Recommendations for community pharmacy to improve access to medication advice for people from ethnic minority communities: A qualitative person-centred codesign study.

Introduction: Medicines-centred consultations are vital to support medicine effectiveness and optimize health outcomes for patients. However, inequalities negatively impact ethnic minority populations when accessing medicines advice. It is important to identify opportunities to improve access for these communities however, knowledge of how best to achieve this is lacking; this study will generate recommendations to improve access to medicines advice from community pharmacies for people from ethnic minority communities.

Improving the identification of patients with a genetic diagnosis of familial hypercholesterolaemia in primary care: A strategy to achieve the NHS long term plan.

Background And Aims: We aimed to validate a nurse-led process using electronic health records to identify those at risk of familial hypercholesterolaemia (FH) for genetic diagnosis in primary care.

Methods: Those at risk of FH were identified using searches developed and refined locally and implemented in primary care by a trained nurse; they were invited for further assessment and genetic testing if indicated. Family members at risk of FH were identified and invited for cascade testing.

Molecular mechanisms of heparin-induced modulation of human interleukin 12 bioactivity.

Human interleukin-12 (hIL-12) is a heparin-binding cytokine whose activity was previously shown to be enhanced by heparin and other sulfated glycosaminoglycans. The current study investigated the mechanisms by which heparin increases hIL-12 activity. Using multiple human cell types, including natural killer cells, an IL-12 indicator cell line, and primary peripheral blood mononuclear and T cells, along with bioactivity, flow cytometry, and isothermal titration calorimetry assays, we found that heparin-dependent modulation of hIL-12 function correlates with several of heparin's biophysical characteristics, including chain length, sulfation level, and concentration.

The "complex" RNA post-transcriptional element of a "simple" retrovirus.

Replication of retroviruses and transposition of endogenous retroelements exploits a unique mechanism of post-transcriptional regulation as a means of exporting their incompletely-spliced mRNAs (which serve as both the genomic RNA and the template for protein synthesis). Following discovery of the Rev response element (RRE) that mediates nucleocytoplasmic export of the full-length and singly-spliced human immunodeficiency virus type 1 (HIV-1) genome, equivalent -acting regulatory elements have been characterized for both complex and simple retroviruses and retroelements, together with the obligate viral and host proteins with which they interact. The exception to this is the gammaretrovirus family of simple retroviruses, exemplified by reticuloendotheliosis virus (REV), murine leukemia virus (MLV) and xenotropic MLV-related retrovirus (XMRV).

A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques.

Background: None of the HIV T-cell vaccine candidates that have reached advanced clinical testing have been able to induce protective T cell immunity. A major reason for these failures may have been suboptimal T cell immunogen designs.

Methods: To overcome this problem, we used a novel immunogen design approach that is based on functional T cell response data from more than 1,000 HIV-1 clade B and C infected individuals and which aims to direct the T cell response to the most vulnerable sites of HIV-1.

Comparative analysis of SIV-specific cellular immune responses induced by different vaccine platforms in rhesus macaques.

To identify the most promising vaccine candidates for combinatorial strategies, we compared five SIV vaccine platforms including recombinant canary pox virus ALVAC, replication-competent adenovirus type 5 host range mutant RepAd, DNA, modified vaccinia Ankara (MVA), peptides and protein in distinct combinations. Three regimens used viral vectors (prime or boost) and two regimens used plasmid DNA. Analysis at necropsy showed that the DNA-based vaccine regimens elicited significantly higher cellular responses against Gag and Env than any of the other vaccine platforms.

Gammaretrovirus mRNA expression is mediated by a novel, bipartite post-transcriptional regulatory element.

Post-transcriptional regulatory mechanisms of several complex and simple retroviruses and retroelements have been elucidated, with the exception of the gammaretrovirus family. We found that, similar to the other retroviruses, gag gene expression of MuLV and XMRV depends on post-transcriptional regulation mediated via an RNA sequence overlapping the pro-pol open reading frame, termed the Post-Transcriptional Element (PTE). PTE function can be replaced by heterologous RNA export elements, e.

