The Association Between Allostatic Load and Frailty Trajectories Among Adults Aged 50+ Years: Mediating Role of Physical Activity.

OBJECTIVES: To identify frailty trajectories and examine its association with allostatic load (AL) and mediating effect of physical activity (PA). METHODS: This study included 8,082 adults from the English Longitudinal Study of Aging over Waves 4-9. AL was calculated by 14 biological indicators, and a 53-item frailty index was used to evaluate frailty. Frailty trajectories were classified by group-based trajectory modeling, and the mediated effect of PA was tested by causal mediation analysis. RESULTS: Four frailty trajectories were identified: "Robustness" (n = 4,437, 54.9%), "Incident prefrailty" (n = 2,061, 25.5%), "Prefrailty to frailty" (n = 1,136, 14.1%), and "Frailty to severe frailty" (n = 448, 5.5%). High baseline AL was associated with increased odds of "Incident prefrailty," "Prefrailty to frailty," and "Frailty to severe frailty" trajectories. PA demonstrated significant mediated effects in aforementioned associations. CONCLUSIONS: AL is significantly associated with the onset and progression of frailty, and such associations are partially mediated by PA.

Astragalus Polysaccharide Alleviates Ulcerative Colitis by Regulating the Balance of mTh17/mTreg Cells through TIGIT/CD155 Signaling.

The balance between memory Th17 cells (mTh17) and memory Treg cells (mTreg) plays a key role in the pathogenesis of ulcerative colitis (UC), and TIGIT signaling is involved in the differentiation of mTh17/mTreg cells. Astragalus polysaccharide (APS) has good immunomodulatory and anti-inflammatory effects. Here, the regulatory effects and potential mechanisms of APS on mTh17/mTreg cells in UC are explored. A UC model was induced with dextran sulfate sodium (DSS) and treated simultaneously with APS (200 mg/kg/day) for 10 days. After APS treatment, the mice showed a significant increase in colonic length and a significant decrease in colonic weight, colonic weight index and colonic weight/colonic length, and more intact mucosa and lighter inflammatory cell infiltration. Notably, APS significantly down-regulated the percentages of Th17 (CD4+CCR6+), cmTh17 (CD4+CCR7+CCR6+) and emTh17 (CD4+CCR7-CCR6+) cells and significantly up-regulated the percentages of cmTreg (CD4+CCR7+Foxp3+) and emTreg (CD4+CCR7-Foxp3+) cells in the mesenteric lymph nodes of the colitis mice. Importantly, APS reversed the expression changes in the TIGIT molecule on mTh17/mTreg cells in the colitis mice with fewer CD4+CCR6+TIGIT+, CD4+CCR7-CCR6+TIGIT+ and CD4+CCR7-CCR6+TIGIT+ cells and more CD4+Foxp3+TIGIT+, CD4+CCR7-Foxp3+TIGIT+ and CD4+CCR7-Foxp3+TIGIT+ cells. Meanwhile, APS significantly inhibited the protein expression of the TIGIT ligands CD155, CD113 and CD112 and downstream proteins PI3K and AKT in the colon tissues of the colitis mice. In conclusion, APS effectively alleviated DSS-induced UC in mice by regulating the balance between mTh17/mTreg cells, which was mainly achieved through regulation of the TIGIT/CD155 signaling pathway.

How sodium chloride extends lifetime of bulk nanobubbles in water.

We present a molecular dynamics simulation study on the effects of sodium chloride addition on stability of a nitrogen bulk nanobubble in water. We find that the lifetime of the bulk nanobubble is extended in the presence of NaCl and reveal the underlying mechanisms. We do not observe spontaneous accumulation or specific arrangement of ions/charges around the nanobubble. Importantly, we quantitatively show that the N2 molecule selectively diffuses through water molecules rather than pass by any ions after it leaves the nanobubble due to the much weaker water-water interactions than ion-water interactions. The strong ion-water interactions cause hydration effects and disrupt hydrogen bond networks in water, which leave fewer favorable paths for the diffusion of N2 molecules, and by that reduce the degree of freedom in the dissolution of the nanobubble and prolong its lifetime. These results demonstrate that the hydration of ions plays an important role in stability of the bulk nanobubble by affecting the dynamics of hydrogen bonds and the diffusion properties of the system, which further confirm and interpret the selective diffusion path of N2 molecules and the extension of lifetime of the nanobubble. The new atomistic insights obtained from the present research could potentially benefit the practical application of bulk nanobubbles.

Association between multimorbidity trajectories and incident disability among mid to older age adults: China Health and Retirement Longitudinal Study.

BACKGROUND: Although multimorbidity is a risk factor for disability, the relationship between the accumulative patterns of multimorbidity and disability remains poorly understood. The objective of this study was to identify the latent groups of multimorbidity trajectories among mid to older age adults and to examine their associations with incident disability. METHODS: We included 5,548 participants aged ≥ 45 years who participated in the China Health and Retirement Longitudinal Study from 2011 to 2018 and had no multimorbidity (≥ 2 chronic conditions) at baseline. The group-based multi-trajectory modeling was used to identify distinct trajectory groups of multimorbidity based on the latent dimensions underlying 13 chronic conditions. The association between multimorbidity trajectories and incident disability was analyzed using the generalized estimating equation model adjusting for potential confounders. RESULTS: Of the 5,548 participants included in the current analysis, 2,407 (43.39%) developed multimorbidity during the follow-up. Among participants with new-onset multimorbidity, four trajectory groups were identified according to the combination of newly diagnosed diseases: "Cardiometabolic" (N = 821, 34.11%), "Digestive-arthritic" (N = 753, 31.28%), "Cardiometabolic/Brain" (N = 618, 25.68%), and "Respiratory" (N = 215, 8.93%). Compared to participants who did not develop multimorbidity, the risk of incident disability was most significantly increased in the "Cardiometabolic/Brain" trajectory group (OR = 2.05, 95% CI: 1.55-2.70), followed by the "Cardiometabolic" (OR = 1.96, 95% CI: 1.52 -2.53) and "Digestive-arthritic" (OR = 1.70, 95% CI: 1.31-2.20) trajectory groups. CONCLUSIONS: The growing burden of multimorbidity, especially the comorbid of cardiometabolic and brain diseases, may be associated with a significantly increased risk of disability for mid to older age adults. These findings improve our understanding of multimorbidity patterns that affect the independence of living and inform the development of strategies for the primary prevention of disability.

Longitudinal trajectories of general cognitive and daily functions in data-driven subtypes of MCI: A longitudinal cohort analysis of older adults.

OBJECTIVES: To derive data-driven subtypes of mild cognitive impairment (MCI) and characterize the complicated changes of general cognitive and daily functions over time in MCI subtypes. METHODS: A total of 813 subjects diagnosed as MCI at baseline from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. Data-driven MCI subtypes were derived from group-based multi-trajectory modeling (GBMTM) analyses using longitudinal measurement scores in the cognitive domains of visuospatial function, language, and executive function. General cognitive and daily functions were measured by the Mini-Mental State Examination (MMSE) and the Functional Assessment Questionnaire (FAQ), respectively, whose longitudinal trajectory changes were depicted by Linear mixed models. RESULTS: Three MCI subtypes were derived, which were defined as "Cognitive decline group", "Mild cognitive decline group" and "No cognitive decline group". The "Mild cognitive decline group" had the highest percentage in the sample (46.2 %), followed by the "No cognitive decline group" (35.2 %). Patients in the "Cognitive decline group" had the highest mean age (74.69 years) at baseline, the highest APOE ε4 carriers (63.2 %), and the greatest dementia conversion rate (77.0 %). The changes in MMSE and FAQ score trajectories were fastest in the "Cognitive decline group" in the first 36 months and most slowly in the "No cognitive decline group". CONCLUSION: MCI individuals could be subdivided into more fine-grained cognitive subtypes, and identifying these distinct MCI subtypes and their different trajectories of cognitive decline may have important prognostic value for improving clinical course prediction.

