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Intrinsic capacity (IC), as a comprehensive measure of an individual's functional ability, has gained prominence in the framework for healthy aging introduced by the World Health Organization (WHO). As internet usage continues to integrate into daily life, it is imperative to scrutinize the association between internet use and IC to effectively promote healthy aging among the middle-aged and older population. This study aimed to investigate whether daily internet use in middle-aged and older adults delays or accelerates the decline in IC. Participants included in the China Health and Retirement Longitudinal Study (CHARLS) comprised individuals aged ≥45 years residing in China. We analyzed 4 years of CHARLS data from the first wave (May 2011-March 2012) to the third wave (July 2015-January 2016). Data from the first and third waves were used for longitudinal studies. Self-reported data encompassed internet use, frequency of use, and demographic baseline characteristics. In addition, the IC evaluation involved physical examination and blood test data. Initially, linear regression was used to assess the relationship between daily internet use and IC, followed by regression splines to explore potential nonlinear associations. Subgroup and sensitivity analyses were used to investigate the heterogeneity of IC in specific conditions and the robustness of our results. Mediation effect analysis was conducted to identify the factors that mediate the relationship between daily internet use and IC, focusing on social participation, physical activity, and health status. Among the 12,826 participants included in the longitudinal analyses, 12,305 (95.9%) did not use the internet, while 521 (4.1%) reported daily internet use with a mean age of 52.62 (SD 7.67) years. After adjusting for demographic variables, socioeconomic factors, lifestyle behaviors, and health conditions and examining the impact of daily internet use and frequency on changes in IC, our findings indicated important associations. Specifically, daily internet use is significantly linked to a slower decline in IC over time (marginal effect 1.58, 95% CI 1.03-2.12; P<.001). Individuals with moderate and regular internet use frequency exhibit higher levels of maintenance in IC (marginal effect 0.74, 95% CI 0.45-1.03, P<.001). In addition, the relationship between IC changes and internet use frequency demonstrated a nonlinear inverted U-shaped curve (nonlinear P=.003). Subgroup analysis further revealed that improvements in IC vary based on age and gender. Furthermore, mediation analysis denoted that more than 28.78% (95% CI 21.24-40.33) of the observed association is mediated by social participation (P<.001). The findings of our research underscore the potential benefits of consistent and moderate internet use in promoting and preserving IC, particularly in cognitive capacity, sensory, vitality, and locomotion. The observed effects may be related to social participation. These insights offer valuable guidance for crafting strategies aimed at fostering healthy aging within the middle-aged and older adult demographics.

In this work, tunable plasmonic liquid gallium nanoparticles (Ga NPs) were prepared through surface anodizing of the particles. Shape deformation of the Ga NPs accompanied with dimpled surface topographies could be induced during electrochemical anodization, and the formation of the anodic oxide shell helps maintain the resulting change in the particle shape. The nanoscale dimple-like textures led to changes in the localized surface plasmon resonance (LSPR) wavelength. A maximal LSPR red-shift of ~77 nm was preliminarily achieved using an anodization voltage of 0.7 V. The experimental results showed that an increase in the oxide shell thickness yielded a negligible difference in the observed LSPR, and finite-difference time-domain (FDTD) simulations also suggested that the LSPR tunability was primarily determined by the shape of the deformed particles. The extent of particle deformation could be adjusted in a very short period of anodization time (~7 s), which offers an efficient way to tune the LSPR response of Ga NPs.

Liangshan Prefecture in Sichuan province, China, has a high prevalence of HIV infection, which is reflective of a change in the mode of transmission from injection drug use （IDU） to heterosexual intercourse. However, few studies focus on HIV-related heterosexual risk behaviours among the majority Yi population. The objectives of this study were to explore the characteristics of an egocentric sexual network and estimate the prevalence of casual sexual behaviour. Yi villagers （n= 108）, aged 15-35 years, who reported having had sex within the previous year were interviewed as to their sexual behaviours and networks. In-depth interviews and focus group discussions provided supplementary information on sexual norms. Logistic regression analysis was used to calculate unadjusted odds ratios （ORs） and 95% confidence intervals （CIs）. Most of the respondents reported having had casual sex at some time in their life, and 66.7% reported multiple sexual partnerships. Only 21.3% reported ever having used a condom. During the study year, a total of 137 partners were involved in 153 sexual partnerships. Among the reported sexual partnerships, 67.3% originated from a casual sexual relationship. For network members in components of size ≥3, 56,9% were involved in concurrent sexual partnerships. Having never been married （OR： 2.11; 95% CI： 1.03-4.33） and younger age （OR： 0.89; 95% CI： 0.83-0.95） were both associated with being in a component of size ≥3. Size （OR： 2.99; 95% Ch 1.17-7.66）, pair （OR： 0.54; 95% Ch 0.039-0.74）, the number of weak components of the egocentric sexual network （OR- 30.04; 95% Ch 6.47-139.46） and gender （OR. 0. 19; 95% Ch. 0.06-0.67） were all associated with being in concurrent sexual partnerships. HIV-related interventions for the Yi ethnic minority in Sichuan province must therefore address concurrent sexual partnerships and promote condom use.

