Efficient quality assurance for isocentric stability in stereotactic body radiation therapy using machine learning.

This study aims to predict isocentric stability for stereotactic body radiation therapy (SBRT) treatments using machine learning (ML), covers the challenges of manual assessment and computational time for quality assurance (QA), and supports medical physicists to enhance accuracy. The isocentric parameters for collimator (C), gantry (G), and table (T) tests were conducted with the RUBY phantom during QA using TrueBeam linac for SBRT. This analysis combined statistical features from the IsoCheck EPID software. Five ML models, including logistic regression (LR), decision tree (DT), random forest (RF), naive Bayes (NB), and support vector machines (SVM), were used to predict the outcome of the QA procedure. 247 Winston-Lutz (WL) tests were collected from 2020 to 2022. In our study, both DT and RF achieved the highest score on test accuracy (Acc. test) ranging from 93.5% to 99.4%, and area under curve (AUC) values from 90 to 100% on three modes (C, G, and T). The precision, recall, and F1 scores indicate the DT model consistently outperforms other ML models in predicting isocenter stability deviation in QA. The QA assessment using ML models can assist error prediction early to avoid potential harm during SBRT and ensure safe and effective patient treatments.

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.

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.

Biologically Synthesized Peptides Show Remarkable Inhibition Activity against Angiotensin-Converting Enzyme: A Promising Approach for Peptide Development against Autoimmune Diseases.

Angiotensin-converting enzyme (ACE) regulates several biological functions besides its vital role in immune functions. ACE is elevated in immune cells in inflammatory diseases including atherosclerosis, granuloma, chronic kidney disease, and also autoimmune diseases, like multiple sclerosis, rheumatoid arthritis, and type I diabetes. No significant information prevails in the literature regarding the isolation, identification, and profiling of potential ACE inhibitory peptides. In the present study, indigenous crop varieties like seeds (peanut, corn, oat, sunflower, chickpea, parsley, cottonseed, papaya, sesame, and flaxseed) were used to evaluate their ACE inhibition activity. Variables including hydrolysis time, enzyme-to-substrate ratio (E/S), pH, and temperature were standardized to acquire the most suitable and optimum ACE inhibition activity. Seeds of cotton, chickpea, and peanuts displayed remarkably maximum ACE inhibition activity than other plants. The study disclosed that maximum ACE inhibitory activity (86%) was evaluated from cottonseed at pH 8.0, temperature of 45°C, hydrolysis time of 2 hrs, and enzyme to the substrate (E/S) ratio of 1 : 5 followed by peanuts (76%) and chickpea (55%). SDS-PAGE confirmed that vicilin protein is present in cottonseed and peanut seed while cruciferin and napin proteins are present in chickpeas. LC-MS/MS analysis disclosed potential novel peptides in hydrolyzed cottonseed that can be ascribed as potential ACE inhibitors which have never been reported and studied earlier. The current study further showed that cottonseed peptides due to their promising ACE inhibitory activity can be a valuable source in the field of ACE inhibitor development.

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.

To Study the Effect of Noninvasive Ventilation on Hemodynamics and Respiratory Parameters in Postoperative CABG Patients.

Background and Aim: Bilevel positive airway pressure (BIPAP) is emerging as a useful modality in prevention as well as the management of postoperative respiratory dysfunction in patients undergoing coronary artery bypass graft (CABG). Materials and Methods: A total of 50 patients who underwent CABG were managed using BIPAP during postoperative period. Acid-base gas parameters, electrolyte levels, respiratory and hemodynamic parameters, and 24 h urine output before and after BIPAP application were measured. Data were analyzed using SPSS 21.0 version. Paired "t"-test was used to compare the changes in different parameters. Results: The mean age of patients was 57.72 ± 9.67 years (range: 36-85 years), majority were males (84%). Mean body mass index and mean left ventricular ejection fraction of patients were 24.26 ± 3.74 kg.m -2 and 52.77 ± 10.26%, respectively. Mean pO2, pCO2, and respiratory rate before BIPAP application were 90.62 ± 12.90 torr, 40.26 ± 5.39 torr, and 25.64 ± 6.21/min, respectively, which became 158.52 ± 50.43 torr, 37.77 ± 6.98 torr, and 21.78 ± 4.79/min, respectively, after BIPAP application, thus showing a significant change (P < 0.05). No significant change in other parameters was observed. No other adverse effect was noted. Conclusion: BIPAP application helped in improving ventilatory parameters without any adverse impact on hemodynamics and other parameters. Its application was a safe method to prevent respiratory disturbances following cardiac surgery.

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.

Effect of Peripheral Insulin Administration on Phosphorylation of Tau in the Brain.

