Quantifying the presymptomatic transmission of COVID-19 in the USA.

The emergence of many presymptomatic hidden transmission events significantly complicated the intervention and control of the spread of COVID-19 in the USA during the year 2020. To analyze the role that presymptomatic infections play in the spread of this disease, we developed a state-level metapopulation model to simulate COVID-19 transmission in the USA in 2020 during which period the number of confirmed cases was more than in any other country. We estimated that the transmission rate (i.e., the number of new infections per unit time generated by an infected individual) of presymptomatic infections was approximately 59.9% the transmission rate of reported infections. We further estimated that {at any point in time the} average proportion of infected individuals in the presymptomatic stage was consistently over 50% of all infected individuals. Presymptomatic transmission was consistently contributing over 52% to daily new infections, as well as consistently contributing over 50% to the effective reproduction number from February to December. Finally, non-pharmaceutical intervention targeting presymptomatic infections was very effective in reducing the number of reported cases. These results reveal the significant contribution that presymptomatic transmission made to COVID-19 transmission in the USA during 2020, as well as pave the way for the design of effective disease control and mitigation strategies.

BST2 promotes gastric cancer metastasis under the regulation of HOXD9 and PABPC1.

Gastric cancer (GC) constitutes substantial cancer mortality worldwide. Several cancer types aberrantly express bone marrow stromal cell antigen 2 (BST2), yet its functional and underlying mechanisms in GC progression remain unknown. In our study, RNA sequencing data revealed that BST2 was transcriptionally activated by homeobox D9 (HOXD9). BST2 was significantly upregulated in GC tissues and promoted epithelial-mesenchymal transition and metastasis of GC. BST2 knockdown reversed HOXD9's oncogenic effect on GC metastasis. Moreover, BST2 messenger RNA stability could be enhanced by poly(A) binding protein cytoplasmic 1 (PABPC1) through the interaction between BST2 3'-UTR and PABPC1 in GC cells. PABPC1 promoted GC metastasis, which BST2 silencing attenuated in vitro and in vivo. In addition, positive correlations among HOXD9, BST2, and PABPC1 were established in clinical samples. Taken together, increased expression of BST2 induced by HOXD9 synergizing with PABPC1 promoted GC cell migration and invasion capacity.

What influences newly graduated registered nurses' intention to leave the nursing profession? An integrative review.

BACKGROUND: Newly graduated registered nurses leaving the nursing profession in the early stages of their career have enormous financial and time implications for nursing organizations and affect the quality of nursing care. OBJECTIVE: To identify the factors influencing newly graduated registered nurses' intention to leave the nursing profession over the past 10 years. METHODS: The framework developed by Whittemore and Knafl was used to conduct this integrative review. An electronic search was conducted for English articles to identify research studies published between 2011-2022 using the following databases of PubMed, MEDLINE, CINAHL, PsycINFO, and Scopus. Eligible publications were critically reviewed and scored using the Critical Appraisal Skills Program Checklist and the Center for Evidence-Based Management appraisal. RESULTS: Twenty-one studies were analyzed. The main factors affecting newly graduated registered nurses' intention to leave the nursing profession included demographic factors (age, educational level, year of experience, professional title, employment status, health status, shift, hospital location and size), supervisor and peer support, challenges in the workplace, cognitive and affective response to work, work environment (collegial nurse-physician relations, insufficient staffing level, person-work environment fit), gender stereotypes, autonomous motivation, role models, and resilience. CONCLUSIONS: The factors affecting newly graduated registered nurses' intention to leave the nursing profession are multifaceted and should receive continuous attention from nurse managers. The findings provide more comprehensive for nurse administrators to develop intervention strategies to mitigate newly graduated registered nurses' turnover intention.

Demand and influencing factors of "Internet + Traditional Chinese Medicine" home nursing service for older adult patients with chronic diseases: a mixed research perspective.