Longitudinal trajectory effects of different MCI subtypes on general cognitive and daily functions in a population-based cohort of older adults.

OBJECTIVES: To identify different mild cognitive impairment (MCI) phenotypes based on substantial relative impairment in specific cognitive domains and then characterize the complex process of general cognitive and daily functions over time in older adults with these MCI subtypes. METHODS: A total of 1020 participants with MCI at baseline from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were recruited. MCI subtypes were obtained based on neuropsychological tests in five cognitive domains: memory (M), visuospatial function (V), language (L), processing speed (P), and executive function (E). General cognitive function and daily function were measured by the Mini-Mental State Examination (MMSE) and the Functional Assessment Questionnaire (FAQ), respectively. Linear mixed models were fitted to curve their trajectories across different MCI subtypes. RESULTS: Considering visuospatial function, subtypes were MO (memory impaired only), M&V (memory and visuospatial function impaired) and M&nV (memory impaired and visuospatial function non-impaired). Similar subtypes and naming rules were obtained based on language, executive function, and processing speed. Further, depending on the number of relative impaired cognitive domains M&S and M&M were obtained. Participants with MO had the highest prevalence in the sample (53.4 %), followed by M&nV (31.1 %). Participants with M&V had the highest mean age (74.69 years) at baseline and the greatest dementia conversion rate (53.2 %). The MMSE and FAQ score trajectories changed most slowly in participants with MO while fastest in those with M&V. Obvious different trajectories of both MMSE and FAQ scores were observed across different subtypes based on visuospatial function and executive function. CONCLUSION: Compared to MO, individuals with multi-dimensional cognitive impairment have worse general cognitive and daily functions, especially for those with M&V.

Association between multimorbidity trajectories, healthcare utilization, and health expenditures among middle-aged and older adults: China Health and Retirement Longitudinal Study.

BACKGROUND: To identify the latent groups of multimorbidity trajectories among middle-aged and older adults and examine their associations with healthcare utilization and health expenditures. METHODS: We included adults aged ≥45 years who participated in the China Health and Retirement Longitudinal Study from 2011 to 2015 and were without multimorbidities (<2 chronic conditions) at baseline. Multimorbidity trajectories underlying 13 chronic conditions were identified using group-based multi-trajectory modeling based on the latent dimensions. Healthcare utilization included outpatient care, inpatient care, and unmet healthcare needs. Health expenditures included healthcare costs and catastrophic health expenditures (CHE). Random-effects logistic regression, random-effects negative binomial regression, and generalized linear regression models were used to examine the association between multimorbidity trajectories, healthcare utilization, and health expenditures. RESULTS: Of the 5548 participants, 2407 developed multimorbidities during follow-up. Three trajectory groups were identified among those with new-onset multimorbidity according to the increasing dimensions of chronic diseases: "digestive-arthritic" (N = 1377, 57.21 %), "cardiometabolic/brain" (N = 834, 34.65 %), and "respiratory/digestive-arthritic" (N = 196, 8.14 %). All trajectory groups had a significantly increased risk of outpatient care, inpatient care, unmet healthcare needs, and higher healthcare costs than those without multimorbidities. Notably, participants in the "digestive-arthritic" trajectory group had a significantly increased risk of incurring CHE (OR = 1.70, 95%CI: 1.03-2.81). LIMITATIONS: Chronic conditions were assessed using self-reported measures. CONCLUSIONS: The growing burden of multimorbidity, especially multimorbidities of digestive and arthritic diseases, was associated with a significantly increased risk of healthcare utilization and health expenditures. The findings may help in planning future healthcare and managing multimorbidity more effectively.

Mechanistic Study on Enhanced Electrocatalytic Nitrogen Reduction Reaction by Mo Single Clusters Supported on MoS2.