Citrate is an essential substrate for energy metabolism that plays critical roles in regulating cell growth and survival. However, the action of citrate in regulating metabolism, cognition, and aging at the organismal level remains poorly understood. Here, we report that dietary supplementation with citrate significantly reduces energy status and extends lifespan in Drosophila melanogaster. Our genetic studies in fruit flies implicate a molecular mechanism associated with AMP‐activated protein kinase (AMPK), target of rapamycin (TOR), and ketogenesis. Mice fed a high‐fat diet that supplemented with citrate or the ketone body β‐hydroxybutyrate (βOHB) also display improved metabolic health and memory. These results suggest that dietary citrate supplementation may prove to be a useful intervention in the future treatment of age‐related dysfunction. Dietary citrate supplementation can induce lifespan extension in fruit flies, as well as improve memory performance and metabolic health in mice under high‐calorie diets. Our experiments demonstrate that citrate‐induced benefits require Drosophila citrate transporter Indy and act through downstream AMPK and TOR signaling to enhance ketogenesis. These results are critical in implicating citrate as an anti‐aging intervention.

Anxiety-related disorders can be treated by cognitive therapies and transcranial magnetic stimulation, which involve the medial prefrontal cortex (mPFC). Subregions of the mPFC have been implicated in mediating different and even opposite roles in anxiety-related behaviors. However, precise causal targets of these top-down connections among diverse possibilities have not been established. Here, we show that the lateral septum (LS) and the central nucleus of the amygdala (CeA) represent 2 direct targets of the infralimbic cortex (IL), a subregion of the mPFC that modulates anxiety and fear. Two projections were unexpectedly found to exert opposite effects on the anxious state and learned freezing: the IL-LS projection promoted anxiety-related behaviors and fear-related freezing, whereas the IL-CeA projection exerted anxiolytic and fear-releasing effects for the same features. Furthermore, selective inhibition of corresponding circuit elements showed opposing behavioral effects compared with excitation. Notably, the IL-CeA projection implemented top-down control of the stress-induced high-anxiety state. These results suggest that distinct IL outputs exert opposite effects in modulating anxiety and fear and that modulating the excitability of these projections with distinct strategies may be beneficial for the treatment of anxiety disorders.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual loss of midbrain dopaminergic neurons in association with aggregation of α-synuclein. Oxidative damage has been widely implicated in this disease, though the mechanisms involved remain elusive. Here, we demonstrated that preferential accumulation of peroxidized phospholipids and loss of the antioxidant enzyme glutathione peroxidase 4 (GPX4) were responsible for vulnerability of midbrain dopaminergic neurons and progressive motor dysfunctions in a mouse model of PD. We also established a mechanism wherein iron-induced dopamine oxidation modified GPX4, thereby rendering it amenable to degradation via the ubiquitin-proteasome pathway. In conclusion, this study unraveled what we believe to be a novel pathway for dopaminergic neuron degeneration during PD pathogenesis, driven by dopamine-induced loss of antioxidant GPX4 activity.

Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.

Objective: The aim was to systematically compare the drug compatibility with various closed intravenous (i.v.) infusion containers, to provide a reference for selecting a relatively superior infusion container and improve the medication safety for patients in clinical practice. Methods: The compatibility of four commonly used clinical injections (ceftazidime, pantoprazole sodium, ambroxol hydrochloride, edaravone) with three representative closed i. v. infusion containers (non-PVC infusion bags, upright polypropylene infusion bags, inner sealed polypropylene infusion bags) prefilled with infusion fluids (0.9% sodium chloride or 5% dextrose) in the Chinese market were investigated in this study. The particle counts of both infusion fluids and diluted chemical injections by infusion fluids in various infusion containers were determined by the light obscuration method. At 0, 2 and 6 h after four injections following dilution with infusion fluids in each container, the pH of the solutions was detected, and the physical properties were examined by visual inspection. Meanwhile, the drug concentrations were assessed by high performance liquid chromatography (HPLC). Results: As for either infusion fluids or diluted injections by infusion fluids, the particle counts in non-PVC infusion bags were significantly greater than those in the other two bags under some circumstances. The particle counts in diluted injections by infusion fluids increased dramatically compared with those in infusion fluids in all infusion containers, especially for the small-size particles. But pH, physical properties and drug concentrations of diluted infusion solutions in all infusion containers remained nearly unchanged over the test period. Conclusion: Closed i. v. infusion containers included in this study are all well-compatible with four injections. Moreover, the closed infusion containers produced by Chinese manufacturers have met the international quality standard. Particularly, the intravenous admixture preparation process needs to be optimized to reduce the overall particulate contaminants.

As a marker for tumor cell proliferation, Ki67 has important impacts on breast cancer (BC) prognosis. Although immunohistochemical staining is the current standard method, variations in analytical practice make it difficult for pathologists to manually measure Ki67 index. This study was to develop a fluorescent spectrum-based quantitative analysis of Ki67 expression by quantum-dots (QDs) multiple imaging technique. A QDs-based in situ multiple fluorescent imaging method was developed, which stained nuclear Ki67 as red signal and cytoplasmic cytokeratin (CK) as green signal. Both Ki67 and CK signals were automatically separated and quantified by professional spectrum analysis software. This technique was applied to tissue microarrays from 240 BC patients. Both Ki67 and CK values, and Ki67/CK ratio were obtained for each patient, and their prognostic value on 5-year disease free survival was assessed. This method simultaneously stains nuclear Ki67 and cytoplasmic CK with clear signal contrast, making it easy for signal separation and quantification. The total fluorescent signal intensities of both Ki67 sum and CK sum were obtained, and Ki67/CK ratio calculated. Ki67 sum and Ki67/CK ratio were each attributed into two grades by X-tile software based on the best P value principle. Multivariate analysis showed Ki67 grade (P = 0.047) and Ki67/CK grade (P = 0.004) were independent prognostic factors. Furthermore, area under curve (AUC) of ROC analysis for Ki67/CK grade (AUC: 0.683, 95%CI: 0.613-0.752) was higher than Ki67 grade (AUC: 0.665, 95%CI: 0.596-0.734) and HER-2 gene (AUC: 0.586, 95%CI: 0.510-0.661), but lower than N stage (AUC: 0.760, 95%CI: 0.696-0.823) and histological grade (AUC: 0.756, 95%CI: 0.692-0.820) on predicting the risk for recurrence. A QDs-based quantitative and in situ multiple imaging on Ki67 and CK was developed to improve Ki67 assessment in BC, and Ki67/CK grade had better performance than Ki67 grade in predicting prognosis.

Aim： To evaluate single-dose and multiple-dose pharmacokinetics of cytotoxic T-lymphocyte-associated antigen 4 fusion protein （CTLA4Ig） in healthy volunteers and patients with rheumatoid arthritis （RA）. Methods： The clinical trials included two phase I open studies： study 1 was an open-label dose-escalation study in 27 healthy volunteers and study 2 was a single-group, open-label study in patients with rheumatoid arthritis. In study 2, 9 patients were arranged to receive 10 mg/kg of CTLA4Ig at 0, 2, 4, 8, 12, and 16 weeks. The concentration-time data obtained by a validated ELISA method were subjected to non-compartmental pharmacokinetic analysis by DAS 2.1 software. Results： In study 1, serum CTLA4Ig concentrations climbed rapidly to the peak and declined slowly with a t1/2 of 15.1±2.6 d, 14.2±2.3 d, and 11.8±1.2 d after a single infusion of 1, 10, and 20 mg/kg, respectively. Cmax and AUC0-∞,increased proportionally with the dose. In study 2, the steady-state condition for CTLA4Ig following multiple doses of 10 mg/kg appeared to be attained at the fourth dose （d 56）, with peak and trough concentrations of 239.8±45.3 mg/L and 20.5±7.9 mg/L, respectively. After multiple infusions, serum concentrations dropped slowly and the terminal half-life was 12.6±4.7 d. Conclusion： Intravenous infusion of CTLA4Ig was well tolerated in healthy volunteers and patients with rheumatoid arthritis. CTLA4Ig exhibited linear pharmacokinetics over the dose range of 1 to 20 mg/kg in healthy volunteers. The pharmacokinetics in RA patients appeared to be similar to that in healthy volunteers. No system accumulation appeared upon repeated infusions of 10 mg/kg every 4 weeks.