Activity

Metformin is the first-line therapy for type 2 diabetes, but there are large inter-individual variations in responses to this drug. Its mechanism of action is not fully understood, but activation of AMP-activated protein kinase (AMPK) and changes in the gut microbiota appear to be important. The inhibitory role of microbial metabolites on metformin action has not previously been investigated. Here, we show that concentrations of the microbial metabolite imidazole propionate are higher in subjects with type 2 diabetes taking metformin who have high blood glucose. We also show that metformin-induced glucose lowering is not observed in mice pretreated with imidazole propionate. Furthermore, we demonstrate that imidazole propionate inhibits AMPK activity by inducing inhibitory AMPK phosphorylation, which is dependent on imidazole propionate-induced basal Akt activation. Finally, we identify imidazole propionate-activated p38γ as a novel kinase for Akt and demonstrate that p38γ kinase activity mediates the inhibitory action of imidazole propionate on metformin.

To describe attitudes about abortion among registered nurses (RNs) licensed in California and to determine if demographic characteristics were associated with these attitudes.

Cross-sectional, one-time survey.

Online between 2015 and 2017.

Nurses with active RN licenses in California (N = 2,500).

An anonymous survey was sent to a random sample of 2,500 RNs with active California licenses between 2015 and 2017 to assess their personal and professional demographic characteristics and their attitudes toward abortion. Using scores on the Abortion Attitudes Scale, we dichotomized participants into proabortion and antiabortion categories. We used chi-square tests to determine differences based on demographic characteristics.

Data from 504 RNs licensed in California are included in this analysis. Most respondents identified as female (n= 462, 92%), older than 50 years of age (n= 379, 75%), married (n= 364, 72%), White (n= 354, 70%), and Christian (n= 322, 64%). They were more likely to have negative attitudes toward abortion care if they identified as Christian (p< .001) and more positive attitudes if they identified as White (p< .001) independent of identifying as Christian.

Respondents had a complex range of attitudes about abortion. In some cases, these attitudes aligned and/or conflicted with stated religious orientation. This study highlights the demographic characteristics that are associated with the attitudes and beliefs about abortion among RNs licensed in California.

Respondents had a complex range of attitudes about abortion. find more In some cases, these attitudes aligned and/or conflicted with stated religious orientation. This study highlights the demographic characteristics that are associated with the attitudes and beliefs about abortion among RNs licensed in California.Zika virus capsid protein is involved in multiple essential steps of the viral life cycle. Many vital functionalities are attributed to the dynamic N- terminal domain of this protein, which is intrinsically disordered in ZIKV and among several flaviviruses too. Other than genome encapsulation, studies have shown interaction with host lipid droplets to be crucial for replication and maturation. In Dengue virus, the molecular basis of such interplay has been studied in detail, and residues within the capsid N-terminal disordered domain has been mapped. It revealed a new function of a conserved region in mediating capsid-lipid droplet association through a conformational transition. Therefore, in this study, we attempt to analyze the structural dynamics of Zika virus capsid’s N- terminal domain and analyzed it through a reductionist approach by dividing the N-terminal domain into three truncated segments and studied them individually. Techniques such as Circular dichroism spectroscopy, Dynamic light scattering, Zeta potential and Molecular dynamic simulations were employed to identify the motif responsible for structural flexibility and ability to interact with membrane models. Our results confirm that the truncated segments 5-26 and 1-30 readily adopt an α-helical conformation in the presence of 2,2,2-trifluoro-ethanol, detergent and negatively charged phospholipids. However, in contrast to Dengue virus, we report the conserved residues 14-23 region to be unstructured and do not undergo a conformational switch in Zika virus. Thus, our study illustrates the possibility of conserved 14-23 region’s non-involvement in ZIKV capsid-lipid droplet association, unlike DENV.Supported lipid multi-bilayers or bilayer stacks are an important model membrane system, particularly suitable for surface-sensitive characterization methods like X-ray and neutron diffraction. Spreading organic solution (sOS) is one of the most widely used protocols for the preparation of lipid multi-bilayers. Despite its great popularity, the self-assembly mechanism of the bilayers is not yet fully elucidated, limiting further improvements of this protocol. In order to solve this problem, we investigated the formation process of lipid bilayers in the sOS protocol, using in-situ time-resolved X-ray diffraction, complemented by X-ray reflectivity and molecular dynamics simulation. Results reveal a simultaneous self-assembly scheme for both cholesterol-free and cholesterol-containing bilayers, with one bilayer phase forming at the surface and the other forming in the solution. The solution phase gradually transforms into the surface phase, yielding clean single phase in the end.Brown adipocytes (BAs) are a potential cell source for the treatment of metabolic disease, including type 2 diabetes. In this report, human pluripotent stem cells (hPSCs) are subject to directed differentiation through a paraxial mesoderm progenitor state that generates BAs at high efficiency. Molecular analysis identifies potential regulatory networks for BA development, giving insight into development along this lineage. hPSC-derived BAs undergo elevated rates of glycolysis, uncoupled respiration, and lipolysis that are responsive to changes in cyclic AMP (cAMP)-dependent signaling, consistent with metabolic activity in BA tissue depots. Transplanted human BAs engraft into the inter-scapular region of recipient mice and exhibit thermogenic activity. Recipient animals have elevated metabolic activity, respiratory exchange ratios, and whole-body energy expenditure. Finally, transplanted BAs reduce circulating glucose levels in hyperglycemic animals. These data provide a roadmap for brown adipocyte development and indicate that BAs generated from hPSCs have potential as a tool for therapeutic development.