Rice-Magnaporthe oryzae interactions in resistant and susceptible rice cultivars under panicle blast infection based on defense-related enzyme activities and metabolomics.

Rice blast, caused by rice blast fungus (Magnaporthe oryzae), is a global threat to food security, with up to 50% yield losses. Panicle blast is a severe form of rice blast, and disease responses vary between cultivars with different genotypes. Reactive oxygen species (ROS)-mediated signaling reactions and the phenylpropanoid pathway are important defense mechanisms involved in recognizing and resisting against fungal infection. To understand rice-M. oryzae interactions in resistant and susceptible cultivars, we determined dynamic changes in the activities of five defense-related enzymes in resistant cultivar jingsui 18 and susceptible cultivar jinyuan 899 infected with M. oryzae from 4 to 25 days after infection. We then performed untargeted metabolomics analyses to profile the metabolomes of the cultivars under infected and non-infected conditions. Dynamic changes in the activities of five defense-related enzymes were closely related to panicle blast resistance in rice. Metabolome data analysis identified 634 differentially accumulated metabolites (DAMs) between resistant and susceptible cultivars following infection, potentially explaining differences in disease response between varieties. The most enriched DAMs were associated with lipids and lipid-like molecules, phenylpropanoids and polyketides, organoheterocyclic compounds, organic acids and derivatives, and lignans, neolignans, and related compounds. Multiple metabolic pathways are involved in resistance to panicle blast in rice, including biosynthesis of other secondary metabolites, amino acid metabolism, lipid metabolism, phenylpropanoid biosynthesis, arachidonic acid metabolism, arginine biosynthesis, tyrosine metabolism, tryptophan metabolism, tyrosine and tryptophan biosynthesis, lysine biosynthesis, and oxidative phosphorylation.

Association between social isolation and depression: Evidence from longitudinal and Mendelian randomization analyses.

BACKGROUND: Increasing evidence shows that social isolation and depression are likely to interact with each other, yet the direction and causality of the association are not clear. This study aims to examine the possible reciprocity in the relationship between social isolation and depression. METHODS: This study fitted a cross-lagged panel model (CLPM) by using data from the English Longitudinal Study of Aging (ELSA, 2014-2019, n = 6787) to examine the temporal relationship between social isolation and depressive symptoms in older adults. We then conducted two-sample bidirectional Mendelian randomization (MR) analyses by using independent genetic variants associated with multiple social isolation phenotypes (n = 448,858-487,647) and with depression (n = 215,644-2,113,907) as genetic instruments from genome-wide association studies to assess the causality between social isolation and onset of depression. RESULTS: The CLPM in the ELSA cohort showed a significant and positive lagged effect of social isolation on depressive symptoms (ß = 0.037, P < .001). The reverse cross-lagged path from depressive symptoms to social isolation was also statistically significant (ß = 0.039, P < .001). In two-sample bidirectional MR, the genetically predicted loneliness and social isolation combined phenotype (LNL-ISO) was positively associated with occurrence of depression (OR = 1.88, 95 % CI: 1.41-2.50, P < .001), vice versa (OR = 1.16, 95 % CI:1.13-1.20, P < .001). LIMITATIONS: The self-report nature of the assessments and missing data are study limitations. CONCLUSIONS: These findings suggest a bidirectional relationship between social isolation and depression. It is important to develop interventions that highlight the reciprocal consequences of improving either mental health or social connection in older adults.

Age-dependent changes in the gut microbiota and serum metabolome correlate with renal function and human aging.

Human aging is invariably accompanied by a decline in renal function, a process potentially exacerbated by uremic toxins originating from gut microbes. Based on a registered household Chinese Guangxi longevity cohort (n = 151), we conducted comprehensive profiling of the gut microbiota and serum metabolome of individuals from 22 to 111 years of age and validated the findings in two independent East Asian aging cohorts (Japan aging cohort n = 330, Yunnan aging cohort n = 80), identifying unique age-dependent differences in the microbiota and serum metabolome. We discovered that the influence of the gut microbiota on serum metabolites intensifies with advancing age. Furthermore, mediation analyses unveiled putative causal relationships between the gut microbiota (Escherichia coli, Odoribacter splanchnicus, and Desulfovibrio piger) and serum metabolite markers related to impaired renal function (p-cresol, N-phenylacetylglutamine, 2-oxindole, and 4-aminohippuric acid) and aging. The fecal microbiota transplantation experiment demonstrated that the feces of elderly individuals could influence markers related to impaired renal function in the serum. Our findings reveal novel links between age-dependent alterations in the gut microbiota and serum metabolite markers of impaired renal function, providing novel insights into the effects of microbiota-metabolite interplay on renal function and healthy aging.