Background: In the context of global aging, the characteristics of chronic diseases seriously affect the quality of life of older adults. It is urgent to carry out continuous nursing basis for older adult patients with chronic diseases. In view of the remarkable efficacy of Chinese medicine in the treatment of chronic diseases, this study may help to understand the demand for "Internet + Chinese medicine" home care service and its influencing factors of older adult chronic disease patients, and to provide a reference basis for improving the quality of life of the older adult chronic disease population. Methods: This is a mixed study. The quantitative study adopted the convenience sampling method, and a total of 308 patients in a third-grade hospital in Shaanxi Province were investigated by general data questionnaire, traditional Chinese medicine service demand questionnaire, traditional Chinese medicine knowledge questionnaire, older adult Chinese medicine attitude questionnaire, and home care demand questionnaire from March to April 2022. In the qualitative study, semi-structured interviews were adopted, and patients were interviewed until the content was saturated. Colaizzi analysis method was used to analyze and summarize the topic of the interview data. Results: 308 valid questionnaires were collected, and the patients scored (58.42 ± 17.16) on the demand for TCM nursing services, (59.86 ± 11.54) on the knowledge of TCM, (73.03 ± 9.11) on the attitude toward TCM, and (136.84 ± 46.39) on the demand for home care. The results of multiple linear regression showed that learning about the nursing service pathway, knowledge of general knowledge of Chinese medicine, and attitude toward Chinese medicine among the older adult and home care demand were the influencing factors of the demand for Chinese medicine nursing services for older adult patients with chronic diseases (p < 0.05). The results of the in-depth interviews were summarized into three themes: facilitating factor, hindering factor, and the "Internet + Chinese medicine" multiple needs of home care. Conclusion: Older adult patients with chronic diseases have a high intention of home care demand and they are affected by multiple factors. Consequently, the actual demand situation of older adult patients with chronic diseases should be used as a guide to provide directed and diversified Chinese medicine home care services to meet the individualized needs of the older adult.

The ATF2/miR-3913-5p/CREB5 axis is involved in the cell proliferation and metastasis of colorectal cancer.

Various miRNAs have been shown to participate in the tumor progression and development of colorectal cancer (CRC). However, the role of miR-3913-5p in CRC are yet to be clearly defined. In the present study, we determine that miR-3913-5p is downregulated in CRC cell lines and CRC tissues. Exogenous miR-3913-5p expression weakens the CRC cells growth, migration and invasion. Mechanistically, miR-3913-5p directly targets the 3'UTR of CREB5. Overexpression of CREB5 reverses the suppression of CRC cells proliferation, migration and invasion induced by miR-3913-5p. Furthermore, ATF2 negatively regulates the transcription of miR-3913-5p by binding to its promoter. CREB5 can cooperate with ATF2. CREB5 is required for ATF2 in regulating miR-3913-5p. Finally, inverse correlations can be found between the expressions of miR-3913-5p and CREB5 or ATF2 in CRC tissues. Thus, a plausible mechanism of ATF2/miR-3913-5p/CREB5 axis regulating CRC progression is elucidated. Our findings suggest that miR-3913-5p functions as a tumor suppressor in CRC. ATF2/miR-3913-5p/CREB5 axis might be a potential therapeutic target against CRC progression.

The VAX2-LINC01189-hnRNPF signaling axis regulates cell invasion and migration in gastric cancer.

Transcription factors (TFs) and long noncoding RNAs (lncRNAs) contribute to gastric cancer (GC). However, the roles of TFs and lncRNAs in the invasion and metastasis of GC remain largely unknown. Here, we observed that the transcription factor VAX2 is significantly upregulated in GC cells and tissues and acts as an oncogene. Moreover, high VAX2 expression is associated with the advancement of tumors in GC. In terms of functionality, the enforced expression of VAX2 promotes the proliferation and metastasis of GC cells. Mechanistically, VAX2 specifically interacts with the LINC01189 promoter and represses LINC01189 transcription. Furthermore, LINC01189 exhibits significant downregulation in GC and functions as a suppressor gene. Functionally, it inhibits migratory and invasive abilities in GC cells. In the context of GC metastasis, VAX2 plays a role in modulating it by trans-repressing the expression of LINC01189. Additionally, LINC01189 binds to hnRNPF to enhance hnRNPF degradation through ubiquitination. The cooperation between LINC01189 and hnRNPF regulates GC cell invasion and migration. In addition, both VAX2 and hnRNPF are highly expressed, while LINC01189 is expressed in at low levels in GC tissues compared to normal gastric tissues. Our study suggests that VAX2 expression facilitates, while LINC01189 expression suppresses, metastasis and that the VAX2-LINC01189-hnRNPF axis plays a contributory role in GC development.

Global, regional, and national epidemiology of migraine and tension-type headache in youths and young adults aged 15-39 years from 1990 to 2019: findings from the global burden of disease study 2019.