BACKGROUND: Abnormally hyperphosphorylated tau is the major protein of neurofibrillary tangles in Alzheimer's disease. Insulin activates PI3K-AKT signaling and regulates tau phosphorylation. Impaired brain insulin signaling is involved in Alzheimer's disease pathogenesis. However, the effect of peripheral insulin on tau phosphorylation is controversial. OBJECTIVE: In the present study, we determined the effect of peripheral insulin administration on tau phosphorylation in brain. METHODS: We intraperitoneally injected a super physiological dose of insulin to mice and analyzed PI3K-AKT signaling and tau phosphorylation in brains by western blots. RESULTS: We found that peripherally administered insulin activated the PI3K-AKT signaling pathway immediately in the liver, but not in the brain. Tau phosphorylation in the mouse brain was found to be first decreased (15 min) and then increased (30 min and 60 min) after peripheral insulin administration and these changes correlated inversely with body temperature and the level of brain protein O-GlcNAcylation. Maintaining body temperature of mice post peripheral insulin administration prevented the insulin/hypoglycemia-induced tau hyperphosphorylation after peripheral insulin administration. CONCLUSION: These findings suggest that peripheral insulin can induce tau hyperphosphorylation through both hypothermia and downregulation of brain protein O-GlcNAcylation during hypoglycemia.

Glycogen synthase kinase-3ß suppresses the expression of protein phosphatase methylesterase-1 through ß-catenin.

Protein phosphatase 2A (PP2A) is the major tau phosphatase. Its activity toward tau is regulated by the methylation of PP2A catalytic subunit (PP2Ac) at Leu309. Protein phosphatase methylesterase-1 (PME-1) demethylates PP2Ac and suppresses its activity. We previously found that glycogen synthase kinase-3ß (GSK-3ß) suppresses PME-1 expression. However, the underlying molecular mechanism is unknown. In the present study, we analyzed the promoter of PME-1 gene and found that human PME-1 promoter contains two lymphoid enhancer binding factor-1/T-cell factor (LEF1/TCF) cis-elements in which ß-catenin serves as a co-activator. ß-catenin acted on these two cis-elements and promoted PME-1 expression. GSK-3ß phosphorylated ß-catenin and suppressed its function in promoting PME-1 expression. Inhibition and activation of GSK-3ß by PI3K-AKT pathway promoted and suppressed, respectively, PME-1 expression in primary cultured neurons, SH-SY5Y cells and in the mouse brain. These findings suggest that GSK-3ß phosphorylates ß-catenin and suppresses its function on PME-1 expression, resulting in an increase of PP2Ac methylation.

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.

Effective and Reliable Framework for Lung Nodules Detection from CT Scan Images.

Lung cancer is considered more serious among other prevailing cancer types. One of the reasons for it is that it is usually not diagnosed until it has spread and by that time it becomes very difficult to treat. Early detection of lung cancer can significantly increase the chances of survival of a cancer patient. An effective nodule detection system can play a key role in early detection of lung cancer thus increasing the chances of successful treatment. In this research work, we have proposed a novel classification framework for nodule classification. The framework consists of multiple phases that include image contrast enhancement, segmentation, optimal feature extraction, followed by employment of these features for training and testing of Support Vector Machine. We have empirically tested the efficacy of our technique by utilizing the well-known Lung Image Consortium Database (LIDC) dataset. The empirical results suggest that the technique is highly effective for reducing the false positive rates. We were able to receive an impressive sensitivity rate of 97.45%.

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.

A comparative study of RapidArc and intensity-modulated radiotherapy plan quality for cervical cancer treatment.

BACKGROUND: RapidArc therapy, a complex form of intensity-modulated radiotherapy (IMRT), is now widely used to treat cancer patients. AIMS: This study aimed to investigate and compare the plan quality of IMRT and RapidArc techniques using various dosimetric indices to find the better treatment modality for treating patients with cervix cancer. MATERIALS AND METHODS: Thirteen cervical cancer patients treated with IMRT were selected for analysis and original plans were subsequently re-optimized using the RapidArc technique. Plans were generated such that dose of 5000 cGy was delivered in 25 equal fractions. Inverse planning was done by Eclipse (Varian Medical Systems, Palo Alto, CA) treatment planning system for 15 MV photon beams from computed tomographic data. Double arcs were used for RapidArc plans. Quality of treatment plans was evaluated by calculating conformity index (CI), homogeneity index (HI), gradient index (GI), coverage, and unified dosimetry index (UDI) for each plan. RESULTS AND CONCLUSION: RapidArc resulted in better planning target volume (PTV) coverage as is evident from its superior conformation number, coverage, CI, HI, GI, and UDI. Regarding organs at risk (OARs), RapidArc plans exhibit superior organ sparing as is evident from integral dose comparison. Difference between both techniques was determined by statistical analysis. For all cases under study, modest differences between IMRT and RapidArc treatment were observed. RapidArc-based treatment planning is safer with similar planning goals compared to the standard fixed IMRT technique. This study clearly demonstrated that favorable dose distribution in PTV and OARs was achieved using RapidArc technique, and hence, the risk of damage to normal tissues is reduced.

