Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer's disease? From preclinical studies to the clinical trials.

Protein kinases (PKs) have emerged as one of the most intensively investigated drug targets in current pharmacological research, with indications ranging from oncology to neurodegeneration. Tau protein hyperphosphorylation was the first pathological post-translational modification of tau protein described in Alzheimer's disease (AD), highlighting the role of PKs in neurodegeneration. The therapeutic potential of protein kinase inhibitors (PKIs)) and protein phosphatase 2 A (PP2A) activators in AD has recently been explored in several preclinical and clinical studies with variable outcomes. Where a number of preclinical studies demonstrate a visible reduction in the levels of phospho-tau in transgenic tauopathy models, no reduction in neurofibrillary lesions is observed. Amongst the few PKIs and PP2A activators that progressed to clinical trials, most failed on the efficacy front, with only a few still unconfirmed and potential positive trends. This suggests that robust preclinical and clinical data is needed to unequivocally evaluate their efficacy. To this end, we take a systematic look at the results of preclinical and clinical studies of PKIs and PP2A activators, and the evidence they provide regarding the utility of this approach to evaluate the potential of targeting tau hyperphosphorylation as a disease modifying therapy.

Toxicity and bioassimilation of lead and nickel in farm ruminants fed on diversified forage crops grown on contaminated soil.

The cultivation of forage crops on wastewater-irrigated soils, while common in many developing countries, poses significant risks due to heavy metal pollution, particularly Lead (Pb) and Nickel (Ni). This practice, aimed at addressing water scarcity challenges and providing affordable irrigation, was investigated for its ecological and human health implications across three diverse sites (site A, site B, and site C). Our study unveiled increases in Pb concentrations in contaminated soil, cultivated with Sesbania bispinosa showing the highest Pb accumulation. The Ni concentrations ranged from 5.34 to 10.43 across all forage crop samples, with S. fruticosa from site C displaying the highest Ni concentration and S. bicolor from site A exhibiting the lowest. Trace element concentrations in the specimens were determined using an atomic absorption spectrophotometer. The Pb levels in the blood, hair, and feces of farm ruminants (cows, buffaloes, and sheep) varied across the sites, with buffaloes consistently displaying the highest Pb levels. Insights into daily Pb intake by ruminant's highlighted variations influenced by plant species, animal types, and sites, with site C, the cows exhibiting the highest Health Risk Index (HRI) associated with lead exposure from consuming forage crops. Soil and forage samples showed Pb concentrations ranging from 8.003 to 12.29 mg/kg and 6.69-10.52 mg/kg, respectively, emphasizing the severe health risks associated with continuous sewage usage. Variations in Ni concentrations across animal blood, hair, and feces samples underscored the importance of monitoring Ni exposure in livestock, with sheep at site B consistently showing the highest Ni levels. These findings highlight the necessity of vigilance in monitoring trace element (Pb and Ni) exposure in forage crops and livestock, to mitigate potential health risks associated with their consumption, with variations dependent on species, site, and trace element concentrations.

Evobrutinib pathway to its major metabolite M463-2 and insights from a biotransformation and DDI perspective.

Evobrutinib is a highly selective, covalent, central nervous system-penetrant Bruton's tyrosine kinase (BTK) inhibitor, currently in Phase III trials for the treatment of relapsing multiple sclerosis. One major circulating metabolite of evobrutinib has been previously identified as the racemic dihydro-diol M463-2 (MSC2430422) in a Phase I human mass balance study.Phenotyping experiments were conducted to confirm the metabolic pathway of evobrutinib to M463-2. Ratio of the enantiomers was determined by enantioselective liquid chromatography with tandem mass spectrometry analysis of plasma samples from humans and preclinical species. Drug-drug interaction (DDI) characterisation, evaluation of pharmacological activity on BTK, and off-target screening experiments followed assessing safety of the metabolite.The biotransformation of evobrutinib to M463-2 was determined to be a two-step process with a CYP-mediated oxidation acting to form an epoxide intermediate, which was further hydrolysed by soluble and mitochondrial epoxide hydrolase. Only the (S)-enantiomer was determined to be a major metabolite, the (R)-enantiomer was minor. In vitro studies demonstrated the (S)-enantiomer lacked clinically relevant pharmacological activity, off-target effects and DDIs.The biotransformation of evobrutinib to its major metabolite has been elucidated, with the major (S)-enantiomer being shown to pose no on/off target or DDI risks.

