Height at Late Adolescence and Incident Diabetes among Young Men

Background

Short stature was suggested as a risk factor for diabetes onset among middle age individuals, but whether this is the case among young adults is unclear. Our goal was to assess the association between height and incident diabetes among young men.

Methods and Findings

Incident diabetes was assessed among 32,055 men with no history of diabetes, from the prospectively followed young adults of the MELANY cohort. Height was measured at two time points; at adolescence (mean age 17.4±0.3 years) and grouped according to the US-CDC percentiles and at young adulthood (mean age 31.0±5.6 years). Cox proportional hazards models were applied. There were 702 new cases of diabetes during a mean follow-up of 6.3±4.3 years. There was a significant increase in the crude diabetes incidence rate with decreasing adolescent height percentile, from 4.23 cases/10⁴ person-years in the <10^th percentile group to 2.44 cases/10⁴ person-years in the 75^th≤ percentile group. These results persisted when clinical and biochemical diabetes risk factors were included in multivariable models. Compared to the 75^th≤ percentile group, height below the 10^th percentile was associated with a hazard ratio (HR) of 1.64 (95%CI 1.09–2.46, p = 0.017) for incident diabetes after adjustment for age, body mass index (BMI), fasting plasma glucose, HDL-cholesterol and triglyceride levels, white blood cells count, socioeconomic status, country of origin, family history of diabetes, sleep quality and physical activity. At age 30 years, each 1-cm decrement in adult height was associated with a 2.5% increase in diabetes adjusted risk (HR 1.025, 95%CI 1.01–1.04, p = 0.001).

Conclusions

Shorter height at late adolescence or young adulthood was associated with an increased risk of incident diabetes among young men, independent of BMI and other diabetes risk factors.     

Preclinical study of the long-range safety and anti-inflammatory effects of high-dose oral meglumine

Meglumine is a methylamino derivative of sorbitol that is an approved drug excipient. Recent preclinical studies suggest that administration of high-dose oral meglumine can exert beneficial medicinal effects to treat diabetes, obesity, and fatty liver disease (NAFLD/nonalcoholic steatohepatitis [NASH]). Here we address gaps in knowledge about the pharmacology and toxicology of this substance administered at high concentrations to explore its medicinal potential. We observed that high-dose meglumine limited secretion of proinflammatory cytokines and cell adhesion molecules from activated human THP-1 or murine RAW264.7 monocytes. Preclinical pharmacokinetic analysis in Swiss mice confirmed that meglumine was orally available. Informed by this data, oral doses of 18 to 75 mM meglumine were administered ad libitum in the drinking water of Sprague-Dawley rats and two cohorts of C57BL/6 mice housed in different vivariums. In a 32-week study, urinary isoprostane levels trended lower in subjects consistent with the possibility of anti-inflammatory effects. In full lifespan studies, there was no detrimental effect on longevity. Heart function evaluated in C57BL/6 mice using an established noninvasive cardiac imaging system showed no detrimental effects on ejection fraction, fractional shortening, left ventricle function or volume, and cardiac output in mice up to 15-month old, with a potential positive trend in heart function noted in elderly mice consistent with earlier reported benefits on muscle stamina. Finally, in a transgenic model of inflammation-associated skin carcinogenesis, the incidence, number, and growth of skin tumors trended lower in subjects receiving meglumine. Overall, the evidence obtained illustrating the long-range safety of high-dose oral meglumine support the rationale for its evaluation as a low-cost modality to limit diabetes, hypertriglyceridemia, and NAFLD/NASH.     

Chemistry and Microbial Functional Diversity Differences in Biofuel Crop and Grassland Soils in Multiple Geographies

We obtained soil samples from geographically diverse switchgrass (Panicum virgatum L.) and sorghum (Sorghum bicolor L.) crop sites and from nearby reference grasslands and compared their edaphic properties, microbial gene diversity and abundance, and active microbial biomass content. We hypothesized that soils under switchgrass, a perennial, would be more similar to reference grassland soils than sorghum, an annual crop. Sorghum crop soils had significantly higher NO₃ ^? -N, NH₄ ⁺ -N, SO₄ ^2? -S, and Cu levels than grassland soils. In contrast, few significant differences in soil chemistry were observed between switchgrass crop and grassland soils. Active bacterial biomass was significantly lower in sorghum soils than switchgrass soils. Using GeoChip 4.0 functional gene arrays, we observed that microbial gene diversity was significantly lower in sorghum soils than grassland soils. Gene diversity at sorghum locations was negatively correlated with NO₃ ^? -N, NH₄ ⁺ -N, and SO₄ ^2? -S in C and N cycling microbial gene categories. Microbial gene diversity at switchgrass sites varied among geographic locations, but crop and grassland sites tended to be similar. Microbial gene abundance did not differ between sorghum crop and grassland soils, but was generally lower in switchgrass crop soils compared to grassland soils. Our results suggest that switchgrass has fewer adverse impacts on microbial soil ecosystem services than cultivation of an annual biofuel crop such as sorghum. Multi-year, multi-disciplinary regional studies comparing these and additional annual and perennial biofuel crop and grassland soils are recommended to help define sustainable crop production and soil ecosystem service practices.     