Comparison of Transcriptome between Tolerant and Susceptible Rice Cultivar Reveals Positive and Negative Regulators of Response to Rhizoctonia solani in Rice.

Rice (Oryza sativa L.) is one of the world's most crucial food crops, as it currently supports more than half of the world's population. However, the presence of sheath blight (SB) caused by Rhizoctonia solani has become a significant issue for rice agriculture. This disease is responsible for causing severe yield losses each year and is a threat to global food security. The breeding of SB-resistant rice varieties requires a thorough understanding of the molecular mechanisms involved and the exploration of immune genes in rice. To this end, we conducted a screening of rice cultivars for resistance to SB and compared the transcriptome based on RNA-seq between the most tolerant and susceptible cultivars. Our study revealed significant transcriptomic differences between the tolerant cultivar ZhengDao 22 (ZD) and the most susceptible cultivar XinZhi No.1 (XZ) in response to R. solani invasion. Specifically, the tolerant cultivar showed 7066 differentially expressed genes (DEGs), while the susceptible cultivar showed only 60 DEGs. In further analysis, we observed clear differences in gene category between up- and down-regulated expression of genes (uDEGs and dDEGs) based on Gene Ontology (GO) classes in response to infection in the tolerant cultivar ZD, and then identified uDEGs related to cell surface pattern recognition receptors, the Ca2+ ion signaling pathway, and the Mitogen-Activated Protein Kinase (MAPK) cascade that play a positive role against R. solani. In addition, DEGs of the jasmonic acid and ethylene signaling pathways were mainly positively regulated, whereas DEGs of the auxin signaling pathway were mainly negatively regulated. Transcription factors were involved in the immune response as either positive or negative regulators of the response to this pathogen. Furthermore, our results showed that chloroplasts play a crucial role and that reduced photosynthetic capacity is a critical feature of this response. The results of this research have important implications for better characterization of the molecular mechanism of SB resistance and for the development of resistant cultivars through molecular breeding methods.

Comparative metabolomic profiling reveals molecular mechanisms underlying growth promotion and disease resistance in wheat conferred by Piriformospora indica in the field.

Piriformospora indica, a plant root-colonizing basidiomycete fungus, exhibits strong growth-promoting activity in symbiosis with a broad range of plants. Here, we report the potential of P. indica to improve growth, yield, and disease resistance in wheat in the field. In the present study, P. indica successfully colonized wheat through chlamydospores and formed dense mycelial networks that covered roots. Plants subjected to the seed soaking (SS) treatment with P. indica chlamydospore suspensions enhanced tillering 2.28-fold compared to the non-inoculated wheat in the tillering stage. In addition, P. indica colonization promoted vegetative growth significantly during the three-leaf, tillering, and jointing stages. Moreover, the P. indica-SS-treatment enhanced wheat yield by 16.37 ± 1.63%, by increasing grains per ear and panicle weight and decreased damage to wheat shoot and root architecture markedly, with high field control effects against Fusarium pseudograminearum (81.59 ± 1.32%), Bipolaris sorokiniana (82.19 ± 1.59%), and Rhizoctonia cerealis (75.98 ± 1.36%). Most of the primary metabolites, such as amino acids, nucleotides, and lipids, involved in vegetative reproduction were increased in P. indica-SS-treatment plants, whereas secondary metabolites, such as terpenoids, polyketides, and alkaloids, decreased following P. indica inoculation. The up-regulated processes of protein, carbohydrate, and lipid metabolism indicated that P. indica colonization increased growth, yield, and disease resistance via the acceleration of plant primary metabolism. In conclusion, P. indica improved morphological, physiological, and metabolic substance levels, and further promoted its growth, yield, and disease resistance in wheat.

Astragalus polysaccharides alleviates cardiac hypertrophy in diabetic cardiomyopathy via inhibiting the BMP10-mediated signaling pathway.

