Activation of α7 Nicotinic Acetylcholine Receptor Improves Muscle Endurance by Upregulating Orosomucoid Expression and Glycogen Content in Mice.

There are presently no acknowledged therapeutic targets or official drugs for the treatment of muscle fatigue. The alpha7 nicotinic acetylcholine receptor (α7nAChR) is expressed in skeletal muscle, with an unknown role in muscle endurance. Here, we try to explore whether α7nAChR could act as a potential therapeutic target for the treatment of muscle fatigue. Results showed that nicotine and PNU-282987 (PNU), as nonspecific and specific agonists of α7nAChR, respectively, could both significantly increase C57BL6/J mice treadmill-running time in a time- and dose-dependent manner. The improvement effect of PNU on running time and ex vivo muscle fatigue index disappeared when α7nAChR deletion. RNA sequencing revealed that the differential mRNAs affected by PNU were enriched in glycolysis/gluconeogenesis signaling pathways. Further studies found that PNU treatment significantly elevates glycogen content and ATP level in the muscle tissues of α7nAChR+/+ mice but not α7nAChR-/- mice. α7nAChR activation specifically increased endogenous glycogen-targeting protein orosomucoid (ORM) expression both in vivo skeletal muscle tissues and in vitro C2C12 skeletal muscle cells. In ORM1 deficient mice, the positive effects of PNU on running time, glycogen and ATP content, as well as muscle fatigue index, were abolished. Therefore, the activation of α7nAChR could enhance muscle endurance via elevating endogenous anti-fatigue protein ORM and might act as a promising therapeutic strategy for the treatment of muscle fatigue.

Orosomucoid 2 is an endogenous regulator of neuronal mitochondrial biogenesis and promotes functional recovery post-stroke.

Development of functional recovery therapies is critical to reduce the global impact of stroke as the leading cause of long-term disability. Our previous studies found that acute-phase protein orosomucoid (ORM) could provide an up to 6h therapeutic time window to reduce infarct volume in acute ischemic stroke by improving endothelial function. However, its role in neurons and functional recovery post-stroke remains largely unknown. Here, we showed that exogenous ORM administration with initial injection at 0.5h (early) or 12h (delayed) post-MCAO daily for consecutive 7 days significantly decreased infarct area, improved motor and cognitive functional recovery, and promoted mitochondrial biogenesis after MCAO. While neuron-specific knockout of ORM2, a dominant subtype of ORM in the brain, produced opposite effects which could be rescued by exogenous ORM. In vitro, exogenous ORM protected SH-SY5Y cells from OGD-induced damage and promoted mitochondrial biogenesis, while endogenous ORM2 deficiency worsened these processes. Mechanistically, inactivation of CCR5 or AMPK eliminated the protective effects of ORM on neuronal damage and mitochondrial biogenesis. Taken together, our findings demonstrate that ORM, mainly ORM2, is an endogenous regulator of neuronal mitochondrial biogenesis by activating CCR5/AMPK signaling pathway, and might act as a potential therapeutic target for the functional recovery post-stroke.

A non-antibiotic erythromycin derivative improves muscle endurance by regulating endogenous anti-fatigue protein orosomucoid in mice.

At present, there are no official approved drugs for improving muscle endurance. Our previous research found acute phase protein orosomucoid (ORM) is an endogenous anti-fatigue protein, and macrolides antibiotics erythromycin can elevate ORM level to increase muscle bioenergetics and endurance parameters. Here, we further designed, synthesized and screened a new erythromycin derivative named HMS-01, which lost its antibacterial activity in vitro and in vivo. Data showed that HMS-01 could time- and dose-dependently prolong mice forced-swimming time and running time, and improve fatigue index in isolated soleus muscle. Moreover, HMS-01 treatment could increase the glycogen content, mitochondria number and function in liver and skeletal muscle, as well as ORM level in these tissues and sera. In Orm-deficient mice, the anti-fatigue and glycogen-elevation activity of HMS-01 disappeared. Therefore, HMS-01 might act as a promising small molecule drug targeting ORM to enhance muscle endurance.