Comparison of metabolite networks from four German population-based studies.

Background: Metabolite networks are suggested to reflect biological pathways in health and disease. However, it is unknown whether such metabolite networks are reproducible across different populations. Therefore, the current study aimed to investigate similarity of metabolite networks in four German population-based studies. Methods: One hundred serum metabolites were quantified in European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam (n = 2458), EPIC-Heidelberg (n = 812), KORA (Cooperative Health Research in the Augsburg Region) (n = 3029) and CARLA (Cardiovascular Disease, Living and Ageing in Halle) (n = 1427) with targeted metabolomics. In a cross-sectional analysis, Gaussian graphical models were used to construct similar networks of 100 edges each, based on partial correlations of these metabolites. The four metabolite networks of the top 100 edges were compared based on (i) common features, i.e. number of common edges, Pearson correlation (r) and hamming distance (h); and (ii) meta-analysis of the four networks. Results: Among the four networks, 57 common edges and 66 common nodes (metabolites) were identified. Pairwise network comparisons showed moderate to high similarity (r = 63-0.96, h = 7-72), among the networks. Meta-analysis of the networks showed that, among the 100 edges and 89 nodes of the meta-analytic network, 57 edges and 66 metabolites were present in all the four networks, 58-76 edges and 75-89 nodes were present in at least three networks, and 63-84 edges and 76-87 edges were present in at least two networks. The meta-analytic network showed clear grouping of 10 sphingolipids, 8 lyso-phosphatidylcholines, 31 acyl-alkyl-phosphatidylcholines, 30 diacyl-phosphatidylcholines, 8 amino acids and 2 acylcarnitines. Conclusions: We found structural similarity in metabolite networks from four large studies. Using a meta-analytic network, as a new approach for combining metabolite data from different studies, closely related metabolites could be identified, for some of which the biological relationships in metabolic pathways have been previously described. They are candidates for further investigation to explore their potential role in biological processes.

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.

Involvement of Activation of Asparaginyl Endopeptidase in Tau Hyperphosphorylation in Repetitive Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) is an established risk factor for the development of neurodegeneration and dementia late in life. Repetitive mild TBI (r-mTBI) is directly associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder characterized by focal perivascular to widespread Alzheimer-type neurofibrillary pathology of hyperphosphorylated tau. Studies in animal models have shown hyperphosphorylation of tau after TBI. However, the molecular mechanisms by which TBI leads to tau pathology are not understood. In this study, we employed western blots and immunohistochemistry to test, in triple-transgenic mouse model of Alzheimer's disease (3xTg-AD), the effect of r-mTBI on tau hyperphosphorylation and activation of asparaginyl endopeptidase (AEP), a cysteine proteinase which is known to be involved in tau hyperphosphorylation. We found that the level of active AEP was increased and correlated with the level of tau hyperphosphorylation following r-mTBI, and that fimbria showed increased immunoreactivity to phospho-tau. In addition, inhibitor 2 of protein phosphatase 2A (I2PP2A) was translocated from neuronal nucleus to the cytoplasm and colocalized with hyperphosphorylated tau. These data suggest the involvement of AEP-I2PP2A-PP2A-ptau pathway in tau pathology in TBI.

Circulating Metabolites Associated with Alcohol Intake in the European Prospective Investigation into Cancer and Nutrition Cohort.

Identifying the metabolites associated with alcohol consumption may provide insights into the metabolic pathways through which alcohol may affect human health. We studied associations of alcohol consumption with circulating concentrations of 123 metabolites among 2974 healthy participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Alcohol consumption at recruitment was self-reported through dietary questionnaires. Metabolite concentrations were measured by tandem mass spectrometry (BIOCRATES AbsoluteIDQTM p180 kit). Data were randomly divided into discovery (2/3) and replication (1/3) sets. Multivariable linear regression models were used to evaluate confounder-adjusted associations of alcohol consumption with metabolite concentrations. Metabolites significantly related to alcohol intake in the discovery set (FDR q-value < 0.05) were further tested in the replication set (Bonferroni-corrected p-value < 0.05). Of the 72 metabolites significantly related to alcohol intake in the discovery set, 34 were also significant in the replication analysis, including three acylcarnitines, the amino acid citrulline, four lysophosphatidylcholines, 13 diacylphosphatidylcholines, seven acyl-alkylphosphatidylcholines, and six sphingomyelins. Our results confirmed earlier findings that alcohol consumption was associated with several lipid metabolites, and possibly also with specific acylcarnitines and amino acids. This provides further leads for future research studies aiming at elucidating the mechanisms underlying the effects of alcohol in relation to morbid conditions.

