Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease.

Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation: Aß: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.

Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies.

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

Chemotaxis assay for evaluation of memory-like behavior in wild-type and Alzheimer's-disease-like C. elegans models.

Here, we present an olfactory-dependent chemotaxis assay for evaluating changes in memory-like behavior in both wild-type and Alzheimer's-disease-like C. elegans models. We describe steps for synchronizing and preparing C. elegans populations and for performing isoamyl alcohol conditioning during starvation and chemotaxis assaying. We then detail counting and quantification procedures. This protocol is applicable to mechanistic exploration and drug screening in neurodegenerative diseases and brain aging.

Implications of altered sirtuins in metabolic regulation and oral cancer.

Sirtuins (SIRTs 1-7) are a group of histone deacetylase enzymes with a wide range of enzyme activities that target a range of cellular proteins in the nucleus, cytoplasm, and mitochondria for posttranslational modifications by acetylation (SIRT1, 2, 3, and 5) or ADP ribosylation (SIRT4, 6, and 7). A variety of cellular functions, including mitochondrial functions and functions in energy homeostasis, metabolism, cancer, longevity and ageing, are regulated by sirtuins. Compromised sirtuin functions and/or alterations in the expression levels of sirtuins may lead to several pathological conditions and contribute significantly to alterations in metabolic phenotypes as well as oral carcinogenesis. Here, we describe the basic characteristics of seven mammalian sirtuins. This review also emphasizes the key molecular mechanisms of sirtuins in metabolic regulation and discusses the possible relationships of sirtuins with oral cancers. This review will provide novel insight into new therapeutic approaches targeting sirtuins that may potentially lead to effective strategies for combating oral malignancies.

The effects of epigenetic modifications on bone remodeling in age-related osteoporosis.

PURPOSE: As the population ages, there is an increased risk of fracture and morbidity diseases associated with aging, such as age-related osteoporosis and other bone diseases linked to aging skeletons. RESULTS: Several bone-related cells, including multipotent bone mesenchymal stem cells, osteoblasts that form bone tissue, and osteoclasts that break it down, are in symbiotic relationships throughout life. Growing evidence indicates that epigenetic modifications of cells caused by aging contribute to compromised bone remodeling and lead to osteoporosis. A number of epigenetic mechanisms are at play, including DNA/RNA modifications, histone modifications, microRNAs (miRNAs), and long noncoding RNAs (lncRNAs), as well as chromatin remodeling. CONCLUSION: In this review, we summarized the epigenetic modifications of different bone-related cells during the development and progression of osteoporosis associated with aging. Additionally, we described a compensatory recovery mechanism under epigenetic regulation that may lead to new strategies for regulating bone remodeling in age-related osteoporosis.

Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow.

A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer's disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-ß and tau pathologies, and improved the animals' memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational-experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.

[Effects of elevated CO2 concentration on production and water use efficiency of spring wheat in semi-arid area.] / CO2æµ“åº¦å¢žåŠ å¯¹åŠå¹²æ—±åŒºæ˜¥å°éº¦ç”Ÿäº§å’Œæ°´åˆ†åˆ©ç”¨æ•ˆçŽ‡çš„å½±å“.

In the present study, the response of spring wheat production and water use efficiency (WUE) to the elevated CO2 concentrations was investigated based on the open-top chamber (OTC) experiment platform in Dingxi, a typical semi-arid area. Three different CO2 concentrations (390 µmol·mol-1, 480 µmol·mol-1 and 570 µmol·mol-1) were involved. The results showed that the air temperature above plant canopy increased and the soil temperature at depth of 10 cm decreased by elevated CO2. The increased CO2 concentration substantially enhanced the total and each component biomass. The aboveground dry mass under the increased CO2 concentrations (480 and 570 µmol·mol-1) was increased by 20.6% and 41.5%, respectively, and the total dry mass was increased by 19.3% and 39.6%, respectively. The biomass enhacement was mainly due to the increases of dry mass of stems and leaves, which was strongly related to the material production capacity during the middle growth stage. The root/shoot ratio under the increased CO2 concentrations (480 and 570 µmol·mol-1) was decreased by 7.3% and 11.8%, respectively, indicating that the elevated CO2 affected the dry matter accumulation of aboveground more than that of belowground. The yields of spring wheat under the increased CO2 concentrations (480 and 570 µmol·mol-1) were higher than that of the control by 8.9% and 19.9%, respectively, mainly due to the increase of grains per spike. The long-term effect of elevated CO2 concentration on the photosynthesis of spring wheat was not obvious. The photosynthetic rate significantly increased, the transpiration rate decreased and the evapotranspiration reduced with the increases of CO2 concentration. WUE at the leaf, population, and yield levels increased under elevated CO2 concentration, with the increase range of WUE being the largest at the population level and the lowest at the yield level.

Prognostic Significance of Neutrophil to Lymphocyte Ratio in Oncologic Outcomes of Cholangiocarcinoma: A Meta-analysis.

Increasing evidence indicates that the neutrophil to lymphocyte ratio (NLR) is a useful biomarker of long-term outcomes in patients with cholangiocarcinoma. However, the prognostic role of NLR in patients with cholangiocarcinoma remains unclear. Thus, the current meta-analysis was undertaken to clarify the correlation between NLR and overall survival (OS) in cholangiocarcinoma, and a comprehensive literature research was conducted to understand the association of NLR and prognosis of cholangiocarcinoma. The hazard ratio (HR) with 95% confidence interval (CI) was used to assess OS. The synthesized HR of 1.449 (95% CI: 1.296-1.619, P < 0.001) indicated that a high NLR had an unfavourable effect on OS. Overall, this meta-analysis suggested that elevated preoperative NLR is associated with poorer rates of survival in cholangiocarcinoma patients.

[Effects of air temperature increase and precipitation change on grain yield and quality of spring wheat in semiarid area of Northwest China].

In order to predict effects of climate changing on growth, quality and grain yields of spring wheat, a field experiment was conducted to investigate the effects of air temperature increases (0 °C, 1.0 °C, 2.0° C and 3.0°) and precipitation variations (decrease 20%, unchanging and increase 20%) on grain yields, quality, diseases and insect pests of spring wheat at the Dingxi Arid Meteorology and Ecological Environment Experimental Station of the Institute of Arid Meteorology of China Meteorological Administration (35°35' N ,104°37' E). The results showed that effects of precipitation variations on kernel numbers of spring wheat were not significant when temperature increased by less than 2.0° C , but was significant when temperature increased by 3.0° C. Temperature increase enhanced kernel numbers, while temperature decrease reduced kernel numbers. The negative effect of temperature on thousand-kernel mass of spring wheat increased with increasing air temperature. The sterile spikelet of spring wheat response to air temperature was quadratic under all precipitation regimes. Compared with control ( no temperature increase), the decreases of grain yield of spring wheat when air temperature increased by 1.0°C, 2.0°C and 3.0°C under each of the three precipitation conditions (decrease 20%, no changing and increase 20%) were 12.1%, 24.7% and 42.7%, 8.4%, 15.1% and 21.8%, and 9.0%, 15.5% and 22.2%, respectively. The starch content of spring wheat decreased and the protein content increased with increasing air temperature. The number of aphids increased when air temperature increased by 2.0°C , but decreased when air temperature increased by 3.0°CT. The infection rates of rust disease increased with increasing air temperature.

[Effects of increasng field temperature on growth, development and yield of spring wheat in semi-arid area].

A field infrared temperature-increasing simulation experiment was conducted to investi- gate the effects of air temperature increases (0, 1 and 2 °C ) on growth, development and yield of spring wheat at the Dingxi Arid Meteorology and Ecological Environment Experimental Station of the Institute of Arid Meteorology of China Meteorological Administration. The results showed that the growth period of spring wheat was shortened by 7-11 d when the temperature increased by 1-2 °C. The plant height and leaf area index increased at early growth stage, decreased after entering the jointing stage, and warming 2 °C had a higher effect than warming 1 °C. Warming treatment induced an obvious decrease in chlorophyll content, especially from late grain filling stage to milk ripe stage. Compared with the control, increasing temperature by 1-2 °C decreased the spring wheat yield by 25.4%-45.5%, mainly due to obvious decreases in number of grains and grain mass per panicle. Water consumption of 0-100 cm soil horizons increased with the increase of temperature, while the variation tendency of water consumption of 100-160 cm soil horizons was not obvious.

Relationships between abnormal MMP2 expression and prognosis in gastric cancer: a meta-analysis of cohort studies.

We carried out this current meta-analysis of relevant cohort studies in an attempt to investigate the relationships between abnormal matrix metalloproteinases-2 (MMP2) expression and gastric cancer (GC) prognosis. A range of electronic databases were searched for relevant articles without any language restrictions: Web of Science (1945-2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966-2013), EMBASE (1980-2013), CINAHL (1982-2013), and the Chinese Biomedical Database (CBM) (1982-2013). Meta-analysis was conducted using the STATA 12.0 software. Crude hazard ratios (HRs), with 95% confidence intervals (95% CIs), were calculated. Ten clinical cohort studies with a total of 1669 GC patients were included in this meta-analysis. The results of our meta-analysis suggested that MMP2-positive patients display a shorter overall survival (OS) than MMP2-negative patients (HR=1.31, 95% CI=0.98-1.63, p<0.001). Subgroup analysis based on ethnicity revealed that abnormal MMP2 expression was associated with significantly worse OS in patients with GC among both Caucasian and Asian populations (all p<0.05). Our meta-analysis indicated that abnormal MMP2 expression may be strongly correlated with poor prognosis in patients with GC. Thus, MMP2 expression may serve as an independent prognostic factor for GC.

Abnormal FHIT protein expression may be correlated with poor prognosis in gastric cancer: a meta-analysis.

Our current meta-analysis is aimed to investigate the relationships between fragile histidine triad (FHIT) protein expression and prognosis in gastric cancer patients. We searched MEDLINE (1966 ~ 2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), Web of Science (1945 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013) without any language restrictions. The meta-analysis was conducted using the STATA 12.0 software. Crude hazard ratios (HR) with its 95 % confidence interval (95 % CI) were calculated. Eight clinical cohort studies with a total of 1,361 gastric cancer patients were involved in our meta-analysis. Our results revealed that FHIT-negative patients exhibited a shorter overall survival (OS) time than FHIT-positive patients (HR = 1.23, 95 % CI = 1.01 ~ 1.44, P < 0.001). Ethnicity-stratified analysis demonstrated that FHIT-negative patients have significantly poorer prognosis than FHIT-positive patients among both Caucasians and Asians (all P < 0.05). In conclusion, our meta-analysis provides evidences that negative expression of FHIT protein may be correlated with poor prognosis in patients with gastric cancer. Thus, FHIT expression level may be utilized as an independent prognostic marker for gastric cancer.

Role of p16 gene promoter methylation in gastric carcinogenesis: a meta-analysis.

This meta-analysis was performed to evaluate the relationships between promoter DNA methylation in tumor suppressor gene p16 and gastric carcinogenesis. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated. Forty-seven clinical cohort studies that met all inclusion criteria were included in this meta-analysis. A total of 2,813 gastric cancer (GC) patients were assessed. Our meta-analysis results revealed that the frequencies of p16 promoter methylation in the GC tissues were higher than those of normal and adjacent tissues (Normal: OR = 23.04, 95% CI = 13.55-39.15, P < 0.001; Adjacent: OR = 4.42, 95% CI = 1.66-11.76, P = 0.003; respectively). Furthermore, we observed significant associations of p16 promoter methylation with TNM stage, histologic grade, invasive grade, lymph node metastasis of GC (TNM stage: OR = 3.60, 95% CI: 2.17-5.98, P < 0.001; Histologic grade: OR = 2.63, 95% CI: 1.55-4.45, P < 0.001; Invasive grade: OR = 3.44, 95% CI: 1.68-7.06, P = 0.001; Lymph node metastasis: OR = 2.68, 95% CI: 1.66-4.32, P < 0.001; respectively). However, there were no correlations of p16 promoter methylation with the TNM stage and Helicobacter pylori (HP) infection of GC (Tumor size: OR = 0.76, 95% CI: 0.14-4.07, P = 0.746; HP infection: OR = 1.31, 95% CI: 0.75-2.27, P = 0.342; respectively). Our findings provide empirical evidence that p16 promoter methylation may play an important role in gastric carcinogenesis. Thus, p16 promoter methylation may be a promising potential biomarker for the early diagnosis of GC.

ALDH2 and ADH1 genetic polymorphisms may contribute to the risk of gastric cancer: a meta-analysis.

AIM: We conducted a meta-analysis of case-control studies to determine whether ALDH2, ADH1 and ADH2 genetic polymorphisms contribute to the pathogenesis of gastric cancer. METHODS: The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. We calculated crude odds ratios (ORs) with their 95% confidence intervals (95%CI) to evaluate their relationships under five genetic models. Seven case-control studies with a total of 2,563 gastric cancer patients and 4,192 healthy controls met the inclusion criteria. Nine common polymorphisms were evaluated, including rs671, rs16941667 and rs886205 in the ALDH2 gene, rs1230025, rs13123099, rs698 and rs1693482 in the ADH1 gene, and rs1229984 and rs17033 in the ADH2 gene. RESULTS: The results of our meta-analysis suggested that ALDH2 genetic polymorphisms might be strongly correlated with an increased risk of gastric cancer (allele model: OR = 1.21, 95%CI: 1.11 ∼ 1.32, P<0.001; dominant model: OR = 1.23, 95%CI: 1.09 ∼ 1.39, P = 0.001; respectively), especially for rs671 polymorphism. Furthermore, we observed significant associations between ADH1 genetic polymorphisms and an increased risk of gastric cancer (allele model: OR = 1.21, 95%CI: 1.08 ∼ 1.36, P = 0.001; dominant model: OR = 10.52, 95%CI: 3.04 ∼ 36.41, P<0.001; respectively), especially for rs1230025 polymorphism. Nevertheless, no positive relationships were found between ADH2 genetic polymorphisms and gastric cancer risk (all P>0.05). CONCLUSION: The current meta-analysis suggests that ALDH2 and ADH1 genetic polymorphisms may play crucial roles in the pathogenesis of gastric cancer. However, ADH2 genetic polymorphisms may not be important dominants of susceptibility to gastric cancer.