BACKGROUND: In recent years, headache disorders have garnered significant attention as a pressing global health issue. This concern is especially pronounced in low- to middle-income countries and exhibits a notable increase in prevalence among adolescents and young adults. Such a surge in these disorders has invariably diminished the quality of life for affected individuals. Despite its global impact, comprehensive studies exploring the ramifications of headache disorders in the younger population remain scant. Our study endeavored to quantify the global prevalence of headache disorders in individuals between the ages of 15 and 39, over a three-decade span from 1990 to 2019. METHODS: Our study, conducted from 1990 to 2019, evaluated the impact of headache disorders, specifically migraines and tension-type headaches (TTH), in 204 different countries and territories. This comprehensive assessment included a detailed analysis of incidence rates, prevalence, and disability-adjusted life-years (DALYs) across various demographics such as age, gender, year, geographical location, and Socio-demographic Index (SDI). RESULTS: In 2019, there were an estimated 581,761,847.2 migraine cases globally (95% UI: 488,309,998.1 to 696,291,713.7), marking a 16% increase from 1990. Concurrently, TTH cases numbered at 964,808,567.1 (95% UI: 809,582,531.8 to 1,155,235,337.2), reflecting a 37% rise since 1990. South Asia reported the highest migraine prevalence with 154,490,169.8 cases (95% UI: 130,296,054.6 to 182,464,065.6). High SDI regions exhibited the most substantial migraine prevalence rates both in 1990 (22,429 per 100,000 population) and 2019 (22,606 per 100,000 population). Among the five SDI classifications, the middle SDI region recorded the highest tally of TTH cases in both 1990 (210,136,691.6 cases) and 2019 (287,577,250 cases). Over the past 30 years, East Asia experienced the most pronounced surge in the number of migraine cases. On the whole, there was a discernible positive correlation between the disease burden of migraine and TTH and the SDI. CONCLUSION: Migraine and TTH represent formidable challenges in global health. The intensity of their impact exhibits marked disparities across nations and is distinctly elevated among women, individuals within the 30-39 age bracket, and populations characterized by a high SDI. The results of our research emphasize the imperative of assimilating migraine and TTH management into contemporary healthcare paradigms. Such strategic integration holds the potential to amplify public cognizance regarding pertinent risk factors and the spectrum of therapeutic interventions at hand.

Deconstructing emotion regulation in schizophrenia: The nature of abnormalities at the selection and implementation stages.

Difficulties with emotion regulation are observed across psychiatric diagnoses, including psychotic disorders. Past studies using trait self-report indicate that people with schizophrenia (SZ) are less likely to use adaptive emotion regulation strategies and more likely to use maladaptive emotion regulation strategies than controls (CN). However, more recent evidence using ecological momentary assessment (EMA) indicates that regulation effectiveness and adaptiveness may vary across strategies. The present study aimed to systematically understand abnormalities in state-level emotion regulation strategy selection, effectiveness, and adaptiveness in SZ compared to CN using EMA. Participants (n = 50 SZ; n = 53 CN) completed 6 days of EMA surveys assessing emotional experience, emotion regulation, and symptoms. Results indicated that SZ selected interpersonal emotion regulation and avoidance more often than CN, while both groups selected reappraisal and distraction more often than avoidance and suppression. Overall, strategies were effective at reducing negative emotion and adaptive for reducing delusions over time. Reappraisal, avoidance, and suppression all significantly down-regulated delusions over time. Although some selection abnormalities were present in terms of rate of selection and effort exertion, people with SZ select strategies which are effective and adaptive in the short term. The present results have implications for how cognitive therapy for psychosis may target delusions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Environmental resource reductions predict greater severity of negative symptoms in schizophrenia.

