Impaired mitochondrial function has been implicated in the pathogenesis of type 2 diabetes, heart failure, and neurodegeneration as well as during aging. Studies with the PGC-1 transcriptional ...coactivators have demonstrated that these factors are central components of the regulatory network that controls mitochondrial function in mammalian cells. Here we describe a genome-wide coactivation assay to globally identify transcription factors and cofactors in this pathway. These analyses revealed a molecular signature of the PGC-1alpha transcriptional network and identified BAF60a (SMARCD1) as a molecular link between the SWI/SNF chromatin-remodeling complexes and hepatic lipid metabolism. Adenoviral-mediated expression of BAF60a stimulates fatty acid beta-oxidation in cultured hepatocytes and ameliorates hepatic steatosis in vivo. PGC-1alpha mediates the recruitment of BAF60a to PPARalpha-binding sites, leading to transcriptional activation of peroxisomal and mitochondrial fat-oxidation genes. These results define a role for the SWI/SNF complexes in the regulation of lipid homeostasis.
BACKGROUND
Inadequate management of cancer related pain has resulted primarily from attitudinal barriers and a lack of knowledge about clinical assessment, the administration of analgesics, and ...therapeutic interventions.
METHODS
Fifty health‐care providers (13 physicians, 21 nurses, and 16 pharmacists), working as a team, participated in a Role Model Program that presented principles of cancer pain management. A questionnaire that evaluated the fund of knowledge and attitudes regarding cancer pain management was administered prior to the 1‐day workshop, at the end of the workshop, and at 4 and 12 months follow‐up.iu61 The workshop consisted of lectures and discussion groups; in the discussion groups, concepts were clarified, cases presented, and barriers to optimal cancer pain management identified.
RESULTS
Significant improvements in attitudes (P < 0.01), knowledge (P < 0.01), and total scores (P < 0.002) were observed when the preworkshop responses were compared with those obtained immediately after instruction. Scores on the questionnaire were the same or slightly better at both 4 and 12 months in follow‐up, demonstrating no loss in acquired knowledge or attitude. Comparison of the postworkshop scores with those at 12 months follow‐up were significantly better in attitude (P < 0.03), and in total score (P < 0.01); improvements in knowledge also approached significance (P < 0.06). These represented continuing improvements because significant differences in the attitude scores (P < 0.05) and the total score (P < 0.05) were observed when the 4‐month and 12‐month follow‐up responses were evaluated. The effectiveness of the program in the transference of knowledge was also measured; in the first year of the program, more than 4500 health‐care professionals were subsequently informed about cancer pain management from the Role Model Participants.
CONCLUSIONS
Significant improvements were observed immediately in both attitude and knowledge of cancer pain management principles after the 1‐day Role Model Workshop. These improvements continued, as determined at 4 and 12 months follow‐up. The Role Model Participants were highly motivated to share the learned principles of cancer pain management with other health‐care professionals. These results are consistent with other Role Model Programs that both instruct and involve the participants. The Role Model Program is an efficient and effective means of educating health‐care professionals in the concepts of cancer pain management. Cancer 1996;77:996‐1001.
Engineering estimates of methane emissions from natural gas production have led to varied projections of national emissions. This work reports direct measurements of methane emissions at 190 onshore ...natural gas sites in the United States (150 production sites, 27 well completion flowbacks, 9 well unloadings, and 4 workovers). For well completion flowbacks, which clear fractured wells of liquid to allow gas production, methane emissions ranged from 0.01 Mg to 17 Mg (mean = 1.7 Mg; 95% confidence bounds of 0.67–3.3 Mg), compared with an average of 81 Mg per event in the 2011 EPA national emission inventory from April 2013. Emission factors for pneumatic pumps and controllers as well as equipment leaks were both comparable to and higher than estimates in the national inventory. Overall, if emission factors from this work for completion flowbacks, equipment leaks, and pneumatic pumps and controllers are assumed to be representative of national populations and are used to estimate national emissions, total annual emissions from these source categories are calculated to be 957 Gg of methane (with sampling and measurement uncertainties estimated at ±200 Gg). The estimate for comparable source categories in the EPA national inventory is ∼1,200 Gg. Additional measurements of unloadings and workovers are needed to produce national emission estimates for these source categories. The 957 Gg in emissions for completion flowbacks, pneumatics, and equipment leaks, coupled with EPA national inventory estimates for other categories, leads to an estimated 2,300 Gg of methane emissions from natural gas production (0.42% of gross gas production).
