Application of a Two-Dimensional Mapping-Based Visualization Technique: Nutrient-Value-Based Food Grouping.

Worldwide, several food-based dietary guidelines, with diverse food-grouping methods in various countries, have been developed to maintain and promote public health. However, standardized international food-grouping methods are scarce. In this study, we used two-dimensional mapping to classify foods based on their nutrient composition. The Standard Tables of Food Composition in Japan were used for mapping with a novel technique-t-distributed stochastic neighbor embedding-to visualize high-dimensional data. The mapping results showed that most foods formed food group-based clusters in the Standard Tables of Food Composition in Japan. However, the beverages did not form large clusters and demonstrated scattered distribution on the map. Green tea, black tea, and coffee are located within or near the vegetable cluster whereas cocoa is near the pulse cluster. These results were ensured by the k-nearest neighbors. Thus, beverages made from natural materials can be categorized based on their origin. Visualization of food composition could enable an enhanced comprehensive understanding of the nutrients in foods, which could lead to novel aspects of nutrient-value-based food classifications.

Frailty-Preventing Effect of an Intervention Program Using a Novel Complete Nutritional "COMB-FP Meal": A Pilot Randomized Control Trial.

Frailty is a huge concern for the aging population, and dietary nutrition is considered a key factor in the prevention of aging. To solve the problem of frailty in the aging population, we developed a novel dietary intervention program using a novel COMpletely Balanced for Frailty Prevention (COMB-FP) meal, based on the Dietary Reference Intake for Japanese; in addition, we conducted a pilot randomized control trial comparing an exercise program only (control group) with exercise plus the COMB-FP meal program (test group). We included 110 male and female healthy volunteers with pre-frailty or frailty; the trial lasted for 12 weeks. Two daily meals were replaced with the COMB-FP meals during the trial in the test group. Walking speed and cognitive function were significantly improved in the test group compared with the control group. We observed a similar pattern in other frailty-related outcomes, such as occupancy of the microbiome, World Health Organization well-being index (WHO-5), and oxidative stress. Our study might indicate the importance of a well-balanced intake of nutrients for frailty prevention.

Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of Akkermansia muciniphila in mice.

OBJECTIVE: Polyphenols have health-promoting effects, such as improving insulin resistance. Isoxanthohumol (IX), a prenylated flavonoid found in beer hops, has been suggested to reduce obesity and insulin resistance; however, the mechanism remains unknown. METHODS: High-fat diet-fed mice were administered IX. We analyzed glucose metabolism, gene expression profiles and histology of liver, epididymal adipose tissue and colon. Lipase activity, fecal lipid profiles and plasma metabolomic analysis were assessed. Fecal 16s rRNA sequencing was obtained and selected bacterial species were used for in vitro studies. Fecal microbiota transplantation and monocolonization were conducted to antibiotic-treated or germ-free (GF) mice. RESULTS: The administration of IX lowered weight gain, decreased steatohepatitis and improved glucose metabolism. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption by decreasing the expression of the fatty acid transporter CD36 in the small intestine, which was confirmed by increased lipid excretion in feces. IX administration increased markers of intestinal barrier function, including thickening the mucin layer and increasing caludin-1, a tight-junction related protein in the colon. In contrast, the effects of IX were nullified by antibiotics. As revealed using 16S rRNA sequencing, the microbial community structure changed with a significant increase in the abundance of Akkermansia muciniphila in the IX-treated group. An anaerobic chamber study showed that IX selectively promoted the growth of A. muciniphila while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct effect of A. muciniphila on lipid and glucose metabolism, we monocolonized either A. muciniphila or Bacteroides thetaiotaomicron to GF mice. A. muciniphila monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism, with decreased levels of multiple classes of fatty acids determined using plasma metabolomic analysis. CONCLUSIONS: Our study demonstrated that IX prevents obesity and enhances glucose metabolism by inhibiting dietary fat absorption. This mechanism is linked to suppressing pancreatic lipase activity and shifts in microbial composition, notably an increase in A. muciniphila. These highlight new treatment strategies for preventing metabolic syndrome by boosting the gut microbiota with food components.

Accumulation of amyloid-ß in the brain of mouse models of Alzheimer's disease is modified by altered gene expression in the presence of human apoE isoforms during aging.