AKT/GSK-3ß signaling is altered through downregulation of mTOR during cerebral Ischemia/Reperfusion injury.

PURPOSE: Cellular responses following cerebral ischemia/reperfusion injury are critical to recovery and survival after ischemic stroke. Understanding of these cellular responses can help the design of therapies to protect brain tissue and promote recovery after stroke. One of these cellular responses may be mediated by the AKT (protein kinase B) signal transduction pathway. This study was aimed to investigate the cerebral ischemia-induced alterations of AKT signaling and the upstream molecular pathways. METHODS: We modeled cerebral ischemia by middle cerebral artery occlusion in 2-3-month-old male C57BL/6J mice and then analyze the brain samples by using quantitative Western blots and phosphorylation/activation-dependent kinase antibodies. Cerebral ischemia was confirmed by staining of brain slices with 1% 2,3,5-triphenyltetrazolium chloride (TTC) and Nissl, as well as neurological assessments of the mice 24 h after ischemia-reperfusion surgery. RESULTS: We found marked downregulation of AKT within 12 h of cerebral ischemia/reperfusion, which leads to overactivation of glycogen synthase kinase-3ß (GSK-3ß). Furthermore, we found that the downregulation of AKT was mediated by downregulation of mTORC2 (the complex 2 of the mechanistic target of rapamycin) instead of its common upstream kinases, phosphatidylinositol 3-kinase and phosphoinositide-dependent kinase-1. CONCLUSION: Our findings provide new insight into the cellular responses to ischemia/reperfusion brain injury and will help develop new treatments targeting the AKT signaling pathway for the treatment of ischemic stroke.

Gut Microbiota and Immunotherapy for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Currently, no effective treatment is available that can slow or halt the progression of the disease. The gut microbiota can modulate the host immune system in the peripheral and central nervous system through the microbiota-gut-brain axis. Growing evidence indicates that gut microbiota dysbiosis plays an important role in the pathogenesis of AD, and modulation of the gut microbiota may represent a new avenue for treating AD. Immunotherapy targeting Aß and tau has emerged as the most promising disease-modifying therapy for the treatment of AD. However, the underlying mechanism of AD immunotherapy is not known. Importantly, preclinical and clinical studies have highlighted that the gut microbiota exerts a major influence on the efficacy of cancer immunotherapy. However, the role of the gut microbiota in AD immunotherapy has not been explored. We found that immunotherapy targeting tau can modulate the gut microbiota in an AD mouse model. In this article, we focused on the crosstalk between the gut microbiota, immunity, and AD immunotherapy. We speculate that modulation of the gut microbiota induced by AD immunotherapy may partially underlie the efficacy of the treatment.

Truncation of Tau selectively facilitates its pathological activities.

