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This paper addresses a growing need in clinical diagnostics for parallel, multiplex analysis of biomarkers from small biological samples. It describes a new procedure for assembling arrays of ssDNA and proteins on paper. This method starts with the synthesis of DNA oligonucleotides covalently linked to paper and proceeds to assemble microzones of DNA-conjugated paper into arrays capable of simultaneously capturing DNA, DNA-conjugated protein antigens, and DNA-conjugated antibodies. The synthesis of ssDNA oligonucleotides on paper is convenient and effective with 32% of the oligonucleotides cleaved and eluted from the paper substrate being full-length by HPLC for a 32-mer. These ssDNA arrays can be used to detect fluorophore-linked DNA oligonucleotides in solution, and as the basis for DNA-directed assembly of arrays of DNA-conjugated capture antibodies on paper, detect protein antigens by sandwich ELISAs. Paper-anchored ssDNA arrays with different sequences can be used to assemble paper-based devices capable of detecting DNA and antibodies in the same device and enable simple microfluidic paper-based devices.

Background: High-quality carbohydrate sources, such as whole grains, have been associated with a lower risk of type 2 diabetes (T2D), whereas low-quality carbohydrate sources, such as refined grains and added sugar, have been associated with a higher T2D risk. However, few studies have considered how replacing dietary carbohydrate with other macronutrients may influence T2D risk. Objective: We examined whether isocaloric substitution of high- or low-quality carbohydrate for fat, protein, and their subtypes is associated with T2D risk. Methods: We included 75,430 women from the Nurses' Health Study (1984-2016), 85,630 women from the Nurses' Health Study II (1991-2017), and 40,261 men from the Health Professionals Follow-Up Study (1986-2016) who were free of T2D, CVD, and cancer at baseline. Dietary data were collected every 2-4 years using a validated, semi-quantitative food frequency questionnaire. High-quality carbohydrate was defined as carbohydrate from whole grains, fruits, vegetables, and legumes. Low-quality carbohydrate was defined as carbohydrate from refined grains, added sugars, and potatoes. We used Cox proportional hazards regression with time-varying covariates to model the substitution of 5% of energy intake from high- and low-quality carbohydrate for isocaloric amounts of fat, protein, and their subtypes [polyunsaturated fat (PUFA), animal and plant monounsaturated fat (MUFA), saturated fat, trans fat, and animal and plant protein]. Cohort-specific estimates were combined using inverse variance-weighted fixed effects meta-analyses. Results: During 4,859,845 years of follow-up, we documented 20,141 incident T2D cases. In multivariable-adjusted meta-analyses, isocaloric substitution of high-quality carbohydrate for total fat [HR (95% CI) 0.94 (0.93, 0.96)], total MUFA [0.95 (0.91, 0.98)], MUFA from animal sources [0.92 (0.88, 0.95)], total protein [0.91 (0.89, 0.94)], or animal protein [0.94 (0.91, 0.97] was associated with a lower T2D risk. On the other hand, the substitution of low-quality carbohydrate for plant MUFA [1.06 (1.02-1.10)] or plant protein [1.06 (1.02-1.11)] was associated with a higher risk of T2D. When we restricted high-quality carbohydrate sources to whole grains, the results were similar or stronger. Additionally, substitution of whole grain carbohydrate for saturated fat [0.87 (0.84, 0.91)], trans fat [0.87 (0.83, 0.92)], PUFA [0.88 (0.84, 0.92)], plant MUFA [0.92 (0.87, 0.96)], or plant protein [0.91 (0.86, 0.97)] was associated with lower T2D risk. Conclusions: The effect of carbohydrate substitution on T2D risk depends not only on the nutrient being substituted but also on the quality of the carbohydrate. Substitution of high-quality carbohydrate, especially carbohydrate from whole grains (i.e. whole wheat bread, oatmeal), for fat or protein, especially animal sources (i.e. beef, poultry), may lower T2D risk.