Apolipoprotein E4 (apoE4) is a risk factor for Alzheimer's disease (AD). Here, we investigated brain amyloid-ß (Aß) accumulation throughout the aging process in an amyloid precursor protein (APP) knock-in (KI) mouse model of AD that expresses human APPNL-G-F with or without human apoE4 or apoE3. Brain Aß42 levels were significantly lower in 9-month-old mice that express human isoforms of apoE than in age-matched APP-KI control mice. Linear accumulation of Aß42 began in 5-month-old apoE4 mice, and a strong increase in Aß42 levels was observed in 21-month-old apoE3 mice. Aß42 levels in cerebroventricular fluid were higher in apoE3 than in apoE4 mice at 6-7 months of age, suggesting that apoE3 is more efficient at clearing Aß42 than apoE4 at these ages. However, apoE3 protein levels were lower than apoE4 protein levels in the brains of 21-month-old apoE3 and apoE4 mice, respectively, which may explain the rapid increase in brain Aß42 burden in apoE3 mice. We identified genes that were downregulated in a human apoE-dependent (apoE4 > apoE3) and age-dependent (apoE3 = apoE4) manner, which may regulate brain Aß burden and/or AD progression. Analysis of gene expression in AD mouse models helps identify molecular mechanisms of pleiotropy by the human APOE gene during aging.

The Multi-Domain Intervention Trial in Older Adults With Diabetes Mellitus for Prevention of Dementia in Japan: Study Protocol for a Multi-Center, Randomized, 18-Month Controlled Trial.

Background: The Japan-Multi-domain Intervention Trial for Prevention of Dementia in Older Adults with Diabetes (J-MIND-Diabetes) is an 18-month, multi-centered, open-labeled, randomized controlled trial designed to identify whether multi-domain intervention targeting modifiable risk factors for dementia could prevent the progression of cognitive decline among older adults with type 2 diabetes mellitus (T2DM). This manuscript describes the study protocol for the J-MIND-Diabetes trial. Materials and Methods: Subjects of this trial will comprise a total of 300 T2DM outpatients aged 70-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the stratified permuted-block randomization methods. The intervention group will participate in multi-domain intervention programs aimed at: (1) management of metabolic and vascular risk factors; (2) physical exercise and self-monitoring of physical activity; (3) nutritional guidance; and (4) social participation. The control group will receive usual T2DM care and general instructions on dementia prevention. The primary and secondary outcomes will be assessed at baseline, at 6- and 18-month follow-up. The primary outcome is change from baseline at 18 months in a global composite score combining several neuropsychological domains, including global cognitive function, memory, attention, executive function, processing speed and language. Secondary outcomes include: (1) cognitive changes in neuropsychological tests; (2) changes in geriatrics assessments; (3) metabolic control and diabetic complications; (4) changes in blood and urinary markers. Discussion: This trial will be the first trial to demonstrate the effectiveness of multi-domain intervention in preventing cognitive decline in older adults with T2DM at increased risk of dementia in Japan. Trial Registration: UMIN000035911; Registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) 18 February 2019. (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000040908).

Structural Basis for the Dual Substrate Specificity of DOCK7 Guanine Nucleotide Exchange Factor.

The Dedicator Of CytoKinesis (DOCK) family of atypical guanine nucleotide exchange factors activates the Rho family GTPases Rac and/or Cdc42 through DOCK homology region 2 (DHR-2). Previous structural analyses of the DHR-2 domains of DOCK2 and DOCK9 have shown that they preferentially bind Rac1 and Cdc42, respectively; however, the molecular mechanism by which DHR-2 distinguishes between these GTPases is unclear. Here we report the crystal structure of the Cdc42-bound form of the DOCK7 DHR-2 domain showing dual specificity for Rac1 and Cdc42. The structure revealed increased substrate tolerance of DOCK7 at the interfaces with switch 1 and residue 56 of Cdc42. Furthermore, molecular dynamics simulations showed a closed-to-open conformational change in the DOCK7 DHR-2 domain between the Cdc42- and Rac1-bound states by lobe B displacement. Our results suggest that lobe B acts as a sensor for identifying different switch 1 conformations and explain how DOCK7 recognizes both Rac1 and Cdc42.

A new Classification of Diabetic Nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy.

The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts, such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labor and Welfare of Japan. Major revisions to the Classification are summarized as follows: (i) eGFR is substituted for GFR in the Classification; (ii) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated; (iii) stage 4 (kidney failure) has been redefined as a GFR <30 mL/min/1.73 m(2), regardless of the extent of albuminuria; and (iv) stress has been placed on the differential diagnosis of diabetic nephropathy versus non-diabetic kidney disease as being crucial in all stages of diabetic nephropathy.

