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Nerve growth factor (NGF) promotes growth, differentiation, and survival of sensory neurons in the mammalian nervous system. Little is known about how NGF elicits faster axon outgrowth or how growth cones integrate and transform signal input to motor output. Using cultured mouse dorsal root ganglion neurons, we found that myosin II (MII) is required for NGF to stimulate faster axon outgrowth. From experiments inducing loss or gain of function of MII, specific MII isoforms, and vinculin-dependent adhesion-cytoskeletal coupling, we determined that NGF causes decreased vinculin-dependent actomyosin restraint of microtubule advance. Inhibition of MII blocked NGF stimulation, indicating the central role of restraint in directed outgrowth. The restraint consists of myosin IIB- and IIA-dependent processes: retrograde actin network flow and transverse actin bundling, respectively. The processes differentially contribute on laminin-1 and fibronectin due to selective actin tethering to adhesions. On laminin-1, NGF induced greater vinculin-dependent adhesion–cytoskeletal coupling, which slowed retrograde actin network flow (i.e., it regulated the molecular clutch). On fibronectin, NGF caused inactivation of myosin IIA, which negatively regulated actin bundling. On both substrates, the result was the same: NGF-induced weakening of MII-dependent restraint led to dynamic microtubules entering the actin-rich periphery more frequently, giving rise to faster elongation.

In Brief Study Design. A cross-sectional imaging study of young adults. Objective. To investigate the prevalence of disc degeneration (DD) and displacement, anular tears, and Modic changes in lumbar magnetic resonance imaging (MRI) among young adults. Summary of Background Data. Although low back pain in young adulthood is common, the prevalence of spinal MRI findings at this age remains virtually unknown. Methods. The study population was a subcohort of the Northern Finland Birth Cohort 1986. Subjects living within 100 km of Oulu (n = 874) were invited to participate in lumbar MRI at 20 to 22 years of age (mean: 21.2 years). Degree of DD, type of Modic changes, and presence of disc bulges, herniations, high intensity zone (HIZ) lesions, and radial tears at all lumbar levels were assessed. Results. Three hundred twenty-five women and 233 men (n = 558) attended the MR imaging. DD was significantly more frequent in men (54% vs. 42%, P = 0.005), as was multiple DD (21% vs. 14%, P = 0.036). The prevalences of disc bulges and radial tears were 25% and 9.1%, respectively, without gender differences. HIZ lesions were more common among women than men (8.6% vs. 4.3%, P = 0.046), whereas herniations were significantly more common among men (5.6% vs. 2.5%, P = 0.047). Only 2 disc extrusions were observed, one in each gender. All degenerative disc findings were more common at the L5–S1 level except HIZ lesions, which were most likely at L4–L5. The prevalence of the Modic changes was 1.4%, without gender difference, type I being more common than type II. Typically, Modic changes were located adjacent to a DD Grade 4 disc and at the 2 lowest levels. Conclusion. Almost half of young Finnish adult aged 21 years had at least one degenerated disc, and a quarter had a bulging disc. Modic changes and disc herniations were, however, relatively rare. We found disc degeneration and bulging to be common in the lumbar spine of 21-year-old Finnish man, whereas Modic changes and herniations were rare at this age. A significant gender difference was observed in prevalences of disc degeneration, herniations, and high intensity zone lesions.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTFormation of monolayer films by the spontaneous assembly of organic thiols from solution onto goldColin D. Bain, E. Barry Troughton, Yu Tai Tao, Joseph Evall, George M. Whitesides, and Ralph G. NuzzoCite this: J. Am. Chem. Soc. 1989, 111, 1, 321–335Publication Date (Print):January 1, 1989Publication History Published online1 May 2002Published inissue 1 January 1989https://pubs.acs.org/doi/10.1021/ja00183a049https://doi.org/10.1021/ja00183a049research-articleACS PublicationsRequest reuse permissionsArticle Views19008Altmetric-Citations2931LEARN 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-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