Several cities in the U.S. have implemented taxes on sugar-sweetened beverages (SSBs) in an attempt to improve public health and raise revenue. On July 1, 2017, Oakland California introduced a tax of ...one cent per ounce on SSBs. In this paper, we estimate the impact of the tax on retail prices, product availability, purchases, and child and adult consumption of taxed beverages in Oakland, as well as of potential substitute beverages. We collected data from Oakland stores and their customers and a matched group of stores in surrounding counties and their customers. We collected information in the months prior to the implementation of the tax and again a year later on: (1) prices, (2) purchase information from customers exiting the stores, and (3) a follow-up household survey of adults and child beverage purchases and consumption. We use a difference-in-differences identification strategy to estimate the impact of the tax on prices, purchases, and consumption of taxed beverages. We find that roughly 60 percent of the tax was passed on to consumers in the form of higher prices. There was a slight decrease in the volume of SSBs purchased per shopping trip in Oakland and a small increase in purchases at stores outside of the city, and we find some evidence of increased shopping by Oakland residents at stores outside of the city. We do not find evidence of substantial changes in the overall consumption of SSBs or of added sugars consumed through beverages for either adults or children after the tax.
Individuals with lower socio-economic status (SES) are at increased risk of physical and mental illnesses and tend to die at an earlier age 1–3. Explanations for the association between SES and ...health typically focus on factors that are environmental in origin 4. However, common SNPs have been found collectively to explain around 18% of the phenotypic variance of an area-based social deprivation measure of SES 5. Molecular genetic studies have also shown that common physical and psychiatric diseases are partly heritable 6. It is possible that phenotypic associations between SES and health arise partly due to a shared genetic etiology. We conducted a genome-wide association study (GWAS) on social deprivation and on household income using 112,151 participants of UK Biobank. We find that common SNPs explain 21% of the variation in social deprivation and 11% of household income. Two independent loci attained genome-wide significance for household income, with the most significant SNP in each of these loci being rs187848990 on chromosome 2 and rs8100891 on chromosome 19. Genes in the regions of these SNPs have been associated with intellectual disabilities, schizophrenia, and synaptic plasticity. Extensive genetic correlations were found between both measures of SES and illnesses, anthropometric variables, psychiatric disorders, and cognitive ability. These findings suggest that some SNPs associated with SES are involved in the brain and central nervous system. The genetic associations with SES obviously do not reflect direct causal effects and are probably mediated via other partly heritable variables, including cognitive ability, personality, and health.
•Common SNPs explain 21% of social deprivation and 11% of household income•Two loci attained genome-wide significance for household income•Genes in these loci have been linked to synaptic plasticity•Genetic correlations were found between both measures of SES and many other traits
Individuals with lower socio-economic status (SES) are at increased risk of physical and mental illnesses. Hill et al. find extensive genetic correlations between SES and health, psychiatric, and cognitive traits. This suggests that the link between SES and health is driven, in part, by a shared genetic association.
Alzheimer's disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological ...underpinnings. We show that self-report of parental history of Alzheimer's dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data (n = 74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci (P < 5 × 10
) are identified. These contain genes relevant for AD and neurodegeneration: ADAM10, BCKDK/KAT8 and ACE. Novel gene-based loci include drug targets such as VKORC1 (warfarin dose). We report evidence that the association of SNPs in the TOMM40 gene with AD is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. However, it is likely that multiple variants are affecting the trait and gene methylation/expression. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, as they contain genes that are drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications.
The bacteria of the
Brucella
genus are responsible for a worldwide zoonosis called brucellosis. They belong to the α-proteobacteria group, as many other bacteria that live in close association with a ...eukaryotic host. Importantly, the
Brucellae
are mainly intracellular pathogens, and the molecular mechanisms of their virulence are still poorly understood. Using the complete genome sequence of
Brucella melitensis
, we generated a database of protein-coding open reading frames (ORFs) and constructed an ORFeome library of 3091 Gateway Entry clones, each containing a defined ORF. This first version of the
Brucella
ORFeome (v1.1) provides the coding sequences in a user-friendly format amenable to high-throughput functional genomic and proteomic experiments, as the ORFs are conveniently transferable from the Entry clones to various Expression vectors by recombinational cloning. The cloning of the
Brucella
ORFeome v1.1 should help to provide a better understanding of the molecular mechanisms of virulence, including the identification of bacterial protein-protein interactions, but also interactions between bacterial effectors and their host's targets.
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