A Survey on Multi-Sensor Fusion Perimeter Intrusion Detection in High-Speed Railways.

In recent years, the safety issues of high-speed railways have remained severe. The intrusion of personnel or obstacles into the perimeter has often occurred in the past, causing derailment or parking, especially in the case of bad weather such as fog, haze, rain, etc. According to previous research, it is difficult for a single sensor to meet the application needs of all scenario, all weather, and all time domains. Due to the complementary advantages of multi-sensor data such as images and point clouds, multi-sensor fusion detection technology for high-speed railway perimeter intrusion is becoming a research hotspot. To the best of our knowledge, there has been no review of research on multi-sensor fusion detection technology for high-speed railway perimeter intrusion. To make up for this deficiency and stimulate future research, this article first analyzes the situation of high-speed railway technical defense measures and summarizes the research status of single sensor detection. Secondly, based on the analysis of typical intrusion scenarios in high-speed railways, we introduce the research status of multi-sensor data fusion detection algorithms and data. Then, we discuss risk assessment of railway safety. Finally, the trends and challenges of multi-sensor fusion detection algorithms in the railway field are discussed. This provides effective theoretical support and technical guidance for high-speed rail perimeter intrusion monitoring.

Short-Term Effects of Particle Sizes and Constituents on Blood Biomarkers among Healthy Young Adults in Guangzhou, China.

Evidence of the effects of various particle sizes and constituents on blood biomarkers is limited. We performed a panel study with five repeated measurements in 88 healthy college students in Guangzhou, China between December 2017 and January 2018. Mass concentrations of particles with aerodynamic diameters ≤ 2.5 µm (PM2.5), PM1, and PM0.5 and number concentrations of particles with aerodynamic diameters ≤ 200 nm (PN0.2) and PN0.1 were measured. We used linear mixed-effect models to explore the associations of size-fractionated particulate matter and PM2.5 constituents with five blood biomarkers 0-5 days prior to blood collection. We found that an interquartile range (45.9 µg/m3) increase in PM2.5 concentration was significantly associated with increments of 16.6, 3.4, 12.3, and 8.8% in C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and endothelin-1(ET-1) at a 5-day lag, respectively. Similar estimates were observed for PM1, PM0.5, PN0.2, and PN0.1. For PM2.5 constituents, consistent positive associations were observed between F- and sVCAM-1 and CRP and between NH4+ and MCP-1, and negative associations were found between Na+ and MCP-1 and ET-1, between Cl- and MCP-1, and between Mg2+ and sVCAM-1. Our results suggested that both particle size and constituent exposure are significantly associated with circulating biomarkers among healthy Chinese adults. Particularly, PN0.1 at a 5-day lag and F- and NH4+ are the most associated with these blood biomarkers.

Associations of Particulate Matter Sizes and Chemical Constituents with Blood Lipids: A Panel Study in Guangzhou, China.

Existing evidence is scarce concerning the various effects of different PM sizes and chemical constituents on blood lipids. A panel study that involved 88 healthy college students with five repeated measurements (440 blood samples in total) was performed. We measured mass concentrations of particulate matter with diameters ≤ 2.5 µm (PM2.5), ≤1.0 µm (PM1.0), and ≤0.5 µm (PM0.5) as well as number concentrations of particulate matter with diameters ≤ 0.2 µm (PN0.2) and ≤0.1 µm (PN0.1). We applied linear mixed-effect models to assess the associations between short-term exposure to different PM size fractions and PM2.5 constituents and seven lipid metrics. We found significant associations of greater concentrations of PM in different size fractions within 5 days before blood collection with lower high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A (ApoA1) levels, higher apolipoprotein B (ApoB) levels, and lower ApoA1/ApoB ratios. Among the PM2.5 constituents, we observed that higher concentrations of tin and lead were significantly associated with decreased HDL-C levels, and higher concentrations of nickel were associated with higher HDL-C levels. Our results suggest that short-term exposure to PM in different sizes was deleteriously associated with blood lipids. Some constituents, especially metals, might be the major contributors to the detrimental effects.