Neurofibrillary tangles of abnormally hyperphosphorylated Tau are a hallmark of Alzheimer's disease (AD) and related tauopathies. Tau is truncated at multiple sites by various proteases in AD brain. Although many studies have reported the effect of truncation on the aggregation of Tau, these studies mostly employed highly artificial conditions, using heparin sulfate or arachidonic acid to induce aggregation. Here, we report for the first time the pathological activities of various truncations of Tau, including site-specific phosphorylation, self-aggregation, binding to hyperphosphorylated and oligomeric Tau isolated from AD brain tissue (AD O-Tau), and aggregation seeded by AD O-Tau. We found that deletion of the first 150 or 230 amino acids (aa) enhanced Tau's site-specific phosphorylation, self-aggregation, and binding to AD O-Tau and aggregation seeded by AD O-Tau, but deletion of the first 50 aa did not produce a significant effect. Deletion of the last 50 aa was found to modulate Tau's site-specific phosphorylation, promote its self-aggregation, and cause it to be captured by and aggregation seeded by AD O-Tau, whereas deletion of the last 20 aa had no such effects. Among the truncated Taus, Tau151-391 showed the highest pathological activities. AD O-Tau induced aggregation of Tau151-391in vitro and in cultured cells. These findings suggest that the first 150 aa and the last 50 aa protect Tau from pathological characteristics and that their deletions facilitate pathological activities. Thus, inhibition of Tau truncation may represent a potential therapeutic approach to suppress Tau pathology in AD and related tauopathies.

Using food network analysis to understand meal patterns in pregnant women with high and low diet quality.

BACKGROUND: Little is known about how meal-specific food intake contributes to overall diet quality during pregnancy, which is related to numerous maternal and child health outcomes. Food networks are probabilistic graphs using partial correlations to identify relationships among food groups in dietary intake data, and can be analyzed at the meal level. This study investigated food networks across meals in pregnant women and explored differences by overall diet quality classification. METHODS: Women were asked to complete three 24-h dietary recalls throughout pregnancy (n = 365) within a prospective cohort study in the US. Pregnancy diet quality was evaluated using the Healthy Eating Index-2015 (HEI, range 0-100), calculated across pregnancy. Networks from 40 food groups were derived for women in the highest and lowest HEI tertiles at each participant-labeled meal (i.e., breakfast, lunch, dinner, snacks) using Gaussian graphical models. Network composition was qualitatively compared across meals and between HEI tertiles. RESULTS: In both HEI tertiles, breakfast food combinations comprised ready-to-eat cereals with milk, quick breads with sweets (e.g., pancakes with syrup), and bread with cheese and meat. Vegetables were consumed at breakfast among women in the high HEI tertile only. Combinations at lunch and dinner were more varied, including vegetables with oils (e.g., salads) in the high tertile and sugary foods with nuts, fruits, and milk in the low tertile at lunch; and cooked grains with fats (e.g., pasta with oil) in the high tertile and potatoes with vegetables and meat in the low tertile at dinner. Fried potatoes, sugar-sweetened beverages, and sandwiches were consumed together at all main meals in the low tertile only. Foods were consumed individually at snacks in both tertiles; the most commonly consumed food were fruits in the high HEI tertile and cakes & cookies in the low tertile. CONCLUSIONS: In this cohort of pregnant women, food network analysis indicated that food combinations differed by meal and between HEI tertiles. Meal-specific patterns that differed between diet quality tertiles suggest potential targets to improve food choices at meals; the impact of meal-based dietary modifications on intake of correlated foods and on overall diet quality should be investigated in simulations and intervention studies. TRIAL REGISTRATION: PEAS was registered with number NCT02217462 in Clinicaltrials.gov on August 13, 2014.

Burden of Culture Confirmed Enteric Fever Cases in Karachi, Pakistan: Surveillance For Enteric Fever in Asia Project (SEAP), 2016-2019.