No pharmacological or psychosocial interventions effectively treat negative symptoms in schizophrenia (SZ), despite the identification of biological and psychological mechanistic targets. Limited treatment progress may result from failure to account for non-person-level environmental factors that present barriers to performing recreational, social, and goal-directed activities. The bioecosystem model of negative symptoms proposes that four interactive ecosystems (i.e. microsystem, mesosystem, exosystem, and macrosystem) influence person-level factors (e.g., dysfunctional beliefs, glutamate, cortico-striatal functioning) to initiate and maintain negative symptoms. The current study tested this hypothesis by examining whether indirect environmental factors (e.g., access to resources for performing activities in the built environment) were associated with dysfunctional beliefs (defeatist performance, asocial, anhedonic) and negative symptoms (anhedonia, avolition, asociality). Self-reports of indirect environmental factors (i.e., the built environment), dysfunctional beliefs, and negative symptoms were collected from 31 individuals with SZ and 29 matched healthy controls. Mediation analyses were conducted with dysfunctional beliefs as the predictor, indirect environmental factors as mediator, and negative symptoms as the outcome. Individuals with SZ reported reduced access to environmental resources for performing recreational, goal-directed, and social activities; these reductions were associated with greater negative symptom severity. Mediation analyses indicated that the effect of dysfunctional beliefs on negative symptoms was mediated by participants' satisfaction with resources for performing activities in their environment. These findings suggest that psychosocial treatments could be augmented to not only target dysfunctional beliefs, but also environmental processes that lead these beliefs to emerge and contribute to negative symptoms.

Study on Design and Preparation of Conductive Polyvinylidene Fluoride Fibrous Membrane with High Conductivity via Electrostatic Spinning.

The novel conductive polyvinylidene fluoride (PVDF) fibrous membrane with high conductivity and sensitivity was successfully prepared via electrostatic spinning and efficient silver reduction technology. Based on the selective dissolution of porogen of polyvinylpyrrolidone (PVP), the porous PVDF fibrous membrane with excellent adsorbability and mechanical strength was obtained, providing a structure base for the preparation of conductive PVDF fibrous membrane with silver nanoparticles (AgNPs-PVDF). The Ag+ in the AgNO3 mixed solution with PVP was absorbed and maintained in the inner parts and surface of the porous structure. After the reducing action of ascorbic acid-mixed solution with PVP, silver nanoparticles were obtained tightly in an original porous PVDF fibrous membrane, realizing the maximum conductivity of 2500 S/m. With combined excellent conductivity and mechanical strength, the AgNPs-PVDF fibrous membrane effectively and sensitively detected strain signals of throat vocalization, elbow, wrist, finger, and knee (gauge factor of 23). The electrospun conductive AgNPs-PVDF combined the characteristics of low resistance, high mechanical strength, and soft breathability, which provided a new and effective preparation method of conductive fibers for practical application in wearable devices.

Three-Layered Thin Films for Simultaneous Infrared Camouflage and Radiative Cooling.

With the rapid advancements in aerospace technology and infrared detection technology, there are increasing needs for materials with simultaneous infrared camouflage and radiative cooling capabilities. In this study, a three-layered Ge/Ag/Si thin film structure on a titanium alloy TC4 substrate (a widely used skin material for spacecraft) is designed and optimized to achieve such spectral compatibility by combining the transfer matrix method and the genetic algorithm. The structure exhibits a low average emissivity of 0.11 in the atmospheric windows of 3-5 µm and 8-14 µm for infrared camouflage and a high average emissivity of 0.69 in 5-8 µm for radiative cooling. Furthermore, the designed metasurface shows a high degree of robustness regarding the polarization and incidence angle of the incoming electromagnetic wave. The underlying mechanisms allowing for the spectral compatibility of the metasurface can be elucidated as follows: the top Ge layer selectively transmits electromagnetic waves ranging from 5-8 µm while it reflects those in the ranges of 3-5 µm and 8-14 µm. The transmitted electromagnetic waves from the Ge layer are first absorbed by the Ag layer and then localized in the Fabry-Perot resonance cavity formed by Ag layer, Si layer and TC4 substrate. Ag and TC4 make further intrinsic absorptions during the multiple reflections of the localized electromagnetic waves.

[Analysis of the incidence and related factors of hypothermia in patients with continuous renal replacement therapy].

OBJECTIVE: To investigate the incidence and risk factors of hypothermia in patients with acute renal injury (AKI) receiving continuous renal replacement therapy (CRRT), and to compare the effects of different heating methods on the incidence of hypothermia in patients with CRRT. METHODS: A prospective study was conducted. AKI patients with CRRT who were admitted to the department of critical care medicine of the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital) from January 2020 to December 2022 were enrolled as the study subjects. Patients were divided into dialysate heating group and reverse-piped heating group according to randomized numerical table method. Both groups were provided with reasonable treatment mode and parameter setting by the bedside physician according to the patient's specific condition. The dialysis heating group used the AsahiKASEI dialysis machine heating panel to heat the dialysis solution at 37 centigrade. The reverse-piped heating group used the Barkey blood heater from the Prismaflex CRRT system to heat the dialysis solution, and the heating line temperature was set at 41 centigrade. The patient's temperature was then continuously monitored. Hypothermia was defined as a temperature lower than 36 centigrade or a drop of more than 1 centigrade from the basal body temperature. The incidence and duration of hypothermia were compared between the two groups. Binary multivariate Logistic regression analysis was used to explore the influencing factors of hypothermia during CRRT in AKI patients. RESULTS: A total of 73 patients with AKI treated with CRRT were eventually enrolled, including 37 in the dialysate heating group and 36 in the reverse-piped heating group. The incidence of hypothermia in the dialysis heating group was significantly lower than that in the reverse-piped heating group [40.5% (15/37) vs. 69.4% (25/36), P < 0.05], and the hypothermia occurred later than that in the reverse-piped heating group (hours: 5.40±0.92 vs. 3.35±0.92, P < 0.01). Patients were divided into hypothermic and non-hypothermic groups based on the presence or absence of hypothermia, and a univariate analysis of all indicators showed a significant decrease in mean arterial pressure (MAP) in hypothermic patients (n = 40) compared with the non-hypothermic patients [n = 33; mmHg (1 mmHg ≈ 0.133 kPa): 77.45±12.47 vs. 94.42±14.51, P < 0.01], shock, administration of medium and high doses of vasoactive drug (medium dose: 0.2-0.5 µg×kg-1×min-1, high dose: > 0.5 µg×kg-1×min-1) and CRRT treatment were significantly increased [shock: 45.0% (18/40) vs. 6.1% (2/33), administration of medium and high doses of vasoactive drugs: 82.5% (33/40) vs. 18.2% (6/33), administration of CRRT (mL×kg-1×h-1): 51.50±9.38 vs. 38.42±10.97, all P < 0.05], there were also significant differences in CRRT heating types between the two groups [in the hypothermia group, the main heating method was the infusion line heating, which was 62.5% (25/40), while in the non-hypothermia group, the main heating method was the dialysate heating, which was 66.7% (22/33), P < 0.05]. Including the above indicators in a binary multivariate Logistic regression analysis, it was found that shock [odds ratio (OR) = 17.633, 95% confidence interval (95%CI) was 1.487-209.064], mid-to-high-dose vasoactive drug (OR = 24.320, 95%CI was 3.076-192.294), CRRT heating type (reverse-piped heating; OR = 13.316, 95%CI was 1.485-119.377), and CRRT treatment dose (OR = 1.130, 95%CI was 1.020-1.251) were risk factors for hypothermia during CRRT in AKI patients (all P < 0.05), while MAP was protective factor (OR = 0.922, 95%CI was 0.861-0.987, P < 0.05). CONCLUSIONS: AKI patients have a high incidence of hypothermia during CRRT treatment, and the incidence of hypothermia can be effectively reduced by heating CRRT treatment fluids. Shock, use of medium and high doses of vasoactive drug, CRRT heating type, and CRRT treatment dose are risk factors for hypothermia during CRRT in AKI patients, with MAP is a protective factor.

The LINC00501-HSP90B1-STAT3 positive feedback loop promotes malignant behavior in gastric cancer cells.

Long non-coding RNAs (lncRNAs) have been implicated in gastric cancer (GC) carcinogenesis and progression. However, the role of LINC00501 in GC growth and metastasis remains unclear. In this study, we found that LINC00501 was frequently upregulated in GC cells and tissues and was closely related to adverse GC clinicopathological features. Aberrant overexpression of LINC00501 promoted GC cell proliferation, invasion, and metastasis both in vitro and in vivo. Mechanistically, LINC00501 stabilized client protein STAT3 from deubiquitylation by directly interacting with cancer chaperone protein HSP90B1. Furthermore, the LINC00501-STAT3 axis modulated GC cell proliferation and metastasis. In turn, STAT3 bound directly to the LINC00501 promoter and positively activated LINC00501 expression, thus forming a positive feedback loop, thereby accelerating tumor growth, invasiveness, and metastasis. In addition, LINC00501 expression was positively correlated with STAT3 and p-STAT3 protein expression levels in gastric clinical samples. Our results reveal that LINC00501 acts as an oncogenic lncRNA and that the LINC00501-HSP90B1-STAT3 positive feedback loop contributes to GC development and progression, suggesting that LINC00501 may be a novel potential biomarker and treatment target for GC.