Promoter methylation of the RASSF1A gene may contribute to colorectal cancer susceptibility: a meta-analysis of cohort studies.

This meta-analysis of published cohort studies was conducted to evaluate whether promoter methylation of the RASSF1A gene contributes to colorectal cancer (CRC) susceptibility. A range of electronic databases were searched without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude risk differences (RD) with their 95% confidence intervals (95%CI) were calculated. In this meta-analysis, 11 clinical cohort studies with a total of 630 CRC patients were included. The pooled results revealed that the frequency of RASSF1A gene methylation in cancer tissues was significantly higher than that in benign, adjacent, and normal tissues (cancer tissues vs. benign tissues: RD = 0.25, 95%CI = 0.13-0.38, P < 0.001; cancer tissues vs. adjacent tissues: RD = 0.32, 95%CI: 0.20-0.45, P < 0.001; cancer tissues vs. normal tissues: RD = 0.38, 95%CI: 0.26-0.50, P < 0.001; respectively). Subgroup analysis by ethnicity demonstrated that RASSF1A promoter methylation also exhibited a higher frequency in cancer tissues among both Asians and Caucasians (all P < 0.05). Our meta-analysis has shown positive correlations between RASSF1A promoter methylation and CRC susceptibility. Thus, detection of RASSF1A promoter methylation may be utilized as a valuable diagnostic marker for CRC.

Aberrant promoter methylation of RASSF1A gene may be correlated with colorectal carcinogenesis: a meta-analysis.

We conducted a meta-analysis of cohort studies to evaluate the potential role of RASSF1A promoter methylation in colorectal carcinogenesis. A range of electronic databases were searched: PubMed (1966-2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980-2013), CINAHL (1982-2013), Web of Science (1945-2013) and the Chinese Biomedical Database (CBM) (1982-2013) without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratio (OR) with 95% confidence interval (95% CI) was calculated. Eleven clinical cohort studies with a total of 1,505 colorectal cancer (CRC) patients that met all inclusion criteria were included in our meta-analysis. The results of our meta-analysis revealed that the frequency of RASSF1A promoter methylation was strongly correlated with clinical stage (OR = 1.69, 95% CI 1.16-2.44, P = 0.006), histological grade (OR = 1.92, 95% CI 1.22-3.04, P = 0.005) and distant metastasis (OR = 2.59, 95% CI 1.46-4.60, P = 0.037) of CRC patients. However, we observed no positive correlations of RASSF1A promoter methylation with gender (OR = 1.04, 95% CI 0.74-1.46, P = 0.842), age (OR = 1.70, 95% CI 0.98-2.93, P = 0.057) and lymph node metastasis (OR = 1.65, 95% CI 0.87-3.14, P = 0.127) of CRC patients. Further subgroup analysis by ethnicity demonstrated that RASSF1A promoter methylation was correlated with clinicopathological characteristics of CRC patients among Asians (clinical stage: OR = 2.55, 95% CI 1.55-4.20, P < 0.001; histological grade: OR = 2.70, 95% CI 1.44-5.06, P = 0.002; lymph node metastasis: OR = 4.09, 95% CI 1.49-11.26, P = 0.006; distant metastasis: OR = 5.38, 95% CI 1.73-16.70, P = 0.004), but not among Caucasians and Africans (all P > 0.05). Our meta-analysis has shown positive correlations between aberrant promoter methylation of RASSF1A gene and clinicopathological characteristics of CRC patients, especially among Asians.

[Characteristics of evapotranspiration and crop coefficient of agroecosystems in semi-arid area of Loess Plateau, Northwest China].

Evapotranspiration (ET) is an important component of ground surface energy balance and water balance, and closely related to water cycle. By using eddy covariance technique, this paper studied the ET characteristics of agroecosystems in the semi-arid area of Loess Plateau in growth season (from April to September), 2010, and analyzed the relationships between crop coefficient and environmental factors. During the observation period, the diurnal variation of latent heat flux (LE) in each month was similar to single-peak curve, and the peak value (151.4 W x m(-2)) occurred in August. The daytime energy partitioning manner showed a significant seasonal variation, with LE/R(n) < H/R(n) (R(n) was net radiation, and H was sensible heat flux) from April to June, and LE/R(n) > H/R(n) from July to September. The daily ET rate also showed a significant seasonal variation, with the maximum of 4.69 mm x d(-1). The wind speed (W(s)), relative humidity (RH), soil water content (theta), and atmospheric vapor pressure deficit (D) were the major factors affecting the crop coefficient K(c) which was exponentially decreased with increasing W(s), exponentially increased with increasing RH and theta, and linearly decreased with increasing D.