BACKGROUND: The Surveillance for Enteric Fever in Asia Project (SEAP) is a multicenter, multicountry study conducted in Pakistan, Nepal, and Bangladesh. The objectives of the study were to characterize disease incidence among patients with enteric fever. We report the burden of enteric fever at selected sites of Karachi, Pakistan. METHODS: During September 2016 to September 2019, prospective surveillance was conducted at inpatient, outpatient, surgical departments, and laboratory networks of Aga Khan University Hospital, Kharadar General Hospital, and surgery units of National Institute of Child Health and Jinnah Postgraduate Medical Centre. Socio-demographic, clinical, and laboratory data were obtained from all suspected or confirmed enteric fever cases. RESULTS: Overall, 22% (2230/10 094) of patients enrolled were culture-positive for enteric fever. 94% (2093/2230) of isolates were Salmonella Typhi and 6% (137/2230) were S. Paratyphi. 15% of isolates multi-drug resistant (MDR) to first-line antibiotics and 60% were extensively drug-resistant (XDR), resistant to first-line antibiotics, fluoroquinolones and third generation cephalosporin. CONCLUSION: Enteric fever cases have increased during the last 3 years with large proportion of drug resistant S. Typhi cases. However, the burden of paratyphoid is still relatively low. Strengthening the existing surveillance system for enteric fever and antimicrobial resistance at the national level is recommended in Pakistan to inform prevention measures. While typhoid vaccination can significantly decrease the burden of typhoid and may also impact antimicrobial resistance, water, sanitation, and hygiene improvement is highly recommended to prevent the spread of enteric fever.

Food groups and risk of coronary heart disease, stroke and heart failure: A systematic review and dose-response meta-analysis of prospective studies.

BACKGROUND: Despite growing evidence for food-based dietary patterns' potential to reduce cardiovascular disease risk, knowledge about the amounts of food associated with the greatest change in risk of specific cardiovascular outcomes and about the quality of meta-evidence is limited. Therefore, the aim of this meta-analysis was to synthesize the knowledge about the relation between intake of 12 major food groups (whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages [SSB]) and the risk of coronary heart disease (CHD), stroke and heart failure (HF). METHODS: We conducted a systematic search in PubMed and Embase up to March 2017 for prospective studies. Summary risk ratios (RRs) and 95% confidence intervals (95% CI) were estimated using a random effects model for highest versus lowest intake categories, as well as for linear and non-linear relationships. RESULTS: Overall, 123 reports were included in the meta-analyses. An inverse association was present for whole grains (RRCHD: 0.95 (95% CI: 0.92-0.98), RRHF: 0.96 (0.95-0.97)), vegetables and fruits (RRCHD: 0.97 (0.96-0.99), and 0.94 (0.90-0.97); RRstroke: 0.92 (0.86-0.98), and 0.90 (0.84-0.97)), nuts (RRCHD: 0.67 (0.43-1.05)), and fish consumption (RRCHD: 0.88 (0.79-0.99), RRstroke: 0.86 (0.75-0.99), and RRHF: 0.80 (0.67-0.95)), while a positive association was present for egg (RRHF: 1.16 (1.03-1.31)), red meat (RRCHD: 1.15 (1.08-1.23), RRstroke: 1.12 (1.06-1.17), RRHF: 1.08 (1.02-1.14)), processed meat (RRCHD: 1.27 (1.09-1.49), RRstroke: 1.17 (1.02-1.34), RRHF: 1.12 (1.05-1.19)), and SSB consumption (RRCHD: 1.17 (1.11-1.23), RRstroke: 1.07 (1.02-1.12), RRHF: 1.08 (1.05-1.12)) in the linear dose-response meta-analysis. There were clear indications for non-linear dose-response relationships between whole grains, fruits, nuts, dairy, and red meat and CHD. CONCLUSION: An optimal intake of whole grains, vegetables, fruits, nuts, legumes, dairy, fish, red and processed meat, eggs and SSB showed an important lower risk of CHD, stroke, and HF.

Intake of 12 food groups and disability-adjusted life years from coronary heart disease, stroke, type 2 diabetes, and colorectal cancer in 16 European countries.

