90.1%, a positive predictive of 80%, and a negative predictive value of 80%. CONCLUSION: Shear wave elastography is a sensitive ultrasound method for evaluating muscle strength in patients with PIGD and TD. It also provides a new biological indicator to distinguish between different phenotypes of patients with PD.

RESUMO

Background: For the poor ovarian response (POR) population, the relationship between medroxyprogesterone acetate (MPA) dose in progestin-primed ovarian stimulation (PPOS) and clinical outcome is still unclear. This study aims to explore the effect of MPA dose in PPOS on clinical outcomes in POSEIDON group 3 and 4 patients with different body mass index (BMI) levels, hoping to provide clinical doctors with better options for controlled ovarian hyperstimulation (COH) programs. Methods: This is a retrospective analysis of 253 oocyte retrieval cycles of POSEIDON group 3 and 4 patients who underwent PPOS protocol in IVF/ICSI treatment at the Reproductive Medical Center of Renmin Hospital of Wuhan University from March 2019 to April 2022. The effects of different MPA doses (8 mg/d or 10 mg/d) on pregnancy outcomes were compared in normal BMI (18.5-24 kg/m2) and high BMI (≥24 kg/m2) patients, and multivariate logistic regression analysis was performed to analyze the factors affecting pregnancy outcomes. Results: For normal BMI patients, the 8-mg/d MPA group had a higher embryo implantation rate (33.78% vs. 18.97%, P = 0.012). For high BMI patients, the 10-mg/d MPA group had a higher HCG positive rate (55.00% vs. 25.00%, P = 0.028), clinical pregnancy rate (50.00% vs. 20.00%, P = 0.025), and cumulative pregnancy rate (37.74% vs. 13.79%, P = 0.023) compared with the 8-mg/d MPA group. There was no significant difference in cumulative live birth rate between the 8-mg/d and 10-mg/d MPA groups in patients with normal or high BMI. The results of multivariate logistic regression showed a significant correlation between MPA dose and cumulative pregnancy in the high BMI population (OR = 0.199, 95% CI: 0.046~0.861, P = 0.031). Conclusions: For POR patients with high BMI, 10 mg/d of MPA in the PPOS protocol had a higher cumulative pregnancy rate than 8 mg/d of MPA, but it had no significant effect on the cumulative live birth rate.

Assuntos

Índice de Massa Corporal , Acetato de Medroxiprogesterona , Indução da Ovulação , Resultado da Gravidez , Taxa de Gravidez , Humanos , Feminino , Gravidez , Indução da Ovulação/métodos , Adulto , Estudos Retrospectivos , Acetato de Medroxiprogesterona/administração & dosagem , Progestinas/administração & dosagem , Fertilização in vitro/métodos , Relação Dose-Resposta a Droga

RESUMO

BACKGROUND: Sevoflurane treatment increases the incidence of postoperative cognitive dysfunction (POCD), and patients with POCD show a decline in cognitive abilities compared to preoperative levels. OBJECTIVES: This study aimed to investigate whether the activation of α7 nicotinic acetylcholine receptor (α7nAChR) and the expression of M1 acetylcholine receptor (mAChR M1) in the hippocampus affects the cognitive function of aged rats. METHODS: Forty-eight Sprague-Dawley (SD) rats of 1-week- and 12-months-old were divided into eight groups: four groups for α7nAChR and four groups for mAChR M1, respectively. All SD rats received 1.0-02% sevoflurane for α7nAChR and 1.0-02% sevoflurane for mAChR M1 for 2-6 h, respectively. The Y-maze test was used to assess the ability to learn and memory after receiving sevoflurane for 7 days at the same moment portion. RT-PCR was used to determine the expression of α7nAChR and mAChR M1 in the hippocampus of rats. RESULTS: The α7nAChR mitigated the formation of sevoflurane-induced memory impairment by modulating the translocation of NR2B from the intracellular reservoir to the cell surface reservoir within the hippocampus. Next, sevoflurane-induced decline of cognitive function and significantly decreased mAChR M1 expression at mRNA levels. CONCLUSION: α7nAChR regulates the trafficking of NR2B in the hippocampus of rats via the Src-family tyrosine kinase (SFK) pathway. This regulation is associated with cognitive deficits induced by sevoflurane in hippocampal development. Sevoflurane affects the cognitive function of rats by suppressing the mAChR M1 expression at mRNA levels in the hippocampus.