A new classification of Diabetic Nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy.

The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease. In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labour and Welfare of Japan. Major revisions to the Classification are summarized as follows: (1) eGFR is substituted for GFR in the Classification; (2) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated; (3) stage 4 (kidney failure) has been redefined as a GFR less than 30 mL/min/1.73 m(2), regardless of the extent of albuminuria; and (4) stress has been placed on the differential diagnosis of diabetic nephropathy versus non-diabetic kidney disease as being crucial in all stages of diabetic nephropathy.

Crystal structures of the S6K1 kinase domain in complexes with inhibitors.

Ribosomal protein S6 kinase 1 (S6K1) is a serine/threonine protein kinase that plays an important role in the PIK3/mTOR signaling pathway, and is implicated in diseases including diabetes, obesity, and cancer. The crystal structures of the S6K1 kinase domain in complexes with staurosporine and the S6K1-specific inhibitor PF-4708671 have been reported. In the present study, five compounds (F108, F109, F176, F177, and F179) were newly identified by in silico screening of a chemical library and kinase assay. The crystal structures of the five inhibitors in complexes with the S6K1 kinase domain were determined at resolutions between 1.85 and 2.10 Å. All of the inhibitors bound to the ATP binding site, lying along the P-loop, while the activation loop stayed in the inactive form. Compound F179, with a carbonyl group in the middle of the molecule, altered the αC helix conformation by interacting with the invariant Lys123. Compounds F176 and F177 bound slightly distant from the hinge region, and their sulfoamide groups formed polar interactions with the protein. The structural features required for the specific binding of inhibitors are discussed.

[Classification of Diabetic Nephropathy 2014].

The Committee on Diabetic Nephropathy revised the classification of diabetic nephropathy in view of the current status of eGFR and CKD in Japan. To make revisions for the classification of diabetic nephropathy 2014, the Committee carefully evaluated the report of the Research Group on Diabetic Nephropathy, Ministry of Health, Labour, and Welfare of Japan. The major revisions made were as follows: 1. eGFR can be used for the evaluation of GFR; 2. In stage 3 (overt nephropathy), A and B were combined; 3. Stage 4 (renal failure) was defined as GFR less than 30 mL/min/1.73 m2, regardless of albuminuria; and 4. The importance of differential diagnosis was stressed in all stages.

Kinase crystal identification and ATP-competitive inhibitor screening using the fluorescent ligand SKF86002.

The small kinase inhibitor SKF86002 lacks intrinsic fluorescence but becomes fluorescent upon binding to the ATP-binding sites of p38 mitogen-activated protein kinase (p38α). It was found that co-crystals of this compound with various kinases were distinguishable by their strong fluorescence. The co-crystals of SKF86002 with p38α, Pim1, ASK1, HCK and AMPK were fluorescent. Addition of SKF86002, which binds to the ATP site, to the co-crystallization solution of HCK promoted protein stability and thus facilitated the production of crystals that otherwise would not grow in the apo form. It was further demonstrated that the fluorescence of SKF86002 co-crystals can be applied to screen for candidate kinase inhibitors. When a compound binds competitively to the ATP-binding site of a kinase crystallized with SKF86002, it displaces the fluorescent SKF86002 and the crystal loses its fluorescence. Lower fluorescent signals were reported after soaking SKF86002-Pim1 and SKF86002-HCK co-crystals with the inhibitors quercetin, a quinazoline derivative and A-419259. Determination of the SKF86002-Pim1 and SKF86002-HCK co-crystal structures confirmed that SKF86002 interacts with the ATP-binding sites of Pim1 and HCK. The structures of Pim1-SKF86002 crystals soaked with the inhibitors quercetin and a quinazoline derivative and of HCK-SKF86002 crystals soaked with A-419259 were determined. These structures were virtually identical to the deposited crystal structures of the same complexes. A KINOMEscan assay revealed that SKF86002 binds a wide variety of kinases. Thus, for a broad range of kinases, SKF86002 is useful as a crystal marker, a crystal stabilizer and a marker to identify ligand co-crystals for structural analysis.

Structures of histone methyltransferase SET7/9 in complexes with adenosylmethionine derivatives.