Calpain I Activation Causes GLUT3 Proteolysis and Downregulation of O-GlcNAcylation in Alzheimer's Disease Brain.

Impairment of cerebral glucose uptake/metabolism in individuals with Alzheimer's disease (AD) is believed to lead to downregulation of protein O-GlcNAcylation, which contributes to tau pathogenesis through tau hyperphosphorylation. Level of glucose transporter 3 (GLUT3), a neuronal specific glucose transporter, is decreased in AD brain, which may contribute to impaired brain glucose uptake/metabolism. However, what causes the reduction of GLUT3 in AD brain is not fully understood. Here, we report 1) that decrease of GLUT3 is associated with the reduction of protein O-GlcNAcylation in AD brain, 2) that GLUT3 level is negatively correlated with calpain I activation in human brain, 3) that calpain I proteolyzes GLUT3 at the N-terminus in vitro, and 4) that activation of calpain I is negatively correlated with protein O-GlcNAcylation in AD brain. Furthermore, we found that overexpression of GLUT3 enhances protein O-GlcNAcylation in N2a cells. Overexpression of calpain I suppresses protein O-GlcNAcylation in these cells. These findings suggest a novel mechanism by which calpain I overactivation leads to GLUT3 degradation and the consequent down-regulation of protein O-GlcNAcylation in AD brain.

Mechanism of Tau Hyperphosphorylation Involving Lysosomal Enzyme Asparagine Endopeptidase in a Mouse Model of Brain Ischemia.

Dementias including Alzheimer's disease (AD) are multifactorial disorders that involve several different etiopathogenic mechanisms. Cerebral ischemia has been suspected in the altered regulation of protein kinases and phosphatases that leads to hyperphosphorylation of tau and further neurofibrillary pathology, a key hallmark of AD and related neurodegenerative diseases. However, the deregulation of these enzymes and their relationship with ischemia and AD remain unclear. Previously, we reported a mechanism by which the lysosomal enzyme asparagine endopeptidase (AEP) is associated with brain acidosis and AD. In this study, we subjected mice to middle cerebral artery occlusion and found that compared with wild type mice, the ischemia-induced brain injury and motor deficit in AEP-knockout mice are reduced, probably because ischemia activates AEP. AEP cleaves inhibitor 2 of protein phosphatase 2A (I2PP2A), which translocates from the neuronal nucleus to the cytoplasm and produces hyperphosphorylation of tau through inhibition of PP2A. These findings suggest a possible mechanism of tau pathology associated with ischemia.

Contribution to the understanding of how principal component analysis-derived dietary patterns emerge from habitual data on food consumption.

Background: Principal component analysis (PCA) is a widely used exploratory method in epidemiology to derive dietary patterns from habitual diet. Such dietary patterns seem to originate from intakes on multiple days and eating occasions. Therefore, analyzing food intake of study populations with different levels of food consumption can provide additional insights as to how habitual dietary patterns are formed. Objective: We analyzed the food intake data of German adults in terms of the relations among food groups from three 24-h dietary recalls (24hDRs) on the habitual, single-day, and main-meal levels, and investigated the contribution of each level to the formation of PCA-derived habitual dietary patterns. Design: Three 24hDRs were collected in 2010-2012 from 816 adults for an European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam subcohort study. We identified PCA-derived habitual dietary patterns and compared cross-sectional food consumption data in terms of correlation (Spearman), consistency (intraclass correlation coefficient), and frequency of consumption across all days and main meals. Contribution to the formation of the dietary patterns was obtained through Spearman correlation of the dietary pattern scores. Results: Among the meals, breakfast appeared to be the most consistent eating occasion within individuals. Dinner showed the strongest correlations with "Prudent" (Spearman correlation = 0.60), "Western" (Spearman correlation = 0.59), and "Traditional" (Spearman correlation = 0.60) dietary patterns identified on the habitual level, and lunch showed the strongest correlations with the "Cereals and legumes" (Spearman correlation = 0.60) habitual dietary pattern. Conclusions: Higher meal consistency was related to lower contributions to the formation of PCA-derived habitual dietary patterns. Absolute amounts of food consumption did not strongly conform to the habitual dietary patterns by meals, suggesting that these patterns are formed by complex combinations of variable food consumption across meals. Dinner showed the highest contribution to the formation of habitual dietary patterns. This study provided information about how PCA-derived dietary patterns are formed and how they could be influenced.