Charge ladders of bovine carbonic anhydrase II, hen egg-white lysozyme, and bovine pancreatic trypsin inhibitor, prepared by partial acetylation of primary amino groups on the surface of the protein, have been analyzed by capillary electrophoresis (CE) and on-line electrospray ionization mass spectrometry (ESIMS) using solution conditions that maintain the native structure of the protein. CE was used to separate the proteins that constitute the charge ladder into individual "rungs"protein derivatives that have the same number of acetylated amino groups and approximately the same net charge in solution. ESI was used to produce ions in the gas phase of the proteins that constitute each rung of the charge ladder; the mass spectra of these ions were obtained and analyzed. The distributions in charge states observed in the gas phase for the groups of proteins comprising each rung of the charge ladders were narrow, consistent with the retention of a compact structure of the proteins in the gas phase, and substantially independent of the number of acetylated amino groups. The ions observed in the gas phase had surface charge densities in a relatively narrow range of ∼0.9−1.5 units of charge per 103 Å2 of surface area (as estimated from crystallographic structures). These results demonstrate that the distribution of charge states for proteins produced in the gas phase by ESI do not necessarily reflect the net charge of the protein in solution or the number of amino groups on the protein.

Background While recent literature has highlighted the importance of early childhood development for later life outcomes, comparatively little is known regarding the relative importance of early physical and cognitive development in predicting educational attainment cross-culturally. Methods We used prospective data from three birth cohorts: the Northern Finland Birth Cohort of 1986 (NFBC1986), the 1970 British Cohort Study (BCS1970), and the Cebu Longitudinal Health and Nutrition Survey of 1983 (CLHNS) to assess the association of height-for-age z-score (HAZ) and cognitive development measured prior to age 8 with schooling attainment. Multivariate linear regression models were used to estimate baseline and adjusted associations. Results Both physical and cognitive development were highly predictive of adult educational attainment conditional on parental characteristics. The largest positive associations between physical development and schooling were found in the CLHNS (β = 0.53, 95%-CI: [0.32, 0.74]) with substantially smaller associations in the BCS1970 (β = 0.10, 95% CI [0.04, 0.16]) and the NFBC1986 (β = 0.06, 95% CI [-0.05, 0.16]). Strong associations between cognitive development and educational attainment were found for all three cohorts (NFBC1986: β = 0.22, 95%-CI: [0.12, 0.31], BCS1970: β = 0.58, 95%-CI: [0.52, 0.64], CLHNS: β = 1.08, 95%-CI: [0.88, 1.27]). Models jointly estimating educational associations of physical and cognitive development demonstrated weaker associations for physical development and minimal changes for cognitive development. Conclusion The results indicate that although physical and cognitive early development are both important predictors of educational attainment, cognitive development appears to play a particularly important role. The large degree of heterogeneity in the observed effect sizes suggest that the importance of early life physical growth and cognitive development is highly dependent on socioeconomic and institutional contexts.

Abstract Background Red meat is a nutrient‐dense source of protein fundamental for older adults; however, red meat is also high in detrimental components, including saturated fat. It is unclear whether habitual red meat consumption is associated with risk of frailty. This study aimed to examine the prospective association between the consumption of total, unprocessed, and processed red meat and the risk of frailty in older adults. Methods We analysed data from 85 871 women aged ≥60 participating in the Nurses' Health Study. Consumption of total, unprocessed, and processed red meat was obtained from repeated food frequency questionnaires administered between 1980 and 2010. Frailty was defined as having at least three of the following five criteria from the FRAIL scale: fatigue, low strength, reduced aerobic capacity, having ≥5 chronic illnesses, and unintentional weight loss ≥5%. The occurrence of frailty was assessed every four years from 1992 to 2014. Results During 22 years of follow‐up (median follow‐up 14 years), we identified 13 279 incident cases of frailty. Women with a higher intake of red meat showed an increased risk of frailty after adjustment for lifestyle factors, medication use, and dietary factors. The relative risk (95% confidence interval) for one serving/day increment in consumption was 1.13 (1.08, 1.18) for total red meat, 1.08 (1.02, 1.15) for unprocessed red meat, and 1.26 (1.15, 1.39) for processed red meat. When each component of the frailty syndrome was individually examined, each of them was positively associated with total red meat consumption, except for the weight loss criterion. Replacing one serving/day of unprocessed red meat with other protein sources was associated with significantly lower risk of frailty; the risk reduction estimates were 22% for fish and 14% for nuts, while for replacement of processed red meat, the percentages were 33% for fish, 26% for nuts, 13% for legumes, and 16% for low‐fat dairy. Conclusions Habitual consumption of unprocessed and processed red meat was associated with a higher risk of frailty. Replacement of red meat by other protein sources might reduce the risk of frailty. These findings are in line with dietary guidelines promoting diets that emphasize plant‐based sources of protein.