SET7/9 is a protein lysine methyltransferase that methylates histone H3 and nonhistone proteins such as p53, TAF10 and oestrogen receptor α. In previous work, novel inhibitors of SET7/9 that are amine analogues of the coenzyme S-(5'-adenosyl)-L-methionine (AdoMet) have been developed. Here, crystal structures of SET7/9 are reported in complexes with two AdoMet analogues, designated DAAM-3 and AAM-1, in which an n-hexylaminoethyl group or an n-hexyl group is attached to the N atom that replaces the S atom of AdoMet, respectively. In both structures, the inhibitors bind to the coenzyme-binding site and their additional alkyl chain binds in the lysine-access channel. The N atom in the azaalkyl chain of DAAM-3 is located at almost the same position as the N-methyl C atom of the methylated lysine side chain in the substrate-peptide complex structures and stabilizes complex formation by hydrogen bonding to the substrate-binding site residues of SET7/9. On the other hand, the alkyl chain of AAM-1, which is a weaker inhibitor than DAAM-3, binds in the lysine-access channel only through hydrophobic and van der Waals interactions. Unexpectedly, the substrate-binding site of SET7/9 complexed with AAM-1 specifically interacts with the artificial N-terminal sequence of an adjacent symmetry-related molecule, presumably stabilizing the alkyl chain of AAM-1.

Expression, purification and characterization of isoforms of peripheral stalk subunits of human V-ATPase.

The vacuolar-type H+-ATPase (V-ATPase) is a multi-subunit proton pump that is involved in both intra- and extracellular acidification processes throughout human body. Subunits constituting the peripheral stalk of the V-ATPase are known to have several isoforms responsible for tissue/cell specific different physiological roles. To study the different interaction of these isoforms, we expressed and purified the isoforms of human V-ATPase peripheral stalk subunits using Escherichia coli cell-free protein synthesis system: E1, E2, G1, G2, G3, C1, C2, H and N-terminal soluble part of a1 and a2 isoforms. The purification conditions were different depending on the isoforms, maybe reflecting the isoform specific biochemical characteristics. The purified proteins are expected to facilitate further experiments to study about the cell specific interaction and regulation and thus provide insight into physiological meaning of the existence of several isoforms of each subunit in V-ATPase.

Ice cube stimulation helps to improve dysgeusia.

Dysgeusia causes a decrease in appetite, and it is one of the major factors in undernutrition. Dysgeusia is elicited by numerous causes, and in many cases it is still difficult to treat the various symptoms complained of by patients. We herein report a case in which dysgeusia was improved by transient cooling of the mouth.

Cognitive mediators linking social support networks to colorectal cancer screening adherence.

This paper argues that normative considerations are more important than attitudinal factors in engaging colorectal cancer screening, and tests a model explaining how unique cultural expressions of social networks influence screening adherence. Structural equation modeling was used to understand colorectal cancer screening in a population-based sample of 341 Japanese Americans aged 50 and over. The model accounted for 25% of the variance in screening adherence. Adherence was most strongly associated with family/friend subjective norms about colorectal cancer screening use. Emotional family support, but not the size of the networks, was indirectly related to adherence via increased family/friend subjective norms, while emotional friend support was directly related to adherence. While usual source of care was directly associated with adherence, better provider-patient communication was directly and indirectly associated with adherence via increased perceived benefits. The findings of this study support strengthening informal support networks to enhance adherence among Japanese Americans at risk.

A model of stage of change to recommend colonoscopy among urban primary care physicians.

Theory is little used in the prediction of physician cancer screening stage of change. Structural equation modeling was used to evaluate the theoretical predictors of stage of change to recommend colonoscopy among 235 urban physicians. Constructs from the theory of planned behavior, social-cognitive theory, and the transtheoretical model were systematically tested. As predicted, contextual factors, such as the physicians' ages, their race-ethnicities, patient race-ethnicity, and office-related barriers to preventive care were associated with stage of change through self-efficacy, normative beliefs, and negative behavioral beliefs. The findings demonstrate the relevance of these models to studying the behavior of physicians and support the development of interventions that are tailored to normative beliefs and specific physician cognitions for colonoscopy recommendation.

Modeling pathways to affective barriers on colorectal cancer screening among Japanese Americans.

