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The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1β with the NCoR/HDAC3 complex, resulting in the activation of PGC1β and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation in vitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts.

Regulation of gene expression requires the combinatorial binding of sequence-specific transcription factors (TFs) at promoters and enhancers. Prior studies showed that alterations in the spacing between TF binding sites can influence promoter and enhancer activity. However, the relative importance of TF spacing alterations resulting from naturally occurring insertions and deletions (InDels) has not been systematically analyzed. To address this question, we first characterized the genome-wide spacing relationships of 73 TFs in human K562 cells as determined by ChIP-seq (chromatin immunoprecipitation sequencing). We found a dominant pattern of a relaxed range of spacing between collaborative factors, including 45 TFs exclusively exhibiting relaxed spacing with their binding partners. Next, we exploited millions of InDels provided by genetically diverse mouse strains and human individuals to investigate the effects of altered spacing on TF binding and local histone acetylation. These analyses suggested that spacing alterations resulting from naturally occurring InDels are generally tolerated in comparison to genetic variants directly affecting TF binding sites. To experimentally validate this prediction, we introduced synthetic spacing alterations between PU.1 and C/EBPβ binding sites at six endogenous genomic loci in a macrophage cell line. Remarkably, collaborative binding of PU.1 and C/EBPβ at these locations tolerated changes in spacing ranging from 5 bp increase to >30 bp decrease. Collectively, these findings have implications for understanding mechanisms underlying enhancer selection and for the interpretation of non-coding genetic variation.

This paper provides highlights from an expert meeting to explore opportunities to reduce cancer risk and promote health at older ages. Factors that increase cancer risk among older adults include exposure to carcinogens from multiple sources, chronic conditions such as obesity and diabetes, and unhealthy behaviors. Emerging research points to chronic social stressors - social isolation, loneliness, and financial hardship - as being linked to accelerated biological aging and increased cancer risk later in life. Older adults may disproportionately encounter these stressors as well as barriers to preventive health care services, accurate health information, and environments that promote health. Researchers can use existing cohort studies of older adults to deepen our understanding of the relative benefit of modifying specific behaviors and circumstances. The evidence points to the value of comprehensive, transdisciplinary approaches to promote health and reduce cancer risk across the entire lifespan, extending through older adulthood. Clinical encounters with older adults provide opportunities for psychosocial and behavioral screening and counseling. In the presence of multiple morbidities, preventive health services may offer greater health benefits than cancer-screening tests. Strategies that involve families and caregivers, promote positive attitudes about aging, and engage many different community sectors have the potential to prevent or delay the development of cancer at older ages.

Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes 1 . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL2-4. Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr-/- background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr-/- mice, Ldlr -/- E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis.

B-1 cells are a unique subset of B cells that are positively selected for expressing autoreactive BCRs. We isolated RNA from peritoneal (B-1a, B-1b, B-2) and splenic (B-1a, marginal zone, follicular) B cells from C57BL/6 mice and used 5'-RACE to amplify the IgH V region using massively parallel sequencing. By analyzing 379,000 functional transcripts, we demonstrate that B-1a cells use a distinct and restricted repertoire. All B-1 cell subsets, especially peritoneal B-1a cells, had a high proportion of sequences without N additions, suggesting predominantly prenatal development. Their transcripts differed markedly and uniquely contained VH11 and VH12 genes, which were rearranged only with a restricted selection of D and J genes, unlike other V genes. Compared to peritoneal B-1a, the peritoneal B-1b repertoire was larger, had little overlap with B-1a, and most sequences contained N additions. Similarly, the splenic B-1a repertoire differed from peritoneal B-1a sequences, having more unique sequences and more frequent N additions, suggesting influx of B-1a cells into the spleen from nonperitoneal sites. Two CDR3s, previously described as Abs to bromelain-treated RBCs, comprised 43% of peritoneal B-1a sequences. We show that a single-chain variable fragment designed after the most prevalent B-1a sequence bound oxidation-specific epitopes such as the phosphocholine of oxidized phospholipids. In summary, we provide the IgH V region library of six murine B cell subsets, including, to our knowledge for the first time, a comparison between B-1a and B-1b cells, and we highlight qualities of B-1 cell Abs that indicate unique selection processes.

Background: Older adults in rural areas have unique transportation barriers to accessing medical care, which include a lack of mass transit options and considerable distances to health-related services. This study contrasts non-emergency medical transportation (NEMT) service utilization patterns and associated costs for Medicaid middle-aged and older adults in rural versus urban areas. Methods: Data were analyzed from 39,194 NEMT users of LogistiCare-brokered services in Delaware residing in rural (68.3%) and urban (30.9%) areas. Multivariable logistic analyses compared trip characteristics by rurality designation. Results: Rural (37.2%) and urban (41.2%) participants used services more frequently for dialysis than for any other medical concern. Older age and personal accompaniment were more common and wheel chair use was less common for rural trips. The mean cost per trip was greater for rural users (difference of $2910 per trip), which was attributed to the greater distance per trip in rural areas. Conclusions: Among a sample who were eligible for subsidized NEMT and who utilized this service, rural trips tended to be longer and, therefore, higher in cost. Over 50% of trips were made for dialysis highlighting the need to address prevention and, potentially, health service improvements for rural dialysis patients.