The electrocatalytic N2 reduction reaction (eNRR) at ambient conditions is an appealing method for NH3 synthesis. It has attracted broad research interest in eNRR catalysts. In this work, by a theoretical study based on density functional calculations, we attributed the higher eNRR activity of defective MoS2 than pure MoS2 to the exposed Mo atom with unsaturated coordination sites in the interlayer of defective MoS2. The finding inspired us to explore the eNRR performance of Mo single atom/clusters with one/more active Mo sites supported on MoS2 [Mon@MoS2 (n = 1∼11)] and the corresponding catalytic mechanism. All considered Mon@MoS2 irrespective of N2 or H adsorption selectivity can achieve higher eNRR activity with lower overpotential and lower NH3 desorption free energy than defective MoS2. The competitive hydrogen evolution reaction can be well suppressed on Mon@MoS2 when n = 2∼10. In particular, Mo9@MoS2 with N2 adsorption selectivity exhibits excellent eNRR activity (η = 0.19 V) and high eNRR selectivity, and it can efficiently desorb the produced NH3 with a low desorption free energy (0.50 eV) to achieve a high ammonia yield with the aid of the produced ammonia molecule in the first eNRR process, which is coadsorbed on the Mo9 single cluster during the later eNRR process. The high eNRR activity of Mon@MoS2 can be attributed to its inherent properties of excellent electrical conductivity, electron accessibility, and multiple exposed Mo active sites available for N-containing species coadsorption. The results demonstrate the significance of H preadsorption, the additional N2 adsorption, and the adsorbed product ammonia in the prior eNRR process in enhancing the overall eNRR performance of different-size single-cluster catalysts. Our work provides a guidance for future study of single-cluster catalysts.

Mediating Effect of Physical Activity in the Association between Low 25-Hydroxyvitamin D and Frailty Trajectories: The English Longitudinal Study of Ageing.

BACKGROUND: Frailty is associated with adverse health outcomes, and vitamin D (VD) deficiency may be a risk factor. We aimed to identify frailty trajectories and examine the mediating effect of physical activity (PA) on the association between VD deficiency and frailty trajectories. METHODS: We included 2997 participants aged 60 to 85 years from ELSA. VD was measured using serum 25-hydroxyvitamin D [25(OH)D] (sufficient: >50; insufficient: 30−50; deficient: <30 nmol/L). Frailty was assessed by a 60-item frailty index, and PA was measured on the basis of total energy expenditure. Frailty trajectories were identified using group-based trajectory modeling, and the mediation effect of PA was tested using causal mediation analysis. RESULTS: Three distinct frailty trajectories emerged: "Non-frail" (66.48%), "Pre-frail to frail" (25.67%) and "Frail to severely frail" (7.85%). VD deficiency was associated with the "Pre-frail to frail" (OR = 1.51, 95% CI: 1.14, 1.98) and "Frail to severely frail" trajectories (OR = 2.29, 95% CI: 1.45, 3.62). PA only mediated 48.4% (95% CI: 17.1%−270.8%) of the association between VD deficiency and the "Pre-frail to frail" trajectory. CONCLUSIONS: Vitamin D deficiency is associated with the onset and worsening of frailty in older adults, and reduced PA may mediate its impact on the transition from pre-frailty to frailty.

Efficient Heteronuclear Diatom Electrocatalyst for Nitrogen Reduction Reaction: Pd-Nb Diatom Supported on Black Phosphorus.

Electrocatalytic N2 reduction reaction (eNRR) is a promising alternative to the traditional Haber-Bosch method for large-scale ammonia production because of its low pollution and low energy consumption. By means of density functional theory (DFT) calculations, a thermodynamically stable Pd-Nb heteronuclear diatom catalyst supported on 2D black phosphorus (PdNb@BP) is designed, which is predicted to exhibit excellent catalytic activity toward eNRR with an ultralow overpotential (0.20 V) and a small NH3 desorption free energy (0.17 eV), by combining the advantages of Nb atoms for N2 activation and of Pd atoms for NH3 desorption, and a high eNRR selectivity over the competing hydrogen evolution reaction. It is highlighted that the participation of one additional N2 molecule in the mechanism is important for the catalyst to realize the catalytic process.