Dynamic evolution and response strategy of demand in buffer zone between scattered groundwater sources and hazardous waste landfill.

Groundwater contamination by landfill leachate is a major concern. Ignoring the long-term increase in leakage caused by the aging of engineered materials may lead to underestimation of the buffer distance (BFD) demand of landfills. In this study, a long-term BFD prediction model was developed by coupling an engineering material aging and defect evolution module with leachate leakage and migration transformation model, and was applicated and validated. The results showed that under landfill performance degradation, the required BFD was 2400 m, i.e., 6 times higher than under undegraded conditions. With the degradation of the performance, the BFD required to attenuate the heavy metal concentrations of groundwater increases more than the BFD required to attenuate organic pollutants. For example, the BFD required for zinc (Zn) was 5 times higher than that required for undegraded conditions, while for 2,4-dichlorophenol (2,4-D), the BFD was 1 times higher. Considering the uncertainties of the model parameters and structure, the BFD should be greater than 3000 m to ensure long-term safe water use under unfavorable conditions such as large leachate production and leakage, weak degradation and fast diffusion of pollutants. If the actual BFD does not meet the demand due to landfill performance degradation, the landfill owner can reduce the reliance on the BFD by reducing the waste leaching behavior. For example, the landfill in our case study would require a BFD of 2400 m, but by reducing the leaching concentration of zinc in the waste from 120 to 55 mg/L, this requirement could be reduced to 900 m.

Mitoglitazone ameliorates renal ischemia/reperfusion injury by inhibiting ferroptosis via targeting mitoNEET.

Ischemia/reperfusion- (I/R-) induced injury is unavoidable and a major risk factor for graft failure and acute rejection following kidney transplantation. However, few effective interventions are available to improve the outcome due to the complicated mechanisms and lack of appropriate therapeutic targets. Hence, this research aimed to explore the effect of the thiazolidinedione (TZD) compounds on I/R-induced kidney damage. One of the main causes of renal I/R injury is the ferroptosis of renal tubular cells. In this study, compared with the antidiabetic TZD pioglitazone (PGZ), we found its derivative mitoglitazone (MGZ) exerted significantly inhibitory effects on erastin-induced ferroptosis by suppressing mitochondrial membrane potential hyperpolarization and lipid ROS production in HEK293 cells. Moreover, MGZ pretreatment remarkably alleviated I/R-induced renal damages by inhibiting cell death and inflammation, upregulating the expression of glutathione peroxidase 4 (GPX4), and reducing iron-related lipid peroxidation in C57BL/6 N mice. Additionally, MGZ exhibited excellent protection against I/R-induced mitochondrial dysfunction by restoring ATP production, mitochondrial DNA copy numbers, and mitochondrial morphology in kidney tissues. Mechanistically, molecular docking and surface plasmon resonance experiments demonstrated that MGZ exhibited a high binding affinity with the mitochondrial outer membrane protein mitoNEET. Collectively, our findings indicated the renal protective effect of MGZ was closely linked to regulating the mitoNEET-mediated ferroptosis pathway, thus offering potential therapeutic strategies for ameliorating I/R injuries.

Translation of ionic liquids to be enteric nanoparticles for facilitating oral absorption of cyclosporine A.

Ionic liquids (ILs) attract more and more interests in improving drug transport across membrane, including transdermal, nasal, and oral delivery. However, some drawbacks of ILs impede the application in oral drug delivery, such as rapid precipitation of poorly soluble drugs in stomach. This study aimed to employ enteric mesoporous silica nanoparticles (MSNs) to load ILs to overcome the shortcomings faced in oral administration. The choline sorbate ILs (SCILs) were synthesized by choline bicarbonate and sorbic acid and then adsorbed in mesopores of MSNs after dissolving cyclosporin A (CyA). MSNs loading SCILs and CyA were coated by Eudragit® L100 to form enteric nanoparticles. The in vitro release study showed that the CyA and SCILs released only 10% for 2 h in simulated gastric fluids but more than 90% in simulated intestinal fluid. In addition, SCILs and CyA were able to release from MSNs synchronously. After oral administration, enteric MSNs loading SCILs were capable of improving oral absorption of CyA significantly and the oral bioavailability of CyA was similar with that of oral Neoral®. In addition, the oral absorption of enteric MSNs was higher than that of nonenteric MSNs, which showed that enteric coating was necessary to ILs in oral delivery. These findings revealed great potential of translation of ILs to be enteric nanoparticles for facilitating oral absorption of CyA. It is predictable this delivery system is promising to be a platform for delivering poorly water-soluble drugs and even biologics orally.