Background and Purpose— Many foods have been suggested to influence the risk of stroke. However, no previous studies have examined the relationship between overall dietary patterns and risk of stroke. Methods— Using dietary information collected in 1984 from 71 768 women aged 38 to 63 years without a history of cardiovascular disease or diabetes in 1984, we conducted factor analysis and identified 2 major dietary patterns: “prudent” and “Western.” We calculated scores for each participant for each pattern and prospectively examined their associations with stroke risk using a proportional hazard model, adjusting for other stroke risk factors. Results— The prudent pattern was characterized by higher intakes of fruits, vegetables, legumes, fish, and whole grains, whereas the Western pattern by higher intakes of red and processed meats, refined grains, and sweets and desserts. During 14 years of follow-up, we identified 791 incidents of stroke, with 476 ischemic and 189 hemorrhagic strokes. After adjusting for potential confounders, we observed a relative risk (RR) of 1.58 (95% CI, 1.15 to 2.15; P =0.0002 for trend) for total strokes and 1.56 (95% CI, 1.05 to 2.33; P =0.02 for trend) for ischemic stroke when comparing the highest with lowest quintiles of the Western pattern. For the prudent pattern, the RRs comparing extreme quintiles were 0.78 (95% CI, 0.61 to 1.01) for total stroke and 0.74 (95% CI, 0.54 to 1.02) for ischemic stroke. Conclusions— These data suggest that a dietary pattern typified by higher intakes of red and processed meats, refined grains, and sweets and desserts may increase stroke risk, whereas a diet higher in fruits and vegetables, fish, and whole grains may protect against stroke.

Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.

Background Obesity and pandemic vitamin D (vitD) deficiency both share similar pathological associations with adipose tissue chronic inflammation leading to well‐known conditions such as insulin resistance and hypertension. Understanding adipogenesis is of major relevance for human health, as increased adiposity leads to cellular hypoxia followed by inflammation, oxidative damage and adipocyte dysfunction resulting in metabolic diseases. We have shown earlier that vitD supplementation has significant beneficial effects on adipocyte inflammation and improved insulin sensitivity in vitD deficient mice. The modulation of adipogenesis under these circumstances might be beneficial in improving its metabolic functioning. Therefore, we hypothesize that vitD modulates adipogenesis in pathological conditions (hypoxia). Methods Human mesenchymal stem cells (hMSCs) were differentiated into adipocytes ± vitD [10 −7 M] containing adipogenic induction and maintenance medium under either hypoxic (1% O2) or normoxic (21% O2) conditions. At the end of differentiation cycles the process was assessed by the oil red O staining of the adipocytes. Fully differentiated adipocytes were stimulated with lipopolysaccharide (LPS 10 ng/ml) ± vitD [10 −7 M] for 24 hrs and cells and cell culture supernatants were collected from both hypoxic and normoxic basal ± vitD [10 −7 M] as well LPS stimulated ± vitD [10 −7 M]. The inflammatory marker interleukin‐6 (IL‐6) levels were measured by ELISA. RNA and cell lysate were prepared and analyzed for adipogenic, hypoxic and inflammation regulating proteins. Results The adipogenic differentiation of hMSCs under hypoxia was significantly inhibited in comparison to the normoxia. VitD [10 −9 M to 10 −7 M] significantly enhanced adipogenic differentiations dose dependently under both hypoxic and normoxic culture conditions. VitD [10 −7 M] inhibited basal IL‐6 secretion by 83% in hypoxic and 66% in normoxic hMSCs differentiated adipocytes in comparison to their respective controls (p<0.05). In addition, vitD dose dependently reduced LPS induced IL‐6 secretion from hMSCs differentiated adipocytes under both hypoxic (10 −7 M:10 −8 M:10 −7 M; 66%:40%:19%) and normoxic (10 −7 M:10 −8 M:10 −7 M; 56%:44%:2%) condition in comparison with the LPS 10 ng/ml alone. Conclusion Our data demonstrates that vitD enhances the adipogensis of hMSCs under hypoxic culture condition; it inhibits basal IL‐6 release as well LPS induced IL‐6 release under both hypoxia and normoxia. This suggests that sufficient vitD levels would be able to modulate the hypoxia induced inflammation and adipogenic differentiation potential in obese subjects. These vitD actions might therefore partially mediate the beneficial effect on insulin sensitivity of adipose tissue and reduce the risk of known co‐morbidities of obesity. Support or Funding Information Supported in part by the Academy of Finland and DynaHEALTH EU No.633595