Effectiveness of a WHO self-help psychological intervention to alleviate stress among healthcare workers in the context of COVID-19 in China: a randomised controlled trial.

AIMS: To examine the effectiveness of Self-Help Plus (SH+) as an intervention for alleviating stress levels and mental health problems among healthcare workers. METHODS: This was a prospective, two-arm, unblinded, parallel-designed randomised controlled trial. Participants were recruited at all levels of medical facilities within all municipal districts of Guangzhou. Eligible participants were adult healthcare workers experiencing psychological stress (10-item Perceived Stress Scale scores of ≥15) but without serious mental health problems or active suicidal ideation. A self-help psychological intervention developed by the World Health Organization in alleviating psychological stress and preventing the development of mental health problems. The primary outcome was psychological stress, assessed at the 3-month follow-up. Secondary outcomes were depression symptoms, anxiety symptoms, insomnia, positive affect (PA) and self-kindness assessed at the 3-month follow-up. RESULTS: Between November 2021 and April 2022, 270 participants were enrolled and randomly assigned to either SH+ (n = 135) or the control group (n = 135). The SH+ group had significantly lower stress at the 3-month follow-up (b = -1.23, 95% CI = -2.36, -0.10, p = 0.033) compared to the control group. The interaction effect indicated that the intervention effect in reducing stress differed over time (b = -0.89, 95% CI = -1.50, -0.27, p = 0.005). Analysis of the secondary outcomes suggested that SH+ led to statistically significant improvements in most of the secondary outcomes, including depression, insomnia, PA and self-kindness. CONCLUSIONS: This is the first known randomised controlled trial ever conducted to improve stress and mental health problems among healthcare workers experiencing psychological stress in a low-resource setting. SH+ was found to be an effective strategy for alleviating psychological stress and reducing symptoms of common mental problems. SH+ has the potential to be scaled-up as a public health strategy to reduce the burden of mental health problems in healthcare workers exposed to high levels of stress.

A laser free self-luminous nanosystem for photodynamic therapy of cervical cancer cells.

Photodynamic therapy is a tumor treatment strategy. However, most of the photodynamic therapies rely on laser irradiation triggering, which limits their application in deep tissues. This study designed a self-luminescent nano system, hybrid protein oxygen nanocarrier coated graphene quantum dots (GQDs@HPOC) and mesoporous silica nanoparticles coated Luminol (L@MSNs), which self-assembled into GQDs@HPOC/L@MSNs without laser irradiation. The system utilized the weak acidic environment of tumors to trigger the release of Luminol and the chemiluminescence was catalyzed by HPOC. Next CRET occurred between Luminol and GQDs, producing 1O2, which could generate photodynamic damage to cervical cancer cells without the need for external laser irradiation. The system achieved the peak uptake in primary cervical cancer cells in 3 h, and had good biosafety before self-assembly. The system could significantly kill cells at a concentration of 16 µg/ml. The system will be further applied in in vivo experiments to investigate its therapeutic ability, providing a new strategy for the clinical treatment of cervical cancer.

Intimate Partner Violence and Willingness to Use Pre-Exposure Prophylaxis Among Men Who Have Sex With Men in Chengdu, China.