BACKGROUND: Cardiac hypertrophy can lead to cardiac dysfunction and is closely associated with mortality in diabetic cardiomyopathy (DCM). Astragalus polysaccharides (APS) is the main component extracted from Astragalus membranaceus (Fisch.) Bunge (AM), which exhibits anti-hypertrophic effects on cardiomyocytes in various diseases. However, whether APS exerts anti-hypertrophic effects in DCM remains unclear. PURPOSE: To investigate whether APS can attenuate cardiac hypertrophy in DCM and exert anti-hypertrophic effects by inhibiting the bone morphogenetic protein 10 (BMP10) pathway. METHODS: The anti-hypertrophic effects of APS were studied in high-glucose (HG)-stimulated H9c2 cardiomyocytes and streptozotocin (STZ)-induced DCM rats. BMP10 siRNA was used to inhibit BMP10 expression in H9c2 cardiomyocytes. Cardiac function was assessed by echocardiography. Cardiac hypertrophy was evaluated using heart weight/body weight (HW/BW), RT-PCR, hematoxylin-eosin (HE), and rhodamine phalloidin staining. Changes in hypertrophic components, including BMP10 and downstream factors, were measured using western blotting. RESULTS: In vitro, HG treatment increased the relative cell surface area of H9c2 cardiomyocytes, whereas BMP10 siRNA transfection or APS treatment alleviated the increase induced by HG. APS treatment improved the general condition, increased cardiac function, and decreased the HW/BW ratio, ANP mRNA level, and cardiomyocyte cross-sectional area of DCM rats in vivo. Molecular experiments demonstrated that APS downregulated the levels of the pro-hypertrophic protein BMP10 and its downstream proteins ALK3, BMPRII, and p-Smad1/5/8 without affecting the level of total Smad1/5/8. CONCLUSIONS: Our study demonstrates that APS can alleviate cardiac hypertrophy and protect against DCM by inhibiting activation of the BMP10 pathway. APS is a promising candidate for DCM treatment.

The association of pulse pressure change with memory decline in middle-aged and older adults.

BACKGROUND: Less is known regarding the association of pulse pressure (PP) with memory function. This study aimed to characterize long-term patterns of PP in middle-aged and older adults and explore their impact on subsequent change in memory function. METHODS: Data from the English Longitudinal Study of Ageing (ELSA, 2004-2018), were analyzed. Totally, 3587 dementia-free participants with three measurements of BP were included. All three visits of PP (2004-2012) were used to characterize longitudinal patterns of PP by group-based trajectory modeling (GBTM). Generalized estimating equation (GEE) models were fitted to explore the impact of PP trajectories on change in memory over a subsequent 6-year period (2012-2018). RESULTS: Using GBTM, three distinct trajectories of PP were identified: low-stable (38.1%), moderate-stable (48.6%), and elevated-increasing group (13.3%). GEE model suggested that memory declined over a 6-year period in all PP trajectories (all Ptime <0.001). The overall interactions between patterns of PP changes and time with memory were statistically significant (χ2 interaction  = 20.69, p = 0.002). Compared to participants in the low-stable group, those in the moderate-stable and elevated-increasing group exhibited a faster decline in memory. CONCLUSIONS: Longitudinal patterns of moderate-stable and elevated-increasing PP were associated with an accelerated decrease in memory. Controlling BP instability may be a promising interventional strategy for preventing cognitive decline among older adults.

Acidic oligosaccharide sugar chain combined with hyperbaric oxygen delays D-galactose-induced brain senescence in mice via attenuating oxidative stress and neuroinflammation.

Aging is fundamental to neurodegeneration and dementia. Preventing oxidative stress and neuroinflammation are potential methods of delaying the onset of aging-associated neurodegenerative diseases. The acidic oligosaccharide sugar chain (AOSC) and hyperbaric oxygen (HBO) can increase the expression of antioxidants and have a neuroprotective function. In this study, we investigate the ability of AOSC, HBO, and AOSC + HBO to prevent D-gal-induced brain senescence. The Morris water maze and Y-maze test results showed that all three therapies significantly attenuated D-gal-induced memory disorders. A potential mechanism of this action was decreasing elevated levels of oxidative stress and neuroinflammation. The western blot and morphological results showed that all three therapies decreased D-gal-induced neuroinflammation and downregulated inflammatory mediators including the nuclear factor κ-light-chain-enhancer of activated B cells, cyclooxygenase-2, interleukin-1ß, and tumor necrosis factor alpha. Taken together, our results indicated that AOSC, HBO, and AOSC + HBO therapies attenuated D-gal-induced brain aging in mice by repressing RAGE/NF-KB-induced inflammation, the activation of astrocytes and microglia, and a decrease in neuronal degeneration. These could be useful therapies for treating age-related neurodegenerative diseases such as Alzheimer's disease. Furthermore, HBO combined with AOSC had a better effect than HBO or AOSC alone.