Effects of molecular hydrogen supplementation on fatigue and aerobic capacity in healthy adults: A systematic review and meta-analysis.

Background: Fatigue is oftentimes induced by high-intensity exercise potentially via the exceeded amount of reactive oxygen species, leading to diminished functions (e.g., aerobic capacity) and increased risk of injuries. Studies indicate that molecular hydrogen (H2), with antioxidant and anti-inflammatory properties, may be a promising strategy to alleviate fatigue and improve aerobic capacity. However, such effects have not been comprehensively characterized. Objective: To systematically assess the effects of in taking H2 on fatigue and aerobic capacity in healthy adults. Methods: The search was conducted in August 2022 in five databases. Studies with randomized controlled or crossover designs that investigated the rating of perceived exertion (RPE), maximal oxygen uptake (VO2max), peak oxygen uptake (VO2peak), and endurance performance were selected. The data (mean ± standard deviation and sample size) were extracted from the included studies and were converted into the standardized mean difference (SMD). Random-effects meta-analyses were performed. Subgroup analysis was used to analyze potential sources of heterogeneity due to intervention period, training status, and type of exercise. Results: Seventeen publications (19 studies) consisting of 402 participants were included. The pooled effect sizes of H2 on RPE (SMDpooled = -0.38, 95%CI -0.65 to -0.11, p = 0.006, I 2 = 33.6%, p = 0.149) and blood lactate (SMDpooled = -0.42, 95% CI -0.72 to -0.12, p = 0.006, I 2 = 35.6%, p = 0.114) were small yet significant with low heterogeneity. The pooled effect sizes of H2 on VO2max and VO2peak (SMDpooled = 0.09, 95% CI -0.10 to 0.29, p = 0.333, I 2 = 0%, p = 0.998) and endurance performance (SMDpooled = 0.01, 95% CI -0.23 to 0.25, p = 0.946, I 2 = 0%, p > 0.999) were not significant and trivial without heterogeneity. Subgroup analysis revealed that the effects of H2 on fatigue were impacted significantly by the training status (i.e., untrained and trained), period of H2 implementation, and exercise types (i.e., continuous and intermittent exercises). Conclusions: This meta-analysis provides moderate evidence that H2 supplementation alleviates fatigue but does not enhance aerobic capacity in healthy adults. Systematic review registration: www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022351559.

Design, synthesis, and discovery of Eudistomin Y derivatives as lysosome-targeted antiproliferation agents.

Eudistomin Y is a novel class of ß-carbolines of marine origin with potential antiproliferation activity against MDA-MB-231 cells (triple-negative breast carcinoma). However, the subcellular target or the detailed mechanism against cancer cell proliferation has not yet been identified. In this study, based on its special structure, a novel series of Eudistomin Y fluorescent derivatives were designed and synthesized by enhancing the electron-donor effect of N-9 to endow it with fluorescent properties through N-alkylation. The structure-activity relationships against the proliferation of cancer cells were also analyzed. A quarter of Eudistomin Y derivatives showed much higher potency against cancer cell proliferation than the original Eudistomin Y1. Fluorescent derivative H1k with robust antiproliferative activity could arrest MDA-MB-231 cells in the G2-M phase. The subcellular localization studies of the probes, including H1k, and Eudistomin Y1 were performed in MDA-MB-231 cells, and the co-localization and competitive inhibition assays revealed their lysosome-specific localization. Moreover, H1k could dose-dependently increase the autophagy signal and downregulate the expression of cyclin-dependent kinase (CDK1) and cyclin B1 which principally regulated the G2-M transition. Furthermore, the specific autophagy inhibitor 3-methyladenine significantly inhibited the H1k-triggered antiproliferation of cancer cells and the downregulation of CDK1 and cyclin B1. Overall, the lysosome is identified as the subcellular target of Eudistomin Y for the first time, and derivative H1k showed robust antiproliferative activity against MDA-MB-231 cells by decreasing Cyclin B1-CDK1 complex via a lysosome-dependent pathway.