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α7nAChR attenuates sevoflurane-induced memory deficits by regulating NR2B.α7nAChR controls NR2B via the SFK in the hippocampus of rats that contribute to sevoflurane-induced cognitive deficits.Sevoflurane may affect cognitive function in rats by suppressing the mAChR M1 expression at the mRNA levels in the hippocampus.Dysregulation of the α7nAChR and mAChR M1 receptors may contribute to cognitive deficits and neurodegenerative disorders.

Assuntos

Hipocampo , Ratos Sprague-Dawley , Receptor Muscarínico M1 , Sevoflurano , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Sevoflurano/farmacologia , Sevoflurano/efeitos adversos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/genética , Receptor Nicotínico de Acetilcolina alfa7/biossíntese , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Receptor Muscarínico M1/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Ratos , Aprendizagem em Labirinto/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/biossíntese , Receptores de N-Metil-D-Aspartato/genética , Anestésicos Inalatórios/farmacologia , Anestésicos Inalatórios/efeitos adversos , Modelos Animais de Doenças

RESUMO

BACKGROUND: The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine). METHODS: We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3·3 log10 plaque forming units (PFU; low-dose v7D group), 3·9 log10 PFU (medium-dose v7D group), and 4·2 log10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434. FINDINGS: On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium-dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100·0% (95% CI 95·8-100·0; 87 of 87 participants), 98·9% (93·8-100·0; 87 of 88 participants), 97·8% (92·4-99·7; 91 of 93 participants), and 96·4% (89·8-99·2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30·8 (95% CI 26·2-36·0), 31·3 (26·7-36·6), 28·2 (23·9-33·2), and 38·5 (31·7-46·7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0·027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0·025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0·016). None of the serious adverse events were vaccine related. INTERPRETATION: The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, the Fundamental Research Funds for the Central Universities, and Beijing Wantai. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Assuntos

Anticorpos Antivirais , Vacina contra Varicela , Varicela , Vacinas Atenuadas , Humanos , Vacina contra Varicela/imunologia , Vacina contra Varicela/administração & dosagem , Vacina contra Varicela/efeitos adversos , Método Duplo-Cego , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Masculino , Feminino , Pré-Escolar , Criança , Anticorpos Antivirais/sangue , Varicela/prevenção & controle , Varicela/imunologia , China , Herpesvirus Humano 3/imunologia , Imunogenicidade da Vacina , Vacinação/métodos

RESUMO

BACKGROUND: This study comprehensively examined the demographic and clinical characteristics of patients undergoing valproic acid therapy and explored their potential impact on plasma valproic acid concentrations. All enrolled patients were administered the extended-release formulation. An in-depth investigation of factors, including dose, age, sex, body mass index, co-administered medications, and laboratory test findings, was conducted to evaluate their potential influence on study outcomes. METHODS: In total, 164 patients met the inclusion criteria and were included in the analysis. The patient age ranged from 13 to 60 years, with a median age of 25.71 years. Most patients (89%) received a daily dose of 1 g valproic acid. Co-administered psychiatric medications included aripiprazole, quetiapine, and lorazepam. Laboratory test results, such as hemoglobin and transaminase levels, were also collected as part of the study. RESULTS: The average plasma valproic acid plasma concentration was 79.8 mg/L. The dose significantly affected valproic acid concentrations, as a higher percentage of measurements exceeded the therapeutic range at a daily dose of 1 g. Furthermore, females exhibited significantly higher valproic acid concentrations compared with males at the same dose ( P < 0.05). However, different age groups showed no statistically significant differences in valproic acid concentrations ( P > 0.05). The co-administered antipsychotic and antidepressant medications significantly affected valproate concentrations, as reflected in the multiple regression model ( P < 0.01). CONCLUSIONS: This study offers valuable insights into the demographic and clinical characteristics of patients undergoing valproic acid therapy. It highlights the influence of dose, sex, and concomitant medications on plasma valproic acid concentrations. Overall, these findings can help guide dose adjustments and implement personalized treatment strategies in valproic acid therapy.