Sex Differences in the Associations of Handgrip Strength and Asymmetry With Multimorbidity: Evidence From the English Longitudinal Study of Ageing.

OBJECTIVES: To determine the sex-specific associations of handgrip strength (HGS) and asymmetry with incident multimorbidity and examine whether these relationships differ by sex. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: Secondary analyses of data from the English Longitudinal Study of Ageing (ELSA, waves 2-8). The analytic sample included 3977 participants (51.4% female) aged ≥50 years who had data for HGS on both hands and were living without multimorbidity at baseline. MEASURES: HGS was assessed with a handheld dynamometer. Individuals in the lowest tertile of sex-specific age-adjusted HGS were defined as having low HGS. The largest HGS readings from the nondominant and dominant hand were used to calculate HGS ratio [nondominant HGS (kg)/dominant HGS (kg)]. Those with HGS ratio <0.90 or >1.10 had any HGS asymmetry. Further, those with HGS ratio <0.90 had dominant HGS asymmetry, whereas those with HGS ratio >1.10 had nondominant HGS asymmetry. Multimorbidity was defined as the coexistence of ≥2 chronic diseases. Cox proportional hazards regression models were conducted for analyses. RESULTS: Low HGS was associated with multimorbidity among older men [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.03-1.40] and women (HR 1.19, 95% CI 1.03-1.38). No significant effect modification by sex was observed (P-interaction = .71). HGS asymmetry increased the risk of multimorbidity in women only (HR 1.23, 95% CI 1.07-1.41). The relationship between HGS asymmetry and multimorbidity risk differed by sex (P-interaction = .01). Similarly, both dominant HGS asymmetry (HR 1.21, 95% CI 1.05-1.40) and nondominant HGS asymmetry (HR 1.32, 95% CI 1.03-1.68) were related to incident multimorbidity in women only. There was a significant interaction between dominant HGS asymmetry and sex (P-interaction = .02). CONCLUSIONS AND IMPLICATIONS: Examining HGS asymmetry in HGS test protocols can provide novel insights for the predictive power of HGS in the accumulation of diseases, particularly in women.

Pathways linking abdominal obesity to poor memory function: Explore the mediating role of hypertension and depressive symptoms.

BACKGROUND: The negative effect of abdominal obesity on cognitive function has been widely reported, especially on memory function, however, it is unclear how the effect is mediated. We aim to investigate the mediating role of hypertension and depressive symptoms. METHODS: Data were collected from wave 6 (2012-2013) of the English Longitudinal Study of Ageing (ELSA). Abdominal obesity was defined as a waist circumference (WC) ≥88cm for women and ≥102cm for men. Hypertension was determined on the basis of objective blood pressure measurement and previous physician diagnosis. Depressive symptoms were assessed with the 8-item version of the Center for Epidemiologic Studies (CESD) scale. Memory function was measured with the 10-word immediate and delayed recall tests. Baron and Kenny's causal steps and Karlson/Holm/Breen (KHB) method were used to examine the mediating effect. RESULTS: A total of 7,448 participants aged ≥50 years were included in this study. We found a negative effect of abdominal obesity on memory function (ß=-0.047, p=0.031). KHB method identified significant mediating effect of hypertension and depressive symptoms on the relationship between abdominal obesity and memory function, they explained 16.92 and 6.32% of the total effect of abdominal obesity on memory function, respectively. LIMITATIONS: This study was limited by its cross-sectional design and possibility of residual confounding. CONCLUSIONS: Hypertension and depressive symptoms might be possible pathways linking abdominal obesity and poor memory function, suggesting that collaborative interventions of abdominal obesity, hypertension and depressive symptoms are beneficial in maintaining memory function.

Management of high-grade squamous intraepithelial lesion patients with positive margin after LEEP conization: A retrospective study.

