Dimerization and opposite base-dependent catalytic impairment of polymorphic S326C OGG1 glycosylase

Human 8-oxoguanine-DNA glycosylase (OGG1) is the major enzyme for repairing 8-oxoguanine (8-oxoG), a mutagenic guanine base lesion produced by reactive oxygen species (ROS). A frequently occurring OGG1 polymorphism in human populations results in the substitution of serine 326 for cysteine (S326C). The 326 C/C genotype is linked to numerous cancers, although the mechanism of carcinogenesis associated with the variant is unclear. We performed detailed enzymatic studies of polymorphic OGG1 and found functional defects in the enzyme. S326C OGG1 excised 8-oxoG from duplex DNA and cleaved abasic sites at rates 2- to 6-fold lower than the wild-type enzyme, depending upon the base opposite the lesion. Binding experiments showed that the polymorphic OGG1 binds DNA damage with significantly less affinity than the wild-type enzyme. Remarkably, gel shift, chemical cross-linking and gel filtration experiments showed that S326C both exists in solution and binds damaged DNA as a dimer. S326C OGG1 enzyme expressed in human cells was also found to have reduced activity and a dimeric conformation. The glycosylase activity of S326C OGG1 was not significantly stimulated by the presence of AP-endonuclease. The altered substrate specificity, lack of stimulation by AP-endonuclease 1 (APE1) and anomalous DNA binding conformation of S326C OGG1 may contribute to its linkage to cancer incidence

Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence

Metformin, an oral hypoglycemic agent, has been used for decades to treat type 2 diabetes mellitus. Recent studies indicate that mice treated with metformin live longer and have fewer manifestations of age-related chronic disease. However, the molecular mechanisms underlying this phenotype are unknown. Here, we show that metformin treatment increases the levels of the microRNA-processing protein DICER1 in mice and in humans with diabetes mellitus. Our results indicate that metformin upregulates DICER1 through a post-transcriptional mechanism involving the RNA-binding protein AUF1. Treatment with metformin altered the subcellular localization of AUF1, disrupting its interaction with DICER1 mRNA and rendering DICER1 mRNA stable, allowing DICER1 to accumulate. Consistent with the role of DICER1 in the biogenesis of microRNAs, we found differential patterns of microRNA expression in mice treated with metformin or caloric restriction, two proven life-extending interventions. Interestingly, several microRNAs previously associated with senescence and aging, including miR-20a, miR-34a, miR-130a, miR-106b, miR-125, and let-7c, were found elevated. In agreement with these findings, treatment with metformin decreased cellular senescence in several senescence models in a DICER1- dependent manner. Metformin lowered p16 and p21 protein levels and the abundance of inflammatory cytokines and oncogenes that are hallmarks of the senescence-associated secretory phenotype (SASP). These data lead us to hypothesize that changes in DICER1 levels may be important for organismal aging and to propose that interventions that upregulate DICER1 expression (e.g., metformin) may offer new pharmacotherapeutic approaches for age-related disease

Neighborhood crime is differentially associated with cardiovascular risk factors as a function of race and sex

Background: Neighborhood crime may be an important factor contributing to cardiovascular health disparities, and these relations may vary by race and sex. The present investigation evaluated (a) potential differential associations between neighborhood crime and cardiovascular disease (CVD) risk factors within subgroups of African American (AA) and White men and women, and (b) potential mediation by negative affect. Design and Methods: Participants were 1,718 AAs and Whites (58% AA; 54% female; 59% above poverty; ages 30-64 years) living in Baltimore, Maryland who completed the first wave of the Healthy Aging in Neighborhoods of Diversity across the Life Span study from 2004-2009. CVD risk factors included body mass index, total serum cholesterol, glucose, and systolic and diastolic blood pressure. A negative affect composite was comprised of self-reported depression, anxiety, anger, vigilance, and perceived stress. Hierarchical multiple regression analyses were used to examine associations between per capita overall and violent crime rates, negative affect, and CVD risk factors. Results: There were significant associations of greater overall crime rate with higher fasting glucose (b=.192, P<0.05), and greater violent crime rate with higher systolic (b=86.50, P<0.05) and diastolic (b=60.12, P<0.05) blood pressure in AA women, but not men. These associations were not explained by negative affect. In Whites, there were no significant associations of overall or violent crime rates with cardiovascular risk factors. Conclusions: AA women may be particularly vulnerable to the negative impact of crime on cardiovascular risk. Preventative efforts aimed toward this group may help to deter the detrimental effects that living in a high crime area may have on one’s cardiovascular health

The Bolocam Galactic Plane Survey. XIV. Physical Properties of Massive Starless and Star Forming Clumps

