HE WOMEN'S HEALTH INITIAtive (WHI) trial of estrogen plus progestin was a randomized, controlled, double-blind trial designed to determine the effects of estrogen plus progestin compared with placebo on a number of important chronic diseases of older women. 1 After an average follow-up of 5.2 years, the trial was stopped early because of safety concerns. Hip and clinical vertebral fractures were significantly reduced by 34% and total osteoporotic fractures by 24%. However, the overall risk-benefit profile of estrogen plus progestin, summarized in a global index, was not consis-tent with a viable intervention for primary prevention of chronic diseases in postmenopausal women.This article provides an updated final analysis of fracture end points Author Affiliations, Financial Disclosures, and Women's Health Initiative investigators are listed at the end of this article.

Differences in breast cancer incidence rates between most racial/ethnic groups were largely explained by risk factor distribution except in African Americans. However, breast cancers in African American women more commonly had characteristics of poor prognosis, which may contribute to their increased mortality after diagnosis.

Background/ObjectivesPhysical activity (PA) protects against a wide range of diseases. Habitual PA appears to be heritable, motivating the search for specific genetic variants that may inform efforts to promote PA and target the best type of PA for each individual.Subjects/MethodsWe used data from the UK Biobank to perform the largest genome-wide association study of PA to date, using three measures based on self-report (nmax=377,234) and two measures based on wrist-worn accelerometry data (nmax=91,084). We examined genetic correlations of PA with other traits and diseases, as well as tissue-specific gene expression patterns. With data from the Atherosclerosis Risk in Communities (ARIC; n=8,556) study, we performed a meta-analysis of our top hits for moderate-to-vigorous PA (MVPA).ResultsWe identified ten loci across all PA measures that were significant in both a basic and a fully adjusted model (p<5 × 10−9). Upon meta-analysis of the nine top hits for MVPA with results from ARIC, eight were genome-wide significant. Interestingly, among these, the rs429358 variant in the APOE gene was the most strongly associated with MVPA, whereby the allele associated with higher Alzheimer’s risk was associated with greater MVPA. However, we were not able to rule out possible selection bias underlying this result. Variants in CADM2, a gene previously implicated in obesity, risk-taking behavior and other traits, were found to be associated with habitual PA. We also identified three loci consistently associated (p<5 × 10−5) with PA across both self-report and accelerometry, including CADM2. We find genetic correlations of PA with educational attainment, chronotype, psychiatric traits, and obesity-related traits. Tissue enrichment analyses implicate the brain and pituitary gland as locations where PA-associated loci may exert their actions.ConclusionsThese results provide new insight into the genetic basis of habitual PA, and the genetic links connecting PA with other traits and diseases.

Increased aerobic glycolysis and oxidative stress are important features of cancer cell metabolism, but the underlying biochemical and molecular mechanisms remain elusive. Using a tetracycline inducible model, we show that activation of K-rasG12V causes mitochondrial dysfunction, leading to decreased respiration, elevated glycolysis, and increased generation of reactive oxygen species. The K-RAS protein is associated with mitochondria, and induces a rapid suppression of respiratory chain complex-I and a decrease in mitochondrial transmembrane potential by affecting the cyclosporin-sensitive permeability transition pore. Furthermore, pre-induction of K-rasG12V expression in vitro to allow metabolic adaptation to high glycolytic metabolism enhances the ability of the transformed cells to form tumor in vivo. Our study suggests that induction of mitochondrial dysfunction is an important mechanism by which K-rasG12V causes metabolic changes and ROS stress in cancer cells, and promotes tumor development.

A new series of starburst triarylamine fluorophores SBCHO, DBCHO, CZCHO, CZCN, and SBCN, that incorporate diphenylamine or carbazole as the electron donor and dicyanovinyl or aldehyde as the electron acceptor, has been prepared and their photophysical properties are investigated. In sharp contrast to most red‐emitting dopants, which show serious aggregation‐caused quench phenomena, the new starburst triphenylamine derivatives reported here show unique enhanced emission in the solid state or upon aggregation. Organic light emitting diodes using these compounds as non‐doped host emitters and hole transporters have been fabricated. The highest external quantum yield reaches 2.09 % for CZCHO. SBCHO was investigated as a chlorine gas fluorescence (FL) solid‐film sensor for the first time. The high‐intensity emission was ‘turned off' immediately after being blown by Cl2 gas.

Heavier individuals have higher hip BMD and more robust femur geometry, but it is unclear whether values vary in proportion with body weight in obesity. We studied the variation of hip BMD and geometry across categories of body mass index (BMI) in a subset of postmenopausal non-Hispanic whites (NHWs) from the Women's Health Initiative Observational Cohort (WHI-OS). The implications on fracture incidence were studied among NHWs in the entire WHI-OS. Baseline DXA scans of hip and total body from 4642 NHW women were divided into BMI (kg/m 2 ) categories: underweight (<18.5), healthy weight (18.5-24.9), overweight (25-29.9), and mild (30-34.9), moderate (35-39.9), and extreme obesity (>40). Femur BMD and indices of bone axial (cross-sectional area [CSA]) and bending strength (section modulus [SM]) were extracted from DXA scans using the hip structure analysis (HSA) method and compared among BMI categories after adjustment for height, age, hormone use, diabetes, activity level, femur neck-shaft angle, and neck length. The association between BMI and incident fracture was studied in 78,013 NHWs from the entire WHI-OS over 8.5 ± 2.6 (SD) yr of follow-up. Fracture incidence (cases/1000 person-years) was compared among BMI categories for hip alone, central body (hip, pelvis, spine, ribs, and shoulder girdle), upper extremity (humerus and distal), and lower extremity (femur shaft and distal but not hip). Femur BMD, CSA, and SM were larger in women with higher BMI, but values scaled in proportion to lean and not to fat or total body mass. Women with highest BMI reported more falls in the 12 mo before enrollment, more prevalent fractures, and had lower measures of physical activity and function. Incidence of hip fractures and all central body fractures declined with BMI. Lower extremity fractures distal to the hip trended upward, and upper extremity incidence was independent of BMI. BMD, CSA, and SM vary in proportion to total body lean mass, supporting the view that bones adapt to prevalent muscle loads. Because lean mass is a progressively smaller fraction of total mass in obesity, femur BMD, CSA, and SM decline relative to body weight in higher BMI categories. Traumatic forces increase with body weight, but fracture rates at the hip and central body were less frequent with increasing BMI, possibly because of greater soft tissue padding. There was no evident protective effect in fracture rates at less padded distal extremity sites. Upper extremity fractures showed no variation with BMI, and lower extremity fracture rates were higher only in the overweight (BMI = 25-29.9 kg/m 2 ).

Both PU.1 (also called SFPI1), an Ets-family transcription factor, and AML1 (also called RUNX1), a DNA-binding subunit of the CBF transcription factor family, are crucial for the generation of all hematopoietic lineages, and both act as tumor suppressors in leukemia. An upstream regulatory element (URE) of PU.1 has both enhancer and repressor activity and tightly regulates PU.1 expression. Here we show that AML1 binds to functionally important sites within the PU.1 upstream regulatory element and regulates PU.1 expression at both embryonic and adult stages of development. Analysis of mice carrying conditional AML1 knockout alleles and knock-in mice carrying mutations in all three AML1 sites of the URE proximal region demonstrated that AML1 regulates PU.1 both positively and negatively in a lineage dependent manner. Dysregulation of PU.1 expression contributed to each of the phenotypes observed in these mice, and restoration of proper PU.1 expression rescued or partially rescued each phenotype. Thus, our data demonstrate that PU.1 is a major downstream target gene of AML1.

The design of active,s elective,a nd stable CO 2 reduction electrocatalysts is still challenging.Aseries of atomically dispersed Co catalysts with different nitrogen coordination numbers were prepared and their CO 2 electroreduction catalytic performance was explored. The best catalyst, atomically dispersed Co with two-coordinate nitrogen atoms,achieves both high selectivity and superior activity with 94 %C Of ormation Faradaic efficiency and ac urrent density of 18.1 mA cm À2 at an overpotential of 520 mV.T he CO formation turnover frequency reaches ar ecordv alue of 18 200 h À1 ,s urpassing most reported metal-based catalysts under comparable conditions.O ur experimental and theoretical results demonstrate that lower ac oordination number facilitates activation of CO 2 to the CO 2 C À intermediate and hence enhances CO 2 electroreduction activity.Considering the increased atmospheric carbon dioxide (CO 2 )c oncentration, electroreduction of CO 2 into valueadded products is ap romising approach to curb anthropogenic CO 2 emissions and alleviate the energy crisis. [1] To gain the practical electrocatalyst enabling low overpotential and high selectivity,s everal metal-based nanostructures such as functionalized metals, [2] metal oxides, [3] and metal disulfides [4] have been developed. However,t he intrinsic mechanism in activation of CO 2 into the CO 2 C À intermediate and how the microstructures compose of metal and native moieties influence the electrocatalytic activity still remain elusive. [1e, 3] Thee merging atomically dispersed metal catalysts,w ith definite structure as active sites,p rovide the possibility to explore the structure-activity relationship. [5] To strengthen the molecular understanding in the reaction intermediates and the reactive sites,w ec reate as eries of atomically dispersed Co catalysts with different Ncoordination numbers and study their catalytic performance towards CO 2 reduction. Themodulation in the surrounding Nnumbers of central Co sites is based on controlling the volatile CÀNf ragments at different pyrolysis temperatures.T he decreased coordinating Nresults in more unoccupied 3d orbitals of Co atoms,which benefits the adsorption of CO 2 C À and increases CO 2 reduction rate.A saresult, the catalyst based on Co-N 2 sites gained higher activity and selectivity than an early inert catalyst mainly comprising Co-N 4 sites,with current densities of about 18.1 mA cm À2 and aC OF aradaic efficiencyo f9 4% at al ow overpotential of 520 mV.M oreover,t he CO formation turnover frequency catalyzed by Co-N 2 sites reached ar ecord value of 18 200 h À1 ,w hich surpasses most of the reported metal-based catalysts under comparable conditions. [2a,6] Since the activity,s electivity,a nd durability of single-site catalysts are highly sensitive to their local coordination environment, [5b, 7] our findings underline the importance of coordination tailoring over reactive sites in triggering the efficient CO 2 electroreduction.Atomically dispersed Co catalysts were firstly prepared by am od...