ABSTRACT: To explore the optimal way to manage patients with high-grade squamous intraepithelial lesion (HSIL) and positive margin by identifying the risk factors for its recurrence and residue.A retrospective study was conducted on 267 cases of a pathologically confirmed HSIL with positive margin following conization by loop electrosurgical excisional procedure (LEEP) between January 2010 and December 2015. One hundred two cases were selected for regular follow-up every 6 months, and 165 cases were selected for a second surgery (repeat cervical conization or hysterectomy) within 3 months of initial LEEP. We analyzed the association between recurrent or residual diseases and these factors: age, menopausal status, ThinPrep cytologic test (TCT) results, high-risk human papillomavirus (HR-HPV) infection, pathological grades of the margin, number of involved margins, and glandular involvement.The recurrence rate among 102 cases who underwent follow-up was 17.6% (18/102). The factors: atypical squamous cells of undetermined significance cannot exclude HSIL (ASC-H) or higher lesions in the pre-LEEP TCT (P = .038), persistent HR-HPV infection at the 6th month post-LEEP (P = .03), HSIL-positive margin (P = .003), and multifocal-involved margin (P = .002) were significantly associated with recurrent disease, while age, menopause, and pre-LEEP HR-HPV infection were not associated with recurrent disease (P > .05). The residual rate among 165 patients who underwent a second surgery was 45.5% (75/165), of which 15 cases were residual cervical cancer. The factors: menopause (P = .02), ≥ASC-H in pre-LEEP TCT (P = .04), pre-LEEP HR-HPV infection (P = .04), ≥HSIL-positive margin (P < .001), and multifocal-involved margin (P < .001) significantly increased the risk of residual disease. No correlation existed between residual disease and age or glandular involvement (P > .05).For patients with a positive margin after LEEP, regular follow-up or second surgery should be selected according to fertility requirement and pathological characteristics of the positive margin, as well as TCT and HR-HPV infection condition.

Exosomal miR­663b exposed to TGF­ß1 promotes cervical cancer metastasis and epithelial­mesenchymal transition by targeting MGAT3.

Transforming growth factor (TGF)­ß1 is a key cytokine affecting the pathogenesis and progression of cervical cancer. Tumor­derived exosomes contain microRNAs (miRNAs/miRs) that interact with cancer and stromal cells, thereby contributing to tissue remodeling in the tumor microenvironment (TME). The present study was designed to clarify how TGF­ß1 affects tumor biological functions through exosomes released by cervical cancer cells. Deep RNA sequencing found that TGF­ß1 stimulated cervical cancer cells to secrete more miR­663b­containing exosomes, which could be transferred into new target cells to promote metastasis. Further studies have shown that miR­663b directly targets the 3'-untranslated regions (3'­UTR) of mannoside acetylglucosaminyltransferase 3 (MGAT3) and is involved in the epithelial­mesenchymal transition (EMT) process. Remarkably, the overexpression of MGAT3 suppressed cervical cancer cell metastasis promoted by exosomal miR­663b, causing increased expression of epithelial differentiation marker E­cadherin and decreased expression of mesenchymal markers N­cadherin and ß­catenin. Throughout our study, online bioinformation tools and dual luciferase reporter assay were applied to identify MGAT3 as a novel direct target of miR­663b. Exosome PKH67­labeling experiment verified that exosomal miR­663b could be endocytosed by cervical cancer cells and subsequently influence its migration and invasion functions which were measured by wound healing and Transwell assays. The expression of miR­663b and MGAT3 and the regulation of the EMT pathway caused by MGAT3 were detected by quantitative real­time transcription­polymerase chain reaction (qPCR) and western blot analysis. These results, thus, provide evidence that cancer cell­derived exosomal miR­663b is endocytosed by cervical cancer cells adjacent or distant after TGF­ß1 exposure and inhibits the expression of MGAT3, thereby accelerating the EMT process and ultimately promoting local and distant metastasis.

The mediating role of cognition in the relationship between sleep duration and instrumental activities of daily living disability among middle-aged and older Chinese.

OBJECTIVE: To explore the effect of sleep duration at baseline on the incident IADL disability among middle-aged and older Chinese, and test whether cognition mediates this causality. METHODS: Data were collected from wave 1 (2011-2012) to wave 3 (2015-2016) of the China Health and Retirement Longitudinal Study (CHARLS). Sleep duration was self-reported at baseline. Cognitive function, including episodic memory and mental intactness were measured via a questionnaire. IADL was assessed at baseline and follow-up. Baron and Kenny's causal steps and Karlson/Holm/Breen (KHB) method were conducted to examine the mediating effect. RESULTS: A total of 10,328 participants free of IADL disability at baseline were included in this study. Over 4 years of follow-up, 17.1% of participants developed IADL disability. Compared to 7-8 h sleep duration, both short sleep (OR=1.460; 95% CI: 1.261-1.690 for sleeping ≤5 h; OR= 1.189; 95% CI: 1.011-1.400 for sleeping 5-7 h) and long sleep (OR=1.703; 95% CI: 1.269-2.286 for sleeping >9 h) were linked with incident IADL disability. KHB method identified significant mediating effect of cognition on the relationship between extreme sleep durations (≤5 h or >9 h) and IADL disability and the proportional mediation through cognition was 21.32% and 21.06% for sleeping ≤5 h and >9 h, respectively. CONCLUSION: Both short (sleeping ≤5 h) and long sleep duration (sleeping >9 h) predicted incident IADL disability. Cognition partially mediated the effect of extreme sleep durations on IADL disability.

Astragalus polysaccharide inhibits breast cancer cell migration and invasion by regulating epithelial­mesenchymal transition via the Wnt/ß­catenin signaling pathway.

Epithelial­mesenchymal transition (EMT) serves an important role in tumor migration and invasion. Astragalus polysaccharide (APS), which is the main component of the traditional Chinese medicine Astragalus membranaceus, has been identified to display an antitumor effect. However, the effects and mechanisms of APS during breast cancer migration and invasion are not completely understood. The present study investigated whether APS inhibited breast cancer migration and invasion by modulating the EMT pathway. An MTT assay and a Ki67 immunofluorescence staining assay demonstrated that APS inhibited the proliferation of breast cancer cells. The results of the wound healing and Transwell Matrigel invasion assays suggested that APS decreased the migration and invasion of breast cancer cells. The western blotting and immunofluorescence analyses further demonstrated that APS had a regulatory effect on EMT­related molecules. APS decreased the expression levels of Snail and vimentin, but increased E­cadherin expression. APS also downregulated Wnt1, ß­catenin and downstream target expression. Additionally, the present results suggested that APS decreased the proliferation, and EMT­mediated migration and invasion of cells by inhibiting the Wnt/ß­catenin signaling pathway. The present study suggested that APS may serve as a promising therapeutic agent for breast cancer.

Alcohol Consumption and Functional Limitations in Older Men: Does Muscle Strength Mediate Them?

OBJECTIVES: To evaluate the dose-response relationships between alcohol consumption and functional limitations in older European men, and explore the role of muscle strength as a mediator of these relationships. DESIGN: Cross-sectional study of older men participating in the Survey of Health, Aging and Retirement in Europe (SHARE). SETTING: Urban and rural households in 17 European countries and Israel. PARTICIPANTS: A total of 17 870 men aged 65 years and older from the SHARE (Wave 6, 2015) were included in this study. MEASUREMENTS: Outcome variables were functional limitations: mobility limitation, arm function limitation, and fine motor limitation. Main exposure variable was alcohol consumption. Mediating factor was grip strength. Basic demographics, life habits, and health status were considered as potential confounders. Dose-response analyses with restricted cubic splines and the Karlson/Holm/Breen method were conducted. RESULTS: A total of 17 870 participants were included in this study. Dose-response analyses revealed that moderate alcohol consumption was related to the lower odds of reporting mobility limitation (≤35 units/wk) and arm function limitation (≤41 units/wk), with a minimum odds ratio (OR) occurring at 10 units/week drinks for mobility limitation (OR = .71; 95% confidence interval [CI] = .62-.81) and arm function limitation (OR = .66; 95% CI = .59-.75). The odds of reporting the fine motor limitation monotonically increased with alcohol consumption when alcohol consumption was beyond 15 units/week. No significant mediating effect of grip strength on the relationships between alcohol consumption and mobility limitation and arm function limitation was found. CONCLUSION: Moderate alcohol consumption has a protective role in mobility and arm function limitation in older European men. Grip strength is not the main mediator of these associations, suggesting that the protective effect is independent of muscle strength. Alcohol consumption is associated with higher odds of reporting fine motor limitation in older European men. J Am Geriatr Soc 67:2331-2337, 2019.

Cognition Mediates the Relationship Between Sensory Function and Gait Speed in Older Adults: Evidence from the English Longitudinal Study of Ageing.