Intimate partner violence (IPV) is common in men who have sex with men (MSM). MSM also face increased risk of human immunodeficiency virus infection. However, it is not known whether IPV experience of MSM in China would affect their attitudes toward pre-exposure prophylaxis (PrEP) use. A cross-sectional study was conducted to explore the associations between different types of IPV and willingness to use PrEP in a sample of 608 MSM from November 2018 to May 2019 in Chengdu, China. Univariate and multivariate logistic regression analyses were used to explore the associations between different types of IPV and willingness to use PrEP. The average age of the participants was 31.8 ± 12.3 years, 48.9% of them were aware of PrEP before this study, and only 7.2% were aware of long-acting injectable PrEP (LAI-PrEP). The overall willingness to use any type of PrEP in the next 6 months was 82.2%. Approximately one third of the participants (n = 198) had experienced at least one type of IPV. We found that experience of sexual perpetration was negatively associated with the willingness to use on-demand PrEP (adjusted odds ratio [ORa] = 0.33, 95% CI = 0.16-0.67) and the overall willingness to use any type of PrEP (ORa = 0.31, 95% CI = 0.15-0.64). The willingness to use LAI-PrEP also had negative associations with any type of monitoring IPV (ORa = 0.58, 95% CI = 0.38-0.91), controlling victimization (ORa = 0.41, 95% CI = 0.21-0.82), and emotional victimization (ORa = 0.58, 95% CI = 0.35-0.97). The findings of this study demonstrate that IPV experiences are negatively associated with willingness to use PrEP among MSM, suggesting that PrEP promotion programs should consider IPV screening and develop explicit intervention strategies for both perpetrators and victims.

Synergism of amlodipine and telmisartan or candesartan on blood pressure reduction by using SynergyFinder 3.0 and probability sum test in vivo.

This study was designed to evaluate the synergism of two couples of antihypertensive drugs (amlodipine + telmisartan and amlodipine + candesartan) on blood pressure reduction in vivo by both SynergyFinder 3.0 and probability sum test. Spontaneously hypertensive rats were treated with intragastric administration of amlodipine (0.5, 1, 2, and 4 mg/kg), telmisartan (4, 8, and 16 mg/kg), candesartan (1, 2, and 4 mg/kg), nine combinations for amlodipine and telmisartan, and nine combinations for amlodipine and candesartan. The control rats were treated by 0.5% carboxymethylcellulose sodium. Blood pressure was recorded continuously up to 6 h after administration. Both SynergyFinder 3.0 and the probability sum test were used to evaluate the synergistic action. The synergisms calculated by SynergyFinder 3.0 are consistent with the probability sum test both in two different combinations. There is an obviously synergistic interaction between amlodipine and telmisartan or candesartan. The combinations of amlodipine and telmisartan (2 + 4 and 1 + 4 mg/kg) and amlodipine and candesartan (0.5 + 4 and 2 + 1 mg/kg) might exert an optimum synergism against hypertension. Compared with the probability sum test, SynergyFinder 3.0 is more stable and reliable to analyze the synergism.

Positive Affect Moderates the Influence of Perceived Stress on the Mental Health of Healthcare Workers during the COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has posed a profound psychological impact on healthcare workers. However, the role of positive affect in moderating the effect of perceived stress on the psychological states of healthcare workers remains unknown. This study aimed to analyze the moderating effect of positive affect on the association between stress and the mental health of healthcare workers during the COVID-19 pandemic. This cross-sectional study evaluated the relationships between perceived stress (the Perceived Stress Scale), positive affect (the Positive and Negative Affect Schedule), depression (the Patient Health Questionnaire-9), and anxiety (the Generalized Anxiety Disorder 7-item Scale) during the COVID-19 pandemic in 644 Chinese healthcare workers who completed online self-reports. The results revealed a significant negative association between positive affect and psychological problems, including stress, depression, and anxiety. At the total group level, multiple regression analysis showed that positive affect alleviated the influence of perceived stress on depression, but no significant moderating effect was found for anxiety. In the subgroups divided by perceived stress, the moderating effect of positive affect on depression was only significant in healthcare workers with a high level of perceived stress. These results suggested that positive affect played a moderative role in alleviating the effect of stress on depression among healthcare workers, particularly those with a high level of stress, thus emphasizing the importance of positive affect as an intervention strategy for promoting the mental health of healthcare workers in the context of the ongoing COVID-19 pandemic.

Psychological stress self-help interventions for healthcare workers in the context of COVID-19 in China: A randomized controlled trial protocol.

Background: Public health emergencies may lead to severe psychological stress, especially for healthcare workers, including frontline healthcare workers and public health workers. However, few stress management interventions have been implemented for healthcare workers even though they require more comprehensive interventions than the general public. Self-Help Plus (SH+) is a novel psychological self-help intervention developed by the World Health Organization. It is accessible, scalable, and cost-effective and has the potential to be quickly applied to help people cope with stress and adversity. The major objective of this study is to evaluate the effectiveness of SH+ interventions on the alleviation of stress levels and mental health problems among healthcare workers. Methods: A randomized controlled trial of SH+ will be conducted to investigate the stress level and mental health status of Chinese healthcare workers and control subjects in Guangzhou. Assessments will be performed before (baseline), at the end of (1 month), and 2 months after (3 months) the intervention. After completing the baseline screening questionnaire, eligible participants will be randomly assigned to one of the two groups in a 1:1 ratio by block randomization. During the 1-month intervention period, the intervention group will receive the SH+ intervention and the control group will receive information about mental health promotion. The intervention will be delivered by the research assistant via social media platforms. The primary outcome is the level of stress, which will be measured by a 10-item Perceived Stress Scale. Secondary outcomes including mental health symptoms will also be collected. Discussion: Given the potential for multiple COVID-19 waves and other infectious disease pandemics in the future, we expect that SH+ will be an effective stress management intervention for healthcare workers. The findings from this study will facilitate the application of SH+, and the trial is expected to be extended to a larger population in the future.

High-stabilized polydopamine modified low eutectic fatty acids based on near-infrared response for breast cancer therapy.

Low eutectic of lauric acid and stearic acid is one of drug loading candidates for its phase transformation at a certain temperature. Herein we demonstrated a combined photothermal-chemotherapy for breast cancer with near-infrared (NIR) triggered phase transition materials (PCM), which was conjugated with polydopamine (PDA) as the photosensitive agent. The PCM nanoparticles had diameters of ~75 nm based on scanning electron microscope (SEM) and dynamic laser scattering (DLS) measurement. Systematic in vitro and in vivo studies have been performed to investigate the stability, biosafety, photothermal performance, and drug delivery and release of PCM conjugates. Temperature measurement confirmed the prepared PDA modified material still showed strong photothermal effect after five cycles, which was higher than that of IR780 conjugated ones. In vivo photothermal imaging showed that the temperature of the tumor site reached 50.8 °C after 3 h of intravenous injection of PCM conjugates. More effective therapy of near-infrared (NIR)-assisted PDA-M@PCM in 4T1 bearing mice was witnessed when compared with that of non-NIR-assisted ones. Enhanced therapy in 4T1 tumor was demonstrated in DOX-loaded PDA-M@PCM by fluorescence imaging. This NIR-triggered PCM based nanoplatform can serve as useful tool for light-assisted combined tumor therapy.

Short-Term Effects of Particle Size and Constituents on Blood Pressure in Healthy Young Adults in Guangzhou, China.

Background Although several studies have focused on the associations between particle size and constituents and blood pressure, results have been inconsistent. Methods and Results We conducted a panel study, between December 2017 and January 2018, in 88 healthy university students in Guangzhou, China. Weekly systolic blood pressure and diastolic blood pressure were measured for each participant for 5 consecutive weeks, resulting in a total of 440 visits. Mass concentrations of particles with an aerodynamic diameter of ≤2.5 µm (PM2.5), ≤1.0 µm (PM1.0), ≤0.5 µm (PM0.5), ≤0.2 µm (PM0.2), and number concentrations of airborne particulates of diameter ≤0.1 µm were measured. Linear mixed-effect models were used to estimate the associations between blood pressure and particles and PM2.5 constituents 0 to 48 hours before blood pressure measurement. PM of all the fractions in the 0.2- to 2.5-µm range were positively associated with systolic blood pressure in the first 24 hours, with the percent changes of effect estimates ranging from 3.5% to 8.8% for an interquartile range increment of PM. PM0.2 was also positively associated with diastolic blood pressure, with an increase of 5.9% (95% CI, 1.0%-11.0%) for an interquartile range increment (5.8 µg/m3) at lag 0 to 24 hours. For PM2.5 constituents, we found positive associations between chloride and diastolic blood pressure (1.7% [95% CI, 0.1%-3.3%]), and negative associations between vanadium and diastolic blood pressure (-1.6% [95% CI, -3.0% to -0.1%]). Conclusions Both particle size and constituent exposure are significantly associated with blood pressure in the first 24 hours following exposure in healthy Chinese adults.

Associations of ambient particulate matter with homocysteine metabolism markers and effect modification by B vitamins and MTHFR C677T gene polymorphism.

Evidence concerning effects of ambient air pollution on homocysteine (HCY) metabolism is scarce. We aimed to explore the associations between ambient particulate matter (PM) exposure and the HCY metabolism markers and to evaluate effect modifications by folate, vitamin B12, and methylenetetrahyfrofolate reductase (MTHFR) C677T gene polymorphism. Between December 1, 2017 and January 5, 2018, we conducted a panel study in 88 young college students in Guangzhou, China, and received 5 rounds of health examinations. Real-time concentrations of PMs with aerodynamic diameter ≤2.5 (PM2.5), ≤1.0 (PM1.0), and ≤0.1 (PM0.1) were monitored, and the serum HCY metabolism markers (i.e., HCY, S-Adenosylhomocysteine [SAH], and S-Adenosylmethionine [SAM]) were repeatedly measured. We applied linear mixed effect models combined with a distributed lag model to evaluate the associations of PMs with the HCY metabolism markers. We also explored effect modifications of folate, vitamin B12, and the MTHFR C677T polymorphism on the associations. We observed that higher concentrations of PM2.5 and PM1.0 were associated with higher serum levels of HCY, SAH, SAM, and SAM/SAH ratio (e.g., a 10 µg/m3 increase in PM2.5 during lag 0 day and lag 5 day was significantly associated with 1.3-19.4%, 1.3-28.2%, 6.2-64.4%, and 4.8-28.2% increase in HCY, SAH, SAM, and SAM/SAH ratio, respectively). In addition, we observed that the associations of PM2.5 with the HCY metabolism markers were stronger in participants with lower B vitamins levels. This study demonstrated that short-term exposure to PM2.5 and PM1.0 was deleteriously associated with the HCY metabolism markers, especially in people with lower B vitamins levels.

Wound therapy via a photo-responsively antibacterial nano-graphene quantum dots conjugate.

Common bacterial pathogens have become resistant to traditional antibiotics, representing an indispensable public health crisis. Photodynamic therapy (PDT), especially when common visible light sources are used as photodynamic power, is a promising bactericidal method. Based on the special photodynamic properties triggered by commonly available light emitting diode (LED) lamps, a kind of graphene quantum dots (GQDs) based composite system (termed GQDs@hMSN(EM)) was prepared through loading both GQDs and erythromycin (EM) into the hollow mesoporous silica nanoparticle (hMSN), aiming to achieve joint antimicrobial effect. Bacterial density experiments confirmed that GQDs@hMSN(EM) had combined antimicrobial effects from photodynamic effect and drug release on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). In animal models, the healing degree of wounds infected by bacteria also confirmed that GQDs@hMSN(EM) group had the best therapeutic effect, with the significantly reduced inflammatory factors in blood. Different from traditional GQDs synthesized by solvothermal method, the as-prepared GQDs@hMSN can produce singlet oxygen (1O2) under light exposure to destroy the structure of bacteria, thus achieving highly efficient antimicrobial effect. The GQDs@hMSN(EM) in this work possesses good antimicrobial activity, sufficient drug loading, and controllable drug release ability, which provides a new opportunity for GQDs-based nanoplatform to enhance antimicrobial effect and reduce their drug resistance.