Assuntos

Antimaníacos , Transtorno Bipolar , Ácido Valproico , Humanos , Ácido Valproico/uso terapêutico , Ácido Valproico/sangue , Masculino , Adulto , Feminino , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/sangue , Pessoa de Meia-Idade , Adulto Jovem , Adolescente , Estudos Retrospectivos , Antimaníacos/uso terapêutico , Antimaníacos/sangue , Fatores Sexuais , Povo Asiático , Relação Dose-Resposta a Droga , Antipsicóticos/uso terapêutico , Antipsicóticos/sangue , Antipsicóticos/farmacocinética , China , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Fatores Etários , População do Leste Asiático

RESUMO

Cities are the main carriers of social and economic development, and they are also important sources of carbon emissions. Therefore, it is essential to explore the impact of urban expansion and form changes on carbon emissions. Here, we attempted to analyzes the relationship between urban expansion and carbon emissions at the county level in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) from 1997 to 2017. It further decomposes the driving effects of carbon emissions from multiple factors, and considers the spatial heterogeneity between different urban form changes and driving effects. The results show that: The relationship between urban expansion and carbon emissions in the GBA has gone through three stages from 1997 to 2017, with 2012 as a turning point. Optimization of economic development models and strict protection of the ecological environment can effectively control carbon emissions. After 2012, the economic development effect (GE) and population scale effect (PE) are the driving factors of carbon emissions, while the carbon emission intensity effect (CE) and urban land intensity effect (UE) are the inhibitory factors of carbon emissions. The contribution rate of UE to carbon emission reduction can reach 86 %. The impact of urban form changes on carbon emissions has spatial heterogeneity. The changes in urban form have a significant impact on the carbon emissions of counties in Dongguan and Shenzhen. The increase in fragmentation indirectly promotes carbon emissions. In 2007-2012, the increase in centrality significantly weakened the economic development effect, which is conducive to emission reduction. After 2007, the increase in compactness in counties in the eastern part of the GBA, including Zhongshan and Zhuhai, is not conducive to emission reduction.

RESUMO

Two Gram-negative, non-spore-forming, non-motile, non-flagellated bacteria, designated strains D6T and DH64T, were isolated from surface water of the Pacific Ocean. For strain D6T, growth occurred at 10-40 °C, pH 5.5-9.0 and in the presence of 0-8.0 % NaCl (w/v). For strain DH64T, growth occurred at 10-40 °C, pH 5.5-8.5 and in the presence of 0.5-8.0 % NaCl (w/v). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strains D6T and DH64T both belonged to the genera Flagellimonas, with the highest sequence identities to Flagellimonas taeanensis JCM 17757T (98.2 %) and Flagellimonas marinaquae JCM 11811T (98.6 %), respectively. The 16S rRNA gene sequence identity between strains D6T and DH64T was 95.9 %. The average amino acid identity and digital DNA-DNA hybridization values between the two strains and the nearest phylogenetic neighbours were 66.7-93.3 % and 16.1-38.5 %, respectively. The major respiratory quinone of both strains was menaquinone-6. The major polar lipid was phosphatidylethanolamine. The major fatty acids were identified similarly as iso-C15 : 1 G, iso-C15 : 0 and iso-C17 : 0 3-OH. The genomic G+C contents of strains D6T and DH64T were determined to be 45.5 and 42.6 mol%, respectively. The combined genotypic and phenotypic data show that the strains represent two novel species within genera Flagellimonas, for which the names Flagellimonas baculiformis sp. nov. and Flagellimonas crocea sp. nov. are proposed, with type strains D6T (=MCCC M28982T=KCTC 92604T) and DH64T (=MCCC M28986T=KCTC 92975T).

Assuntos

Ácidos Graxos , Cloreto de Sódio , Oceano Pacífico , Composição de Bases , Ácidos Graxos/química , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , DNA Bacteriano/genética , Técnicas de Tipagem Bacteriana , Água do Mar