BACKGROUND/OBJECTIVE: Gait speed is an important indicator for assessing overall health status. Previous studies have reported the important role of sensory function in gait speed; however, the underlying mechanism is still unclear. This study aimed to examine whether cognition mediates the association of sensory function with gait speed among English older adults. METHODS: Gait speed was assessed by "timed walking test". Hearing was measured by using a hearing screening device. Vision was self-reported. Cognition was assessed by questionnaire. Baron and Kenny's causal steps method and Sobel test were used to examine the mediating effect. RESULTS: Among 4,197 participants aged 60 years and older, 13.5% had poor hearing and 12.6% had poor vision, 2.6% had both poor hearing and poor vision. Multiple linear regression models suggested that poor hearing (ß= - 1.905, p < 0.001), poor vision (ß= - 1.309, p = 0.004), and poor dual sensory function (ß= - 2.442, p = 0.013) was associated with worse cognition. Cognition was correlated with gait speed (ß= 0.004, p < 0.001). Poor hearing (ß= - 0.072, p < 0.001), poor vision (ß= - 0.031, p = 0.029), and poor dual sensory function (ß= - 0.081, p = 0.011) was associated with slower gait speed. After introducing cognition into the models, regression coefficients between sensory function and gait speed decreased (ß= - 0.066, p < 0.001 for hearing; ß= - 0.027, p = 0.054 for vision; ß= - 0.073, p = 0.020 for combined hearing and vision). Sobel test identified the significant mediating effect of cognition on the association between sensory function and gait speed. CONCLUSION: Cognition partially mediates the association between sensory function and gait speed. Efforts to maintain mobility performance in older adults should consider protecting both sensory function and cognition.

Age modify the associations of obesity, physical activity, vision and grip strength with functional mobility in Irish aged 50 and older.

OBJECTIVE: To estimate whether the associations of obesity, physical activity, vision and grip strength with functional mobility were modified by age. METHODS: Data from The Irish Longitudinal Study on Ageing (2009-2012) were analyzed and 5001 individuals were included in this study. Mobility was assessed by the timed up and go test (TUG-test). Main exposure variables were obesity, physical activity, visual acuity and grip strength at baseline. Multiple linear regression models were fitted to assess the associations of baseline main exposure variables with 2-year follow-up functional mobility and potential confounders were adjusted. Stratified analyses by age were used to assess the interaction between main exposures and age on functional mobility. RESULTS: Multiple linear regression models identified significant interactions of obesity (P < 0.001), vigorous physical activity (P = 0.001), vision (P < 0.001) and grip strength (P < 0.001) with age on functional mobility. Stratified analyses suggested that the risk effect of obesity on functional mobility was greater in middle-aged group (ß = 0.025, P < 0.001) than in older group (ß = 0.016, P = 0.017). The protective effects of high level of physical activity and grip strength on functional mobility were stronger in older group (ß = -0.023, P = 0.004 for physical activity; ß = -0.002, P < 0.001 for grip strength) than in middle-aged group (ß = -0.012, P = 0.008 for physical activity; ß = -0.0015, P < 0.001 for grip strength). The benefit of better vision on functional mobility was observed in middle-aged group only (ß = -0.032, P = 0.002). CONCLUSION: Non-obesity, higher level of physical activity, vision and grip strength at baseline were associated with better mobility performance among middle-aged and older Irish. And these associations were modified by age.