Humoral immunity induced by mucosal and/or systemic SIV-specific vaccine platforms suggests novel combinatorial approaches for enhancing responses.

Combinatorial HIV/SIV vaccine approaches targeting multiple arms of the immune system might improve protective efficacy. We compared SIV-specific humoral immunity induced in rhesus macaques by five vaccine regimens. Systemic regimens included ALVAC-SIVenv priming and Env boosting (ALVAC/Env); DNA immunization; and DNA plus Env co-immunization (DNA&Env).

Comparison of intradermal and intramuscular delivery followed by in vivo electroporation of SIV Env DNA in macaques.

A panel of SIVmac251 transmitted Env sequences were tested for expression, function and immunogenicity in mice and macaques. The immunogenicity of a DNA vaccine cocktail expressing SIVmac239 and three transmitted SIVmac251 Env sequences was evaluated upon intradermal or intramuscular injection followed by in vivo electroporation in macaques using sequential vaccination of gp160, gp120 and gp140 expressing DNAs. Both intradermal and intramuscular vaccination regimens using the gp160 expression plasmids induced robust humoral immune responses, which further improved using the gp120 expressing DNAs.

The p40 subunit of interleukin (IL)-12 promotes stabilization and export of the p35 subunit: implications for improved IL-12 cytokine production.

IL-12 is a 70-kDa heterodimeric cytokine composed of the p35 and p40 subunits. To maximize cytokine production from plasmid DNA, molecular steps controlling IL-12p70 biosynthesis at the posttranscriptional and posttranslational levels were investigated. We show that the combination of RNA/codon-optimized gene sequences and fine-tuning of the relative expression levels of the two subunits within a cell resulted in increased production of the IL-12p70 heterodimer.

Kaposi's sarcoma-associated herpesvirus ORF57 is not a bona fide export factor.

Kaposi's sarcoma-associated herpesvirus (KSHV [human herpesvirus 8; HHV-8]) open reading frame 57 (ORF57) is a viral early protein participating in posttranscriptional regulatory events, such as splicing, RNA stabilization, and protein expression. Recent data suggest that ORF57 recruits the transcription and export (TREX) complex to viral RNA and exports these transcripts to the cytoplasm. In this study, we show that although ORF57 promotes expression of a selection of KSHV viral intronless RNAs, it is not a bona fide export factor.

Kaposi's sarcoma-associated herpesvirus ORF57 interacts with cellular RNA export cofactors RBM15 and OTT3 to promote expression of viral ORF59.

Kaposi's sarcoma-associated herpesvirus (KSHV) encodes ORF57, which promotes the accumulation of specific KSHV mRNA targets, including ORF59 mRNA. We report that the cellular export NXF1 cofactors RBM15 and OTT3 participate in ORF57-enhanced expression of KSHV ORF59. We also found that ectopic expression of RBM15 or OTT3 augments ORF59 production in the absence of ORF57.

The RNA transport element of the murine musD retrotransposon requires long-range intramolecular interactions for function.

Retrovirus replication requires specialized transport mechanisms to export genomic mRNA from the nucleus to the cytoplasm of the infected cell. This regulation is mediated by a combination of viral and/or cellular factors that interact with cis-acting RNA export elements linking the viral RNA to the cellular CRM1 or NXF1 nuclear export pathways. Endogenous type D murine LTR retrotransposons (musD) were reported to contain an RNA export element located upstream of the 3'-LTR.

Pat1 contains distinct functional domains that promote P-body assembly and activation of decapping.

The control of mRNA degradation and translation are important aspects of gene regulation. Recent results suggest that translation repression and mRNA decapping can be intertwined and involve the formation of a quiescent mRNP, which can accumulate in cytoplasmic foci referred to as P bodies. The Pat1 protein is a key component of this complex and an important activator of decapping, yet little is known about its function.