Seventeen-year follow-up study on chromosomal aberrations in five victims accidentally exposed to several Gy of 60Co gamma-rays.

On 25 June 1990, a radiation accident occurred in a (60)Co source radiation unit in Shanghai, due to violations in operation regulations. This accident resulted in the exposure of seven individuals to acute high-dose and dose-rate whole-body external irradiation. Conventional chromosomal aberration analysis, G-banding automatic karyotype analysis and/or fluorescent in situ hybridization (FISH) painting methods were used to analyze chromosomal aberrations in peripheral blood lymphocytes from five of the victims 24 h to 17 years after accidental exposure to 1.9-5.1 Gy of (60)Co gamma-rays. The frequency of unstable chromosomal aberrations (dicentrics and rings) remained at constant levels 1 month after exposure. Three months after exposure, the frequency was reduced by 20-40% in three victims, while no reduction was seen in the other two victims. Twelve years after exposure, the number of dicentrics and rings decreased by more than 90%, and did not reveal a dose-dependent relationship. However, even at 12-17 years after exposure, stable chromosome aberrations, dominated by translocations, remained at a high level in a dose-dependent manner. The frequency of stable chromosomal aberrations detected by FISH showed a similar dose-dependent relationship as that detected by karyotype analysis of G-banding chromosomes. The G-banding analysis also suggested that the pattern of chromosome breakpoints is random. The FISH data showed a decreasing tendency with time for chromosome translocation frequency in the peripheral lymphocytes, and the rate of reduction varied among different individuals. It is likely that the higher dose the victim received, the lesser the translocation frequency decreased with time. The G-banding data also showed that the rate of reduction of translocations is different among individuals. From 5 to 17 years after accidental irradiation, a very small reduction (approximately 10%) of translocation frequency was observed in victims C and D, while there was about a 35% reduction (the highest among the victims) for victim G who received the smallest dose (1.9 Gy). These observations can be used to validate the existence of chromosomal aberrations in peripheral blood lymphocytes as a biological dosimeter for radiation exposures.

[Study on polymorphisms of CYP3A5 gene and their clinical role].

OBJECTIVE: To investigate the polymorphisms of CYP3A5 gene in Chinese population and the association between CYP3A5 genotypes and their clinical functions. METHODS: CYP3A5 gene varisances were detected in 180 samples using denaturing high-performance liquid chromatography(DHPLC), and CsA concentrations in 12 of 180 samples from hemopoietic stem cell transplant recipients were monitored by a commercial fluorescence polarization immunoassay. The data were analyzed by a statistical software. RESULTS: In the 180 samples, there was only one allelic variant CYP3A5*3 with a frequency of 76.1% (274/360), and there were three CYP3A5 genotypes, namely CYP3A5*1/*1, CYP3A5*1/*3 and CYP3A5*3/*3 with frequencies of 5.6%, 36.7% and 57.8% respectively. Also, there were significant differences in CsA concentrations, including standardized trough concentrations C(0) and two-hour peak concentrations C(2), between CYP3A5 CYP3A5*1/*1 and CYP3A5*1/*3 found in 12 hemopoietic stem cell transplant recipients, and both C(0) and C(2) in CYP3A5*1/*1 were lower than those in CYP3A5*1/*3. CONCLUSION: CYP3A5*3 is the primary allelic variant in Chinese population. CYP3A5 genotypes are closely associated with blood CsA concentrations in hemopoietic stem cell transplant recipients, and CYP3A5*1/*1 requires a larger CsA dose to maintain the same blood concentration than does CYP3A5*1/*1. CYP3A5 genotyping by DHPLC may predict recipients' phenotype and CsA dose requirement.