Short-term sleep restriction results in impaired glucose tolerance. To test whether habitually short sleep duration increases the risk of developing diabetes, we studied a cohort of 70,026 women enrolled in the Nurses Health Study, without diabetes at baseline, and who responded to a question about daily sleep duration in 1986. Subjects were followed until 1996 for the diagnosis of diabetes (1,969 cases). Long and short sleep durations were associated with an increased risk of diabetes diagnosis. The relative risks (RRs) for short (slept ≤5 h per day) and long (slept ≥9 h per day) sleepers were 1.57 (95% CI 1.28–1.92) and 1.47 (1.19–1.80), respectively. After adjustment for BMI and a variety of confounders, the RR was not significantly increased for short sleepers (1.18 [0.96–1.44]) but remained modestly increased for long sleepers (1.29 [1.05–1.59]). We then performed a similar analysis using only symptomatic cases (n = 1,187). Adjusted RRs for symptomatic diabetes were modestly elevated in both short (1.34 [1.04–1.72]) and long (1.35 [1.04–1.75]) sleepers. Our data suggest that the association between a reduced self-reported sleep duration and diabetes diagnosis could be due to confounding by BMI, or sleep restriction may mediate its effects on diabetes through weight gain. Sleep restriction may be an independent risk factor for developing symptomatic diabetes.

BACKGROUND: High alcohol consumption is a major cause of morbidity, yet alcohol is associated with both favourable and adverse effects on cardiometabolic risk markers. We aimed to characterize the associations of usual alcohol consumption with a comprehensive systemic metabolite profile in young adults. METHODS: Cross-sectional associations of alcohol intake with 86 metabolic measures were assessed for 9778 individuals from three population-based cohorts from Finland (age 24-45 years, 52% women). Metabolic changes associated with change in alcohol intake during 6-year follow-up were further examined for 1466 individuals. Alcohol intake was assessed by questionnaires. Circulating lipids, fatty acids and metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. RESULTS: Increased alcohol intake was associated with cardiometabolic risk markers across multiple metabolic pathways, including higher lipid concentrations in HDL subclasses and smaller LDL particle size, increased proportions of monounsaturated fatty acids and decreased proportion of omega-6 fatty acids, lower concentrations of glutamine and citrate (P < 0.001 for 56 metabolic measures). Many metabolic biomarkers displayed U-shaped associations with alcohol consumption. Results were coherent for men and women, consistent across the three cohorts and similar if adjusting for body mass index, smoking and physical activity. The metabolic changes accompanying change in alcohol intake during follow-up resembled the cross-sectional association pattern (R2 = 0.83, slope = 0.72 ± 0.04). CONCLUSIONS: Alcohol consumption is associated with a complex metabolic signature, including aberrations in multiple biomarkers for elevated cardiometabolic risk. The metabolic signature tracks with long-term changes in alcohol consumption. These results elucidate the double-edged effects of alcohol on cardiovascular risk.