We sort $4683$ molecular clouds between $10^\circ< \ell <65^\circ$ from the Bolocam Galactic Plane Survey based on observational diagnostics of star formation activity: compact $70$ $\mu{\rm m}$ sources, mid-IR color-selected YSOs, ${\rm H_2O}$ and ${\rm CH_3OH}$ masers, and UCHII regions. We also present a combined ${\rm NH_3}$-derived gas kinetic temperature and ${\rm H_2O}$ maser catalog for $1788$ clumps from our own GBT 100m observations and from the literature. We identify a subsample of $2223$ ($47.5\%$) starless clump candidates, the largest and most robust sample identified from a blind survey to date. Distributions of flux density, flux concentration, solid angle, kinetic temperature, column density, radius, and mass show strong ($>1$ dex) progressions when sorted by star formation indicator. The median starless clump candidate is marginally sub-virial ($\alpha \sim 0.7$) with $>75\%$ of clumps with known distance being gravitationally bound ($\alpha < 2$). These samples show a statistically significant increase in the median clump mass of $\Delta M \sim 170-370$ M$_\odot$ from the starless candidates to clumps associated with protostars. This trend could be due to (i) mass growth of the clumps at $\dot{M}\sim200-440$ Msun Myr$^{-1}$ for an average free-fall $0.8$ Myr time-scale, (ii) a systematic factor of two increase in dust opacity from starless to protostellar phases, (iii) and/or a variation in the ratio of starless to protostellar clump lifetime that scales as $\sim M^{-0.4}$. By comparing to the observed number of ${\rm CH_3OH}$ maser containing clumps we estimate the phase-lifetime of massive ($M>10^3$ M$_\odot$) starless clumps to be $0.37 \pm 0.08 \ {\rm Myr} \ (M/10^3 \ {\rm M}_\odot)^{-1}$; the majority ($M<450$ M$_\odot$) have phase-lifetimes longer than their average free-fall time.Comment: Accepted for publication in ApJ; 33 pages; 22 figures; 7 table

Protective Effects of BDNF against C-Reactive Protein-Induced Inflammation in Women

Background. Since high sensitivity C-reactive protein (hsCRP) is predictive of cardiovascular events, it is important to examine the relationship between hsCRP and other inflammatory and oxidative stress markers linked to cardiovascular disease (CVD) etiology. Previously, we reported that hsCRP induces the oxidative stress adduct 8-oxo-7,8-dihydro-2 ὔ deoxyguanosine (8-oxodG) and that these markers are significantly associated in women. Recent data indicates that brain-derived neurotrophic factor (BDNF) may have a role in CVD. Methods and Results. We examined BDNF levels in 3 groups of women that were age-and race-matched with low (&lt;3 mg/L), mid (&gt;3-20 mg/L), and high (&gt;20 mg/L) hsCRP ( = 39 per group) and found a significant association between hsCRP, BDNF, and 8-oxodG. In African American females with high hsCRP, increases in BDNF were associated with decreased serum 8-oxodG. This was not the case in white women where high hsCRP was associated with high levels of BDNF and high levels of 8-oxodG. BDNF treatment of cells reduced CRP levels and inhibited CRP-induced DNA damage. Conclusion. We discovered an important relationship between hsCRP, 8-oxodG, and BDNF in women at hsCRP levels &gt;3 mg/L. These data suggest that BDNF may have a protective role in counteracting the inflammatory effects of hsCRP

Hierarchical Star Formation in Nearby LEGUS Galaxies

Hierarchical structure in ultraviolet images of 12 late-type LEGUS galaxies is studied by determining the numbers and fluxes of nested regions as a function of size from ~1 to ~200 pc, and the number as a function of flux. Two starburst dwarfs, NGC 1705 and NGC 5253, have steeper number-size and flux-size distributions than the others, indicating high fractions of the projected areas filled with star formation. Nine subregions in 7 galaxies have similarly steep number-size slopes, even when the whole galaxies have shallower slopes. The results suggest that hierarchically structured star-forming regions several hundred parsecs or larger represent common unit structures. Small galaxies dominated by only a few of these units tend to be starbursts. The self-similarity of young stellar structures down to parsec scales suggests that star clusters form in the densest parts of a turbulent medium that also forms loose stellar groupings on larger scales. The presence of super star clusters in two of our starburst dwarfs would follow from the observed structure if cloud and stellar subregions more readily coalesce when self-gravity in the unit cell contributes more to the total gravitational potential.Comment: 9 pages, 4 figures, accepted for ApJ

Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes

OBJECTIVE: Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin. RESEARCH DESIGN AND METHODS: C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2) C-peptide positive, with low stimulated values ≥0.017 but <0.2 nmol/L; and 3) C-peptide <0.017 nmol/L. Longitudinal samples were analyzed from C-peptide-positive subjects with diabetes after 1, 2, and 4 years. RESULTS: Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (<0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (<0.017 nmol/L) residual C-peptide. CONCLUSIONS: In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide

Highly phosphorescent perfect green emitting iridium(III) complex for application in OLEDs

A novel iridium complex, [bis-(2-phenylpyridine)(2-carboxy-4-dimethylaminopyridine)iridium(III)] (N984), was synthesized and characterized using spectroscopic and electrochemical methods; a solution processable OLED device incorporating the N984 complex displays electroluminescence spectra with a narrow bandwidth of 70 nm at half of its intensity, with colour coordinates of x = 0.322; y = 0.529 that are very close to those suggested by the PAL standard for a green emitter.Bolink, Henk, [email protected] ; Coronado Miralles, Eugenio, [email protected] ; Garcia Santamaria, Sonsoles Amor, [email protected]