Our aim was to estimate and rank 12 food groups according to disability-adjusted life years (DALYs) from coronary heart disease (CHD), stroke, type 2 diabetes (T2D), and colorectal cancer (CRC) in 16 European countries. De novo published non-linear dose-response meta-analyses of prospective studies (based on 297 primary reports), and food consumption data from the European Food Safety Authority Comprehensive European Food Consumption Database in Exposure Assessment, and DALY estimates from the Institute for Health Metrics and Evaluation were used. By implementing disease-specific counterfactual scenarios of theoretical minimum risk exposure level (TMRELs), the proportion of DALYs attributed to 12 food groups was estimated. In addition, a novel modelling approach was developed to obtain a single (optimized) TMREL across diseases. Four scenarios were analysed (A: disease-specific TMRELs/all food-disease associations; B: disease-specific TMRELs/only significant food-disease associations; C: single TMREL/all food-disease associations; D: single TMREL/only significant food-disease associations). Suboptimal food intake was associated with the following proportions of DALYs; Scenario A (highest-estimate) and D (lowest-estimate): CHD (A: 67%, D: 52%), stroke (A: 49%, D: 30%), T2D (A: 57%, D: 51%), and CRC (A: 54%, D: 40%). Whole grains (10%) had the highest impact on DALYs, followed by nuts (7.1%), processed meat (6.4%), fruit (4.4%) and fish and legumes (4.2%) when combining all scenarios. The contribution to total DALYs of all food groups combined in the different scenarios ranged from 41-52% in Austria to 51-69% in the Czech-Republic. These findings could have important implications for planning future food-based dietary guidelines as a public health nutrition strategy.

Gaussian graphical models identified food intake networks and risk of type 2 diabetes, CVD, and cancer in the EPIC-Potsdam study.

PURPOSE: The aim of the study was to investigate the association between the previously identified Gaussian graphical models' (GGM) food intake networks and risk of major chronic diseases as well as intermediate biomarkers in the European Prospective Investigation into Cancer and nutrition (EPIC)-Potsdam cohort. METHODS: In this cohort analysis of 10,880 men and 13,340 women, adherence to the previously identified sex-specific GGM networks as well as principal component analysis identified patterns was investigated in relation to risk of major chronic diseases, using Cox-proportional hazard models. Associations of the patterns with intermediate biomarkers were cross-sectionally analyzed using multiple linear regressions. RESULTS: Results showed that higher adherence to the GGM Western-type pattern was associated with increased risk (Hazard Ratio: 1.55; 95% CI 1.13-2.15; P trend = 0.004) of type 2 diabetes (T2D) in women, whereas adherence to a high-fat dairy (HFD) pattern was associated with lower risk of T2D both in men (0.69; 95% CI 0.54-0.89; P trend < 0.001) and women (0.71; 95% CI: 0.53, 0.96; P trend = 0.09). Among PCA patterns, HFD pattern was associated with lower risk of T2D (0.74; 95% CI 0.58-0.95; P trend < 0.001) in men and bread and sausage pattern was associated with higher risk of T2D (1.79; 95% CI 1.29-2.48; P trend < 0.001) in women. Moreover, The GGM-HFD pattern was positively associated with HDL-C in men and inversely associated with C-reactive protein in women. CONCLUSION: Overall, these results show that GGM-identified networks reflect dietary patterns, which could also be related to risk of chronic diseases.

Meal analysis for understanding eating behavior: meal- and participant-specific predictors for the variance in energy and macronutrient intake.

BACKGROUND: Meals differ in their nutritional content. This variation has not been fully addressed despite its potential contribution in understanding eating behavior. The aim of this study was to investigate the between-meal and between-individual variance in energy and macronutrient intake as a measure of variation in intake and the meal type-specific relative importance of predictors of these intake variations. METHODS: Energy and macronutrient intake were derived from three 24 h dietary recalls in an EPIC-Potsdam sub-cohort of 814 German adults. Intra-class correlation was calculated for participants and meal type. Predictors of intake were assessed using meal type-specific multilevel regression models in a structural equation modeling framework at intake and participant levels using the Pratt Index. The importance of the predictor energy misreporting was assessed in sensitivity analyses on 682 participants. 95% confidence intervals were calculated based on 1000 bootstrap samples. RESULTS: Differences between meal types explain a large proportion of the variation in intake (intra-class correlation: 39% for energy, 25% for carbohydrates, 47% for protein, and 33% for fat). Between-participant variation in intake was much lower, with a maximum of 3% for carbohydrate and fat. Place of meal was the most important intake-level predictor of energy and macronutrient intake (Pratt Index of up to 65%). Week/weekend day was important in the breakfast meal, and prior interval (hours passed since last meal) was important for the afternoon snack and dinner. On the participant level, sex was the most important predictor, with Pratt Index of up to 95 and 59% in the main and in the sensitivity analysis, respectively. Energy misreporting was especially important at the afternoon snack, accounting for up to 69% of the explained variance. CONCLUSIONS: The meal type explains the highest variation in energy and macronutrient intakes. We identified key predictors of variation in the intake and in the participant levels. These findings suggest that successful dietary modification efforts should focus on improving specific meals.