Astragalus polysaccharides inhibits cardiomyocyte apoptosis during diabetic cardiomyopathy via the endoplasmic reticulum stress pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine Astragalus membranaceus (Fisch.) Bunge (AM) has been utilized for the treatment of diabetes mellitus and its complications for centuries. Astragalus polysaccharides (APS), the main bioactive ingredient extracted from the root of AM, is prescribed widely in China and has definite cardioprotective effect during diabetic cardiomyopathy (DCM). Endoplasmic reticulum (ER) stress-induced apoptosis played a crucial role in the progression of DCM. However, the regulatory mechanisms of APS on ER stress pathway haven't been comprehensively studied so far. AIM OF THE STUDY: The aim of this study was to identify the effect of APS on cardiomyocyte apoptosis and to investigate the mechanisms for the anti-apoptotic effect of APS during DCM. MATERIALS AND METHODS: DCM rat model was induced by intraperitoneal streptozotocin (STZ) injection and treated with APS for 16 weeks. Cardiac function, pathological changes and apoptotic cells were assessed by echocardiography, hematoxylin-eosin (HE) staining and TUNEL assay, respectively. Expressions of key molecules in ER stress pathway were detected by Western blot analysis. Cardiomyocytes were exposed to high glucose (HG) and treated with APS for 24 h. Cell viability, apoptosis and protein expressions were assessed by MTT, flow cytometer and Western blot analysis, respectively. Moreover, lentivirus over-expressing (OE) C/EBP homologous protein (CHOP) was employed to further investigate the causative role of ER stress pathway in APS-mediated effect on cardiomyocyte apoptosis. RESULTS: In vivo, the results demonstrated that APS could improve heart function and attenuate myocardial apoptosis in DCM rat model. Further study demonstrated that APS could down-regulate the protein expressions of activating transcription factor 6 (ATF6) and protein kinase RNA-like ER kinase (PERK) related factors of ER stress pathway. In vitro, APS significantly inhibit HG stimulated H9C2 cell apoptosis and the expressions of ATF6 and PERK related proteins of ER stress pathway. However, after CHOP-OE lentivirus transfection, the protective effects of APS were diminished as increased apoptotic rate and higher expression of CHOP. CONCLUSIONS: APS could attenuate cardiomyocyte apoptosis via down-regulating the expression of ATF6 and PERK related factors of ER stress pathway in DCM rats and HG-stimulated H9C2 cells.

Five ETS family members, ELF-1, ETV-4, ETV-3L, ETS-1, and ETS-2 upregulate human leukocyte-associated immunoglobulin-like receptor-1 gene basic promoter activity.

Human leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1), an immunoinhibitory receptor, is expressed on most types of hematopoietic cells and some tumor cells. LAIR-1 plays an inhibitory role in immune cell maturation, differentiation, and activation. LAIR-1 is also involved in some autoimmune diseases and tumors. However, the mechanism controlling the regulation of the LAIR-1 gene is still unknown. In order to elucidate the molecular mechanisms involved in LAIR-1 regulation, in the present study, we cloned and characterized the promoter region of LAIR-1 gene using a series of truncated promoter plasmids in luciferase reporter assays. Our results show that the basic core promoter of LAIR-1 is located within the region -256/-8 relative to the translational start site. Our further studies indicate that five ETS transcription factors: ELF-1, ETV-4, ETV-3L, ETS-1 and ETS-2, can up-regulate the LAIR-1 basic promoter activity. Of these, ETS-2 is the most effective transcription factor. Moreover, ETS-2 was confirmed to interact directly with the basic promoter of LAIR-1. This study presents the first description of regions/factors capable of up-regulation the promoter activity of LAIR-1. This new knowledge contributes to understanding of the molecular mechanisms involved in LAIR-1 associated immune regulation and diseases.

The effect of Astragalus polysaccharides on attenuation of diabetic cardiomyopathy through inhibiting the extrinsic and intrinsic apoptotic pathways in high glucose -stimulated H9C2 cells.

BACKGROUND: Apoptosis plays a critical role in the progression of diabetic cardiomyopathy (DC). Astragalus polysaccharides (APS), an extract of astragalus membranaceus (AM), is an effective cardioprotectant. Currently, little is known about the detailed mechanisms underlying cardioprotective effects of APS. The aims of this study were to investigate the potential effects and mechanisms of APS on apoptosis employing a model of high glucose induction of apoptosis in H9C2 cells. METHODS: A model of high glucose induction of H9C2 cell apoptosis was adopted in this research. The cell viabilities were analyzed by MTT assay, and the apoptotic response was quantified by flow cytometry. The expression levels of the apoptosis related proteins were determined by Real-time PCR and western blotting. RESULTS: Incubation of H9C2 cells with various concentrations of glucose (i.e., 5.5, 12.5, 25, 33 and 44 mmol/L) for 24 h revealed that cell viability was reduced by high glucose dose-dependently. Pretreatment of cells with APS could inhibit high glucose-induced H9C2 cell apoptosis by decreasing the expressions of caspases and the release of cytochrome C from mitochondria to cytoplasm. Further experiments also showed that APS could modulate the ratio of Bcl-2 to Bax in mitochondria. CONCLUSIONS: APS decreases high glucose-induced H9C2 cell apoptosis by inhibiting the expression of pro-apoptotic proteins of both the extrinsic and intrinsic pathways and modulating the ratio of Bcl-2 to Bax in mitochondria.