The study aimed to identify the mechanisms through which colorectal cancer (CRC)-specific affective barriers, including fear of finding CRC, embarrassment, and concerns for screening discomfort, can be reduced to guide the development of interventions aimed at the secondary prevention of CRC. A model explaining these affective barriers was developed and tested among a random sample of 305 asymptomatic Japanese Americans using a path analysis. The model suggested that affective barriers could be reduced by increasing CRC-related knowledge, which could be enhanced by acculturation, social support, and physician recommendation. Interventions that focus on increasing CRC-related knowledge could reduce affective barriers to CRC screening for this population when taking the enhancement of communication skills and interpersonal interactions into account.

The associations between psychological distress and cancer prevention practices.

The aim of the current study was to determine the extent to which psychological distress is associated with cancer prevention practices among otherwise healthy adults in the community (N=30,223). Using data from the 2000 National Health Interview Survey, a series of multiple logistic regression analyses were used to estimate the associations between psychological distress and selected cancer prevention practices. Results indicate that psychological distress was directly associated with an increased likelihood of daily cigarette smoking, physical inactivity, and obesity. Only smoking status mediated the relation between psychological distress and perceived cancer risk. Individuals who reported higher psychological distress were more likely to engage in specific cancer screenings before reaching the recommended age. This effect was partially mediated by perceived cancer risk. The higher levels of cigarette smoking and physical inactivity among psychologically distressed adults support the need for integration of cancer prevention and mental health interventions to reduce specific cancer risk in high-risk adults. Further research is needed to differentiate the causal pathways and mechanisms linking heightened individual cancer risk, potentially comorbid mental disorders or psychological conditions, and cancer screening adherence.

Psychosocial correlates of smoking cessation among elderly ever-smokers in the United States.

This study was conducted to identify the psychosocial factors associated with successful smoking cessation among ever-smokers aged 60 and older in the United States. Descriptive and multivariate analyses of the 2000 National Health Interview Survey (NHIS) were conducted. Controlling for sociodemographics and medical history of smoking-associated diseases, former smokers were less likely to have psychological distress (adjusted OR=0.71, 95% CI=0.58-0.88) and more likely to believe in the danger of second-hand smoke (adjusted OR=3.01, 95% CI=2.4-3.79) and the appropriateness of a smoking ban in indoor public places (adjusted OR=2.62, 95% CI=2.11-3.26). Having no regular source for care (adjusted OR=0.54, 95% CI=0.37-0.78) was an independent barrier to cessation, as were younger age, female, Hispanic race, being nonmarried and employed, and having lower income and education. This work contributes to a knowledge base for the development of interventions to maximize smoking cessation of elderly smokers. Findings suggest that strategies tailored to psychological distress and beliefs about smoking health harms and smoking restriction policies would aid in successful cessation. Specific measures reinforcing the importance of having a regular source for care may promote cessation. The extent to which these psychosocial factors affect elders' motivation to quit smoking remains to be explored.

Use of complementary and alternative medicine among United States adults: the influences of personality, coping strategies, and social support.

BACKGROUND: Although patterns of utilization of complementary and alternative medicine (CAM) in the community have begun to be described, few studies have addressed the relationships between dispositional psychological factors and the use of CAM. The aim of this study was to examine the associations between CAM use and personality, coping strategies, and perceived social support in a representative sample of adults in the United States. METHODS: Data were drawn from the Midlife Development in the United States Survey (MIDUS), a representative sample of 3,032 adults aged 25-74 in the US population. We analyzed use of acupuncture, biofeedback, chiropractic, energy healing, exercise/movement therapy, herbal medicine, high-dose megavitamins, homeopathy, hypnosis, imagery techniques, massage, prayer/spiritual practice, relaxation/mediation, and special diet within the last year. Multiple logistic regression analyses were used to evaluate the association of personality, dispositional coping strategies (primary and secondary control), and perceived social support and strain with CAM use, controlling for sociodemographic factors, medical care access, and physical and mental disorders. RESULTS: Openness was positively associated with the use of all types of CAM except manipulative body-based methods. Extroversion was inversely correlated with the use of mind-body therapies. Primary control was inversely and secondary control directly correlated with the use of CAM. Perceived friend support was positively associated with the use of mind-body therapies, manipulative body-based methods, and alternative medical systems. Perceived partner strain was positively associated with the use of biologically based therapies, and family strain increased the odds of manipulative body-based methods. CONCLUSIONS: This study is the first to document a significant association between specific domains of personality, coping strategies, and social support, and the use of CAM among adults in the general population. Understanding the relationships between psychological factors and CAM use may help researchers and health care providers to address patients' needs more effectively and to achieve better adherence to treatment recommendations.