Establishment of transgenic herbicide-resistant creeping bentgrass (Agrostis stolonifera L.) in nonagronomic habitats

Concerns about genetically modified (GM) crops include transgene flow to compatible wild species and unintended ecological consequences of potential transgene introgression. However, there has been little empirical documentation of establishment and distribution of transgenic plants in wild populations. We present herein the first evidence for escape of transgenes into wild plant populations within the USA; glyphosate-resistant creeping bentgrass (Agrostis stolonifera L.) plants expressing CP4 EPSPS transgenes were found outside of cultivation area in central Oregon. Resident populations of three compatible Agrostis species were sampled in nonagronomic habitats outside the Oregon Department of Agriculture control area designated for test production of glyphosate-resistant creeping bentgrass. CP4 EPSPS protein and the corresponding transgene were found in nine A. stolonifera plants screened from 20,400 samples (0.04 +/- 0.01% SE). CP4 EPSPS-positive plants were located predominantly in mesic habitats downwind and up to 3.8 km beyond the control area perimeter; two plants were found within the USDA Crooked River National Grassland. Spatial distribution and parentage of transgenic plants (as confirmed by analyses of nuclear ITS and chloroplast matK gene trees) suggest that establishment resulted from both pollen-mediated intraspecific hybridizations and from crop seed dispersal. These results demonstrate that transgene flow from short-term production can result in establishment of transgenic plants at multi-kilometre distances from GM source fields or plants. Selective pressure from direct application or drift of glyphosate herbicide could enhance introgression of CP4 EPSPS transgenes and additional establishment. Obligatory outcrossing and vegetative spread could further contribute to persistence of CP4 EPSPS transgenes in wild Agrostis populations, both in the presence or absence of herbicide selection.     

Activated monocytes resist elimination by retinal pigment epithelium and downregulate their OTX2 expression via TNF‐α

Orthodenticle homeobox 2 (OTX2) controls essential, homeostatic retinal pigment epithelial (RPE) genes in the adult. Using cocultures of human CD14⁺ blood monocytes (Mos) and primary porcine RPE cells and a fully humanized system using human‐induced pluripotent stem cell‐derived RPE cells, we show that activated Mos markedly inhibit RPEOTX2 expression and resist elimination in contact with the immunosuppressive RPE. Mechanistically, we demonstrate that TNF‐α, secreted from activated Mos, mediates the downregulation of OTX2 and essential RPE genes of the visual cycle among others. Our data show how subretinal, chronic inflammation and in particular TNF‐α can affect RPE function, which might contribute to the visual dysfunctions in diseases such as age‐related macular degeneration (AMD) where subretinal macrophages are observed. Our findings provide important mechanistic insights into the regulation of OTX2 under inflammatory conditions. Therapeutic restoration of OTX2 expression might help revive RPE and visual function in retinal diseases such as AMD.     

Seedling responses of four Australian tree species to toxic concentrations of manganese in solution culture

Little is known about the responses of Australian plants to excess metal, including Mn. It is important to remedy this lack of information so that knowledgeable decisions can be made about managing Mn contaminated sites where inhabited by Australian vegetation. Acacia holosericea, Melaleuca leucadendra, Eucalyptus crebra and Eucalyptus camaldulensis were grown in dilute solution culture for 10 weeks. The seedlings (42 days old) were exposed to six Mn treatments viz., 1, 8, 32, 128, 512 and 2048 M. The order of tolerance to toxic concentrations of Mn was A. holosericea E. crebra < M. leucadendra < E. camaldulensis, the critical external concentrations being approximately 5.1, 5.0, 21 and 330 M, respectively. The critical tissue Mn concentrations for the youngest fully expanded leaf and total shoots were, respectively, 265 and 215 g g^–1 DM for A. holosericea, 445 and 495 g g^–1 DM for M. leucadendra, 495 and 710 g g^–1 DM for E. crebra and 7230 and 6510 g g^–1 DM for E. camaldulensis. The high tolerance of E. camaldulensis (as opposed to the sensitivity of E. crebra) to excess Mn raises concern about fauna feeding on the plant and is consistent with hypotheses suggesting the Eucalyptus subgenus Symphomyrtus is particularly tolerant of stress, including excess Mn. The results from this paper provide the first comprehensive combination of growth responses, critical external concentrations, critical tissue concentrations and plant toxicity symptoms for three important Australian genera, viz., Eucalyptus, Acacia and Melaleuca, for use in the management of Mn toxic sites.     

RNA binding and phosphorylation determine the intracellular distribution of nuclear factors 90 and 110

Members of the nuclear factor 90 (NF90) family of human double-stranded RNA (dsRNA) binding proteins are phosphorylated and translocate into the cytoplasm with the onset of mitosis. We investigated the mechanism of translocation for NF90 and NF110, its larger splice variant. During interphase, NF90 is predominantly nuclear, NF110 is exclusively nuclear, and both are bound to RNA. About half of the NF90 is tethered in the nucleus by RNA bound to the protein's dsRNA-binding motifs. The nuclear localization of NF110 is also dependent on RNA binding but is independent of these motifs, and is governed by contacts made to the protein's unique C terminus. During mitosis, about half of the cytoplasmic NF90 becomes dissociated from RNA, but phosphorylation does not impair the binding affinity of either NF90 or NF110 for dsRNA. We conclude that NF90 and NF110 engage RNA differentially and translocate from the nucleus to the cytoplasm in mitosis because phosphorylation disturbs their interactions with other nuclear proteins.     

A study of spin-probe solubility in mitochondrial membranes correlated with ATP-dependent conformational changes

Addition of ATP to submitochondrial particles causes considerable changes in the ESR spectra of hydrophobic spin-probe bound to particles which indicate an improvement in probe solubilization in the submitochondrial particle membranes due to energization. This effect is abolished by 2,4-dinitrophenol (10^-4 M) and oligomycin (I μg/mg of protein). At lower concentrations (0.1–0.2 μg/mg), oligomycin, on the contrary, promotes the action of ATP on the submitochondrial particle-bound spinprobe ESR spectra as well as activates the ATP-dependent transhydrogenase reaction in submitochondrial particles.