We report a new and general strategy for efficient injection of carriers in active nanophotonic devices involving the synthesis of well-defined doped core/shell/shell (CSS) nanowire heterostructures. n-GaN/InGaN/p-GaN CSS nanowire structures were grown by metal-organic chemical vapor deposition. Electron microscopy images reveal that the CSS nanowires are defect-free single crystalline structures, while energy-dispersive X-ray linescan profile studies confirm that shell thickness and composition can be well controlled during synthesis. Photoluminescence data further show that the optical properties are controlled by the CSS structure with strong emission from the InGaN shell centered at 448 nm. Importantly, electrical devices made by simultaneously contacting the n-type core and outer p-type shell of the CSS nanowires demonstrate that in forward bias these individual nanowires behave as light-emitting diodes (LEDs) with bright blue emission from the InGaN shell. The ability to rationally synthesize gallium nitride-based radial heterostructures should open up new opportunities for nanophotonics, including multicolor LEDs and lasers.

Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 × 10−5], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.

Epidemiological data have consistently documented a protective effect of fruit and vegetable intake on risk of coronary heart disease (CHD). Consequently, dietary guidelines recommend increasing fruit and vegetable intake and, most recently, have also suggested increasing variety. Our objective was to examine the independent roles of quantity and variety in fruit and vegetable intake in relation to incident CHD. We prospectively observed 71,157 women from the Nurses’ Health Study (NHS, 1984-2008) and 39,752 men from the Health Professionals Follow-up Study (HPFS, 1986-2008) who were free of diabetes, cardiovascular diseases, and cancer at baseline. We documented 2585 incident CHD cases in women during 24 years of follow-up and 3408 cases in men during 22 years of follow-up. Diet was assessed using a standardized and validated questionnaire and updated every 4 years. Variety was defined as the number of unique fruits and vegetables consumed at least once per week. To account for minor differences in the number of fruit and vegetable items administered at each follow-up cycle, we standardized our variety score to 30 (11 for fruit score and 19 for vegetable score). Potatoes, soy, or other legumes were not included in our analyses. Because the AHA does not consider fruit juice to be equivalent to whole fruit, fruit juice was also not included in our analyses. Quantity (servings/day) and variety in fruit and vegetable intake were correlated (r=0.68, P<0.0001). We, therefore, regressed variety on quantity to assess their independent effects on CHD risk. In multivariable analyses, after adjusting for dietary and non-dietary covariates, those in the highest fifth of fruit and vegetable intake (median intake=7.80 servings/day) had a 13% lower risk (95% CI, 0.79 to 0.95) of CHD compared to those in the lowest fifth (median intake=2.14 servings/day). Conversely, quantity-adjusted variety was not associated with CHD risk (RR for highest fifth compared to lowest fifth=1.04, 95% CI, 0.92 to 1.19). Further, within each category of quantity, higher variety was not associated with CHD risk. Our data suggest that absolute quantity, rather than variety, in fruit and vegetable intake is associated with a significantly lower risk of CHD. Future work should examine the role of variety in reducing biological markers of inflammation and endothelial dysfunction. Meanwhile, policy efforts should continue to focus on increasing overall fruit and vegetable intake.

Prevention of obesity should start as early as possible after birth. We aimed to build clinically useful equations estimating the risk of later obesity in newborns, as a first step towards focused early prevention against the global obesity epidemic.We analyzed the lifetime Northern Finland Birth Cohort 1986 (NFBC1986) (N = 4,032) to draw predictive equations for childhood and adolescent obesity from traditional risk factors (parental BMI, birth weight, maternal gestational weight gain, behaviour and social indicators), and a genetic score built from 39 BMI/obesity-associated polymorphisms. We performed validation analyses in a retrospective cohort of 1,503 Italian children and in a prospective cohort of 1,032 U.S. children.In the NFBC1986, the cumulative accuracy of traditional risk factors predicting childhood obesity, adolescent obesity, and childhood obesity persistent into adolescence was good: AUROC = 0·78[0·74-0.82], 0·75[0·71-0·79] and 0·85[0·80-0·90] respectively (all p<0·001). Adding the genetic score produced discrimination improvements ≤1%. The NFBC1986 equation for childhood obesity remained acceptably accurate when applied to the Italian and the U.S. cohort (AUROC = 0·70[0·63-0·77] and 0·73[0·67-0·80] respectively) and the two additional equations for childhood obesity newly drawn from the Italian and the U.S. datasets showed good accuracy in respective cohorts (AUROC = 0·74[0·69-0·79] and 0·79[0·73-0·84]) (all p<0·001). The three equations for childhood obesity were converted into simple Excel risk calculators for potential clinical use.This study provides the first example of handy tools for predicting childhood obesity in newborns by means of easily recorded information, while it shows that currently known genetic variants have very little usefulness for such prediction.