Correction to: Meal analysis for understanding eating behavior: meal- and participant-specific predictors for the variance in energy and macronutrient intake.

Following publication of the original article [1], the authors reported an error in Table 3. The correct Table 3 is provided below.

TDP-43 suppresses tau expression via promoting its mRNA instability.

In the brains of individuals with Alzheimer's disease (AD) and chronic traumatic encephalopathy, tau pathology is accompanied usually by intracellular aggregation of transactive response DNA-binding protein 43 (TDP-43). However, the role of TDP-43 in tau pathogenesis is not understood. Here, we investigated the role of TDP-43 in tau expression in vitro and in vivo. We found that TDP-43 suppressed tau expression by promoting its mRNA instability through the UG repeats of its 3΄-untranslated region (3΄-UTR). The C-terminal region of TDP-43 was required for this function. Neurodegenerative diseases-causing TDP-43 mutations affected tau mRNA instability differentially, in that some promoted and others did not significantly affect tau mRNA instability. The expression levels of tau and TDP-43 were inverse in the frontal cortex and the cerebellum. Accompanied with cytoplasmic accumulation of TDP-43, tau expression was elevated in TDP-43M337V transgenic mouse brains. The level of TDP-43, which is decreased in AD brains, was found to correlate negatively with the tau level in human brain. Our findings indicate that TDP-43 suppresses tau expression by promoting the instability of its mRNA. Down-regulation of TDP-43 may be involved in the tau pathology in AD and related neurodegenerative disorders.

Distribution pattern of ABO and Rhesus blood groups among different ethnic population of Karachi.

OBJECTIVE: To determine the distribution pattern of ABO and Rhesus blood groups among different ethnic populations in an urban centre. METHODS: The retrospective cross-sectional study was conducted at Kharadar General Hospital, Karachi, from May to Dec 2017, and comprised antenatal and walk-in individuals of different ethnic groups who were tested at the hospital's clinical laboratory. Blood groups typing was carried out using Slide Agglutination (antigen-antibody) method with antisera anti-A, anti-B, and anti-D. SPSS 16 was used for data analysis. RESULTS: Of the 3521 subjects, 1253(35.6%) had blood group O, 1167(33.1%) group B, 849(24.1%) group A and 252(7.2%) had group AB. Also, 3209(91.1%) were Rhesus-positive and 312(8.9%) Rhesus-negative. Blood group Opositive was predominant in Balochi 381(41%), Mohajir 197(36%), Sindhi 147(38%), Hindko 39(44%) and Seraiki14(43.8%) groups, while B-positive was common among Pathan 207(35%), Punjabi 116(35%), Kacchi 123(37%), Memon 79(37%) and Bengali 20(36%) groups. CONCLUSIONS: O positive was the most common and AB negative was the least common blood groups among different ethnic populations of Karachi.

Efficacy of probiotic in perennial allergic rhinitis under five year children: A randomized controlled trial.

OBJECTIVE: To determine the efficacy of probiotic (Lactobacillus Paracasei, LP-33) and compare it with cetirizine for the treatment of perennial allergic rhinitis in under five year's children. METHODS: The randomised clinical trial was conducted at Kharadar General Hospital, Karachi, from Dec 2016 to Nov 2017. Children aged 6 to 60 months, clinically presented with allergic rhinitis were included in the study. Total 212 children, randomized into intervention group A (received probiotic LP-33) and control group B (received cetirizine) for six weeks, were included in the analysis. Baseline allergic rhinitis symptoms (rhinorrhea, sneezing, nasal blocking, coughing, feeding & sleeping difficulties) were assessed after two and six weeks follow up and correlated both groups by using Pearson chi-square test. A p value of <0.05 were considered statistically significant. RESULTS: Total 212 children were analysed, out of them 113 (53.3%) were male. Mean age of study participant was 26 ± 16.64 months and mean body weight was 10.1 ± 3.26 Kg. More than 95% cases have shown significant improvement in their baseline symptoms (rhinorrhea, sneezing, nasal blocking, coughing, feeding difficulties and sleeping difficulties) in both intervention (L-33 Probiotic) and control (Cetirizine) groups. Statistically there was no difference in effectiveness of probiotic and cetirizine treatment for perennial allergic rhinitis (P > 0.05). CONCLUSIONS: Probiotic (LP-33) was equally effective as cetirizine in under five year's children for the treatment of perennial allergic rhinitis. Probiotic has additional benefit to treat allergic rhinitis without causing any major side effect in children reported by the study.

Transactive response DNA-binding protein 43 (TDP-43) regulates alternative splicing of tau exon 10: Implications for the pathogenesis of tauopathies.

Hyperphosphorylation and aggregation of the neuronal protein tau are responsible for neurodegenerative diseases called tauopathies. Dysregulation of the alternative splicing of tau exon 10 results in alterations of the ratio of two tau isoforms, 3R-tau and 4R-tau, which have been seen in several tauopathies. Transactive response DNA-binding protein of 43 kDa (TDP-43) is involved in the regulation of RNA processing, including splicing. Cytoplasmic aggregation of TDP-43 has been observed in the brains of individuals with chronic traumatic encephalopathy or Alzheimer's disease, diseases in which neurofibrillary tangles of hyperphosphorylated tau are hallmarks. Here, we investigated the role of TDP-43 in tau exon 10 splicing. We found that TDP-43 promoted tau exon 10 inclusion, which increased production of the 4R-tau isoform. Moreover, TDP-43 could bind to intron 9 of tau pre-mRNA. Deletion of the TDP-43 N or C terminus promoted its cytoplasmic aggregation and abolished or diminished TDP-43-promoted tau exon 10 inclusion. Several TDP-43 mutations associated with amyotrophic lateral sclerosis or frontotemporal lobar degeneration with ubiquitin inclusions promoted tau exon 10 inclusion more effectively than wild-type TDP-43 but did not affect TDP-43 cytoplasmic aggregation in cultured cells. The ratio of 3R-tau/4R-tau was decreased in transgenic mouse brains expressing human TDP-43 and increased in the brains expressing the disease-causing mutation TDP-43M337V, in which cytoplasmic TDP-43 was increased. These findings suggest that TDP-43 promotes tau exon 10 inclusion and 4R-tau expression and that disease-related changes of TDP-43, truncations and mutations, affect its function in tau exon 10 splicing, possibly because of TDP-43 mislocalization to the cytoplasm.

Food groups and risk of colorectal cancer.

The aim of this systematic review and meta-analysis was to summarize the evidence on the relationship between intake of 12 major food groups, including whole grains, refined grains, vegetables, fruit, nuts, legumes, eggs, dairy, fish, red meat, processed meat and sugar-sweetened beverages with risk of colorectal cancer (CRC). We conducted a systematic search in PubMed and Embase for prospective studies investigating the association between these 12 food groups and risk of CRC until April 2017. Summary risk ratios (RRs) and 95% confidence intervals (95% CI) were estimated using a random effects model for high vs. low intake categories, as well as for linear and nonlinear relationships. An inverse association was observed for whole grains (RR30g/d : 0.95, 95% CI 0.93, 0.97; n = 9 studies), vegetables (RR100g/d : 0.97, 95% CI 0.96, 0.98; n = 15), fruit (RR100g/d : 0.97, 95% CI 0.95, 0.99; n = 16) and dairy (RR200g/d : 0.93, 95% CI 0.91, 0.94; n = 15), while a positive association for red meat (RR100g/d : 1.12, 95% CI 1.06, 1.19; n = 21) and processed meat (RR50g/d : 1.17, 95% CI 1.10, 1.23; n = 16), was seen in the linear dose-response meta-analysis. Some evidence for nonlinear relationships was observed between vegetables, fruit and dairy and risk of colorectal cancer. Findings of this meta-analysis showed that a diet characterized by high intake of whole grains, vegetables, fruit and dairy products and low amounts of red meat and processed meat was associated with lower risk of CRC.

O-GlcNAcylation modulates PKA-CREB signaling in a manner specific to PKA catalytic subunit isoforms.

O-GlcNAcylation is a post-translational modification of proteins. Protein kinase A (PKA)-cAMP response element binding protein (CREB) signaling plays critical roles in multiple biological processes. Isoforms α and ß of PKA catalytic subunit (PKAc) and CREB are modified by O-GlcNAcylation. In the present study, we determined the role of O-GlcNAcylation in PKAc isoform-specific CREB signaling. We found that up-regulation of O-GlcNAcylation enhanced CREB phosphorylation, but suppressed CREB expression in exogenous PKAc isoform-unspecific manner. PKAc isoforms affected exogenous expression of OGT or OGA and protein O-GlcNAcylation differently. Up-regulation of O-GlcNAcylation did not significantly affect net PKAcα-CREB signaling, but enhanced PKAcß-CREB signaling. The role of O-GlcNAcylation in PKA-CREB signaling was desensitized by insulin treatment. This study suggests a role of O-GlcNAcylation in PKA-CREB signaling by affecting phosphorylation of CREB in a PKAc isoform-specific manner.

Nordic diet, Mediterranean diet, and the risk of chronic diseases: the EPIC-Potsdam study.

BACKGROUND: The Mediterranean Diet (MedDiet) has been acknowledged as a healthy diet. However, its relation with risk of major chronic diseases in non-Mediterranean countries is inconclusive. The Nordic diet is proposed as an alternative across Northern Europe, although its associations with the risk of chronic diseases remain controversial. We aimed to investigate the association between the Nordic diet and the MedDiet with the risk of chronic disease (type 2 diabetes (T2D), myocardial infarction (MI), stroke, and cancer) in the EPIC-Potsdam cohort. METHODS: The EPIC-Potsdam cohort recruited 27,548 participants between 1994 and 1998. After exclusion of prevalent cases, we evaluated baseline adherence to a score reflecting the Nordic diet and two MedDiet scores (tMDS, reflecting the traditional MedDiet score, and the MedPyr score, reflecting the MedDiet Pyramid). Cox regression models were applied to examine the association between the diet scores and the incidence of major chronic diseases. RESULTS: During a follow-up of 10.6 years, 1376 cases of T2D, 312 of MI, 321 of stroke, and 1618 of cancer were identified. The Nordic diet showed a statistically non-significant inverse association with incidence of MI in the overall population and of stroke in men. Adherence to the MedDiet was associated with lower incidence of T2D (HR per 1 SD 0.93, 95% CI 0.88-0.98 for the tMDS score and 0.92, 0.87-0.97 for the MedPyr score). In women, the MedPyr score was also inversely associated with MI. No association was observed for any of the scores with cancer. CONCLUSIONS: In the EPIC-Potsdam cohort, the Nordic diet showed a possible beneficial effect on MI in the overall population and for stroke in men, while both scores reflecting the MedDiet conferred lower risk of T2D in the overall population and of MI in women.