PURPOSE: Mobility disability is associated with poor lower body function among older adults. This study examines whether specific types of neighborhood characteristics moderate that association. DESIGN AND METHODS: This study is based on a cross-sectional sample of 884 people aged ≥ 65 years identified through service organizations in Alameda County, CA; Cook County, IL; Allegheny County, PA; and Wake and Durham counties, NC. In-person interviews focus on neighborhood characteristics, physical and cognitive function, depression, and walking. Functional capacity is tested using objective measures of lower body strength, balance, and walking speed. Mobility disability, the main study outcome, is measured as self-reported level of difficulty in walking 2-3 neighborhood blocks. Estimates of main and interactive effects are derived from logistic regression models. RESULTS: Among older adults with poor lower body function, those who report less proximity to goods and services and barriers to walking report more mobility disability than other older adults. In contrast, among older adults with good lower body function, there is a low prevalence of mobility disability and little association between perceptions of the neighborhood and mobility disability. IMPLICATIONS: In addition to more refined longitudinal studies, this research provides a foundation for innovative place-based rehabilitation and hospital discharge programs for older adults newly diagnosed and treated for chronic health conditions.

Non-emergency medical transportation (NEMT) can prevent emergency care as a result of delayed or missed medical appointments. Medicaid provides NEMT for low income individuals who have no other means of transportation and this is a critical component of the health care delivery system. This study examined cancelled trips in Medicaid adults age 65+ to explore whether barriers persist for a growing segment of the population who face particular challenges of age-related declines in health and function. Multivariate logistic regression analyses were conducted using transportation brokerage data for Delaware members who intended to travel during 2008-2010, modeling the odds of all cancellations and then these mutually exclusive types: (1) client cancelled; (2) client obtained alternative transportation; and (3) client cancelled due to health. Over half of the cancelled trips were attributed to client reasons. Black race was associated with client canceling (OR=1.4) and canceling due to alternative transportation (OR=1.9). Compared to dialysis, trips for other medical care were more likely to be cancelled for client and health reasons (ORs ranged 1.6-7.9). Higher levels of service increased cancelling for health reasons (OR=2.9 stretcher; OR=1.8 wheelchair). Finally, pre-scheduled or subscription trips were less likely to be cancelled and client factors differed for the cancellation of trips that were not regularly scheduled. The results of this initial study confirm that for this population additional transportation services are often not available and that more support for utilizing NEMT may be needed. Future research should evaluate persistent barriers, service delivery, and long-term outcomes.

OBJECTIVES: To pilot test a new behavioral intervention to increase walking in sedentary older adults.DESIGN: Pre-post community-based pilot study.SETTING: Three senior centers in greater Los Angeles.PARTICIPANTS: Forty-six sedentary adults aged 65 and older.INTERVENTION: At four weekly 1-hour group sessions held at the senior centers, a trained health educator applied a theoretically grounded, standardized "attribution retraining" curriculum developed by a multidisciplinary team of investigators. Participants were taught that becoming sedentary is not inevitable with aging and that older adults should attribute being sedentary to modifiable attributes rather than to old age. A 1-hour exercise class including strength, endurance, and flexibility training followed each weekly attribution retraining session.MEASUREMENTS: Change from baseline in steps per week recorded using a digital pedometer was measured after 7 weeks. Age expectations (measured using the Expectations Regarding Aging-38 survey, a previously tested instrument on which higher scores indicate that the participant expects high functioning with aging and lower scores indicate that the participant expects physical and mental decline) and health-related quality of life were measured using in-person interviews.RESULTS: Mean steps per week increased from 24,749 to 30,707, a 24% increase-equivalent to 2.5 miles (2-sided t-test P=.002). Age expectation scores increased 30% (P

An interlaboratory comparison (ILC) was organised to characterise 87Sr/86Sr isotope ratios in geological and industrial reference materials by applying the so‐called conventional method for determining 87Sr/86Sr isotope ratios. Four cements (VDZ 100a, VDZ 200a, VDZ 300a, IAG OPC‐1), one limestone (IAG CGL ML‐3) and one slate (IAG OU‐6) reference materials were selected, covering a wide range of naturally occurring Sr isotopic signatures. Thirteen laboratories received aliquots of these six reference materials together with a detailed technical protocol. The consensus values for the six reference materials and their associated measurement uncertainties were obtained by applying a Gaussian, linear mixed effects model fitted to all the measurement results. By combining the consensus values and their uncertainties with an uncertainty contribution for potential heterogeneity, reference values ranging from 0.708134 mol mol‐1 to 0.729778 mol mol‐1 were obtained with relative expanded uncertainties of ≤ 0.007 %. This study represents an ILC on conventional 87Sr/86Sr isotope ratios, within which metrological principles were considered and the compatibility of measurement results obtained by MC‐ICP‐MS and by MC‐TIMS is demonstrated. The materials characterised in this study can be used as reference materials for validation and quality control purposes and to estimate measurement uncertainties in conventional 87Sr/86Sr isotope ratio measurement. [ABSTRACT FROM AUTHOR]

BackgroundNew strategies to increase physical activity among sedentary older adults are urgently needed.ObjectiveTo examine whether low expectations regarding aging (age-expectations) are associated with low physical activity levels among older adults.DesignCross-sectional survey.ParticipantsSix hundred and thirty-six English- and Spanish-speaking adults aged 65 years and above attending 14 community-based senior centers in the Los Angeles region. Over 44% were non-Latino whites, 15% were African American, and 36% were Latino. The mean age was 77 years (range 65 to 100).MeasurementsSelf-administered written surveys including previously tested measures of age-expectations and physical activity level in the previous week.ResultsOver 38% of participants reported