Introduction: Both sleep apnea and diabetes are strong cardiovascular disease (CVD) risk factors with substantial healthcare burden. It is hypothesized that intermittent hypoxemia and sleep fragmentation resulting from sleep apnea may contribute to diabetes through inflammation, insulin resistance and glucose intolerance. Conversely, pre-existing diabetes may promote sleep apnea development through increased abnormalities in autonomic nervous system activity and ventilatory control due to peripheral neuropathy, or through effects on inflammatory pathways. However, no population-based study has simultaneously evaluated the potential bidirectional association between these two highly prevalent disorders. Methods: We followed 161,824 participants from the Nurses' Health Study (NHS; 2002-2012), NHSII (1995-2013), and the Health Professional Follow-up Study (1996-2012) who were free of diabetes, CVD and cancer at baseline. Cox proportional hazards model was used to estimate hazard ratios (HR) for developing diabetes according to sleep apnea status. In parallel, we used similar approaches to estimate risk of developing sleep apnea according to diabetes status among 167,277 participants free of sleep apnea, CVD and cancer at baseline. In all 3 cohorts, diagnoses of diabetes or sleep apnea were identified by validated self-reports. Results: Similar results were observed across 3 cohorts. In the pooled analysis, 9,370 incident diabetes cases were identified during follow-up. After adjusting for age, sex, menopausal status in women, smoking, alcohol drinking, diet quality, physical activity, sleep duration, regular physical exams, and hypertension, the HR (95% CI) for diabetes was 2.28 (2.07, 2.51) comparing those with versus without sleep apnea. The association was attenuated but remained statistically significant after accounting for waist circumference (WC) and BMI (HR: 1.57; 95% CI: 1.42, 1.73). By contrast, we documented 9,409 incident sleep apnea cases during follow-up. Compared with those without diabetes, the multivariable HR (95% CI) for sleep apnea prior to adjustment for BMI and WC was 1.44 (1.25, 1.67) in individuals with diabetes. Although there was no overall association after the adjustment (HR: 1.04; 95% CI: 0.95, 1.14), an increased risk was observed among those with diabetes who used insulin compared with those without diabetes (HR: 1.38; 95% CI: 1.11, 1.72). Conclusions: Sleep apnea is independently associated with an increased risk of diabetes, whereas insulin-dependent diabetes is associated with a higher risk of sleep apnea. Clinical awareness of this bidirectional association may improve prevention and treatment of both diseases and reduce their adverse impact on CVD. Future research aimed at elucidating the mechanisms that underlie each association may identify novel intervention targets.

Abstract Light and moderate alcohol use has been reported to be associated with both impaired and enhanced cognition. The purpose of this study was to explore whether there was a linear relationship between visual memory and alcohol consumption in males and females in a large middle-aged birth cohort population in cross-sectional and longitudinal settings. Data were collected from 5585 participants completing 31-year (1997–1998) and 46-year (2012–2014) follow-ups including Paired Associate Learning (PAL) test at 46-years follow-up. The participants were originally from 12,231 study population of the Northern Finland Birth Cohort 1966 (NFBC1966). The PAL test was conducted to assess visual memory. Reported alcohol use was measured as total daily use of alcohol, beer, wine, and spirits converted into grams and as frequency and amount of use of beer, wine, and spirits. The total daily alcohol use was not associated with reduced visual memory. The frequency of use of beer and wine in males was associated with better visual memory in cross-sectional and longitudinal settings. Using six or more servings of spirits was associated with worse visual memory in males in cross-sectional and longitudinal settings. The study suggested a lack of a linear association between drinking and visual memory in the middle-aged population.

Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHypercrosslinked organic solids: preparation from poly(aromatic diacetylenes) and preliminary measurements of their Young's modulus, hardness, and thermal stabilityThomas X. Neenan, Matthew R. Callstrom, Louis M. Scarmoutzos, Kevin Randall Stewart, George M. Whitesides, and V. R. HowesCite this: Macromolecules 1988, 21, 12, 3525–3528Publication Date (Print):December 1, 1988Publication History Published online1 May 2002Published inissue 1 December 1988https://pubs.acs.org/doi/10.1021/ma00190a033https://doi.org/10.1021/ma00190a033research-articleACS PublicationsRequest reuse permissionsArticle Views229Altmetric-Citations45LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts