Crystal structures reveal the framework of cis -acyltransferase modular polyketide synthases.

Although the domains of cis -acyltransferase ( cis -AT) modular polyketide synthases (PKS's) have been understood at atomic resolution for over a decade, the domain-domain interactions responsible for the architectures and activities of these giant molecular assembly lines remain largely uncharacterized. The multimeric structure of the α 6 ß 6 fungal fatty acid synthase (FAS) provides 6 equivalent reaction chambers for its acyl carrier protein (ACP) domains to shuttle carbon building blocks and the growing acyl chain between surrounding, oriented enzymatic domains. The presumed homodimeric oligomerization of cis -AT assembly lines is insufficient to provide similar reaction chambers; however, the crystal structure of a ketosynthase (KS)+AT didomain presented here and three already reported show an interaction between the AT domains appropriate for lateral multimerization. This interaction was used to construct a framework for the pikromycin PKS from its KS, AT, and docking domains that contains highly-ordered reaction chambers. Its AT domains also mediate vertical interactions, both with upstream KS domains and downstream docking domains.

Social Determinants of Health and Retention in HIV Care Among Recently Incarcerated Women Living with HIV in Canada.

Women living with HIV (WLWH) are over-represented in corrections in Canada, yet little is known about women's experiences post-release. We used CHIWOS cross-sectional data from WLWH to estimate associations between social determinants of health and HIV-related care outcomes among WLWH with recent (within past year) or ever (before past year) incarceration experience. Lifetime incarceration prevalence was 36.9% (6.5% recent; 30.4% ever), with significant differences by province of residence (British Columbia: 10% recent; 52% ever; Ontario: 5%; 24%; Quebec: 6%; 22%; p < 0.001). In adjusted multinomial logistic regression analyses, compared with never incarcerated, recent incarceration was associated with Indigenous ancestry, lower annual income (< $20,000 CAD), unstable housing, current sex work, injection drug use (IDU), and sub-optimal antiretroviral therapy (ART) adherence, while ever incarceration was associated with current sex work, IDU, and experiencing adulthood violence. Our findings have implications regarding supports needed by WLWH in the post-release period, including ART adherence and achieving health and social goals.

Gay Men's Understanding and Education of New HIV Prevention Technologies in Vancouver, Canada.

Effective rollout of HIV treatment-based prevention such as pre-exposure prophylaxis and treatment as prevention has been hampered by poor education, limited acceptability, and stigma among gay men. We undertook a thematic analysis regarding the education sources and acceptability of these New Prevention Technologies (NPTs) using 15 semistructured interviews with gay men in Vancouver, Canada, who were early adopters of NPTs. NPT education was derived from a variety of sources, including the Internet, health care providers, community organizations, sexual partners, and peers; participants also emphasized their own capacities as learners and educators. Acceptable forms of NPT education featured high-quality factual information, personal testimony, and easy access. Stigma was highlighted as a major barrier. For public health, policy makers, and gay communities to optimize the personal and population benefits of NPTs, there is a need for increased community support and dialogue, antistigma efforts, early NPT adopter testimony, and personalized implementation strategies.

Acute macular neuroretinopathy: A comprehensive review of the literature.

Acute macular neuroretinopathy is a relatively rare condition originally defined by the presence of intraretinal, reddish-brown, wedge-shaped lesions, the apices of which tend to point toward the fovea. Acute onset of paracentral scotomas corresponding to the clinically evident lesions is both common and characteristic. Although the pathogenesis of acute macular neuroretinopathy is complex, recent research suggests a microvascular etiology. Advances in multimodal imaging have enabled better characterization of this retinal disorder and have led to newly proposed diagnostic criteria. We review 101 reported cases in the English and non-English language literature identified from 1975, when acute macular neuroretinopathy was first described, to December, 2014. We discuss common risk factors, demographic and clinical characteristics, and multimodal imaging findings, which together provide insights into pathogenesis and guide areas of future investigation.

Pre-exposure Prophylaxis Awareness Among Gay and Other Men who have Sex with Men in Vancouver, British Columbia, Canada.

Men who have sex with men (MSM) account for approximately half of Canada's new HIV infections. Pre-exposure prophylaxis (PrEP), a recently established and effective HIV prevention tool for MSM is currently not approved nor publicly funded. We recruited MSM via respondent-driven sampling to complete a self-administered computer-based interview. Stratified by HIV status, multivariable logistic regression identified factors associated with PrEP awareness. Of 673 participants, 102/500 (20.9 %) HIV-negative and 63/173 (26.5 %) HIV-positive men were aware of PrEP, but none had used it. One third of PrEP-aware MSM spoke about it with friends or sex partners. Self-declared knowledge was limited. Factors associated with PrEP awareness varied by HIV status, but included greater HAART optimism for HIV-negative MSM. Among HIV-negative MSM, being PrEP unaware was associated with younger age, not always having condoms, and preferring receptive versus insertive anal sex. Future longitudinal research should identify early adopters of PrEP and its associated impacts.

Ribonucleic acid polymerase II binding subunit 3 (Rpb3), a potential nuclear target of insulin-like growth factor binding protein-3.

IGF-binding protein (IGFBP)-3 has intrinsic antiproliferative and proapoptotic functions that are independent of IGF binding and may involve nuclear localization. We determined that exogenous IGFBP-3 rapidly translocates to myoblast nuclei and that a 22-residue peptide containing the metal binding domain (MBD) and nuclear localization sequence (NLS) can similarly direct chimeric GFP into myoblast nuclei. Furthermore, a non-IGF-binding IGFBP-3 mutant inhibited myoblast proliferation without stimulating apoptosis. These results suggest that IGFBP-3 inhibits muscle cell growth in an IGF-independent manner that may be influenced by its rapid nuclear localization. We therefore identified IGFBP-3 interacting proteins by screening a rat L6 myoblast cDNA library using the yeast two-hybrid assay and two N-terminal deletion mutants as bait: BP3/231 (231 residues, L61 to K291) and BP3/111 (K181-K291). Proteins previously known to interact with IGFBP-3 as well as several novel proteins were identified, including RNA polymerase II binding subunit 3 (Rpb3). The domain necessary for Rpb3 binding was subsequently identified using different IGFBP-3 deletion mutants and was localized to the MBD/NLS epitope. Rpb3/IGFBP-3 binding was confirmed by coimmunoprecipitation assays with specific antisera, whereas a NLS mutant IGFBP-3 did not associate with Rpb3, suggesting that a functional NLS is required. Rpb3 facilitates recruitment of the polymerase complex to specific transcription factors and is necessary for the transactivation of many genes. Its association with IGFBP-3 provides a functional role for IGFBP-3 in the direct modulation of gene transcription.