Mitotic deacetylase complex (MiDAC) recognizes the HIV-1 core promoter to control activated viral gene expression.

The human immunodeficiency virus (HIV) integrates into the host genome forming latent cellular reservoirs that are an obstacle for cure or remission strategies. Viral transcription is the first step in the control of latency and depends upon the hijacking of the host cell RNA polymerase II (Pol II) machinery by the 5' HIV LTR. Consequently, "block and lock" or "shock and kill" strategies for an HIV cure depend upon a full understanding of HIV transcriptional control.

Identification of aryl hydrocarbon receptor as a barrier to HIV-1 infection and outgrowth in CD4 T cells.

The aryl hydrocarbon receptor (AhR) regulates Th17-polarized CD4 T cell functions, but its role in HIV-1 replication/outgrowth remains unknown. Genetic (CRISPR-Cas9) and pharmacological inhibition reveal AhR as a barrier to HIV-1 replication in T cell receptor (TCR)-activated CD4 T cells in vitro. In single-round vesicular stomatitis virus (VSV)-G-pseudotyped HIV-1 infection, AhR blockade increases the efficacy of early/late reverse transcription and subsequently facilitated integration/translation.

Treatment of pulmonary artery pseudoaneurysms and stenosis with balloon-expandable stents.

We describe our use of balloon-expandable stents in pulmonary arteries for a variety of indications. This is an endovascular technique that provides an alternative treatment option to treat some forms of complex pulmonary artery disease when standard surgical or other endovascular options are not possible. This case series describes the successful treatment of four patients with different pulmonary artery diseases.

Opposing roles of CLK SR kinases in controlling HIV-1 gene expression and latency.

Background: The generation of over 69 spliced HIV-1 mRNAs from one primary transcript by alternative RNA splicing emphasizes the central role that RNA processing plays in HIV-1 replication. Control is mediated in part through the action of host SR proteins whose activity is regulated by multiple SR kinases (CLK1-4, SRPKs).

Methods: Both shRNA depletion and small molecule inhibitors of host SR kinases were used in T cell lines and primary cells to evaluate the role of these factors in the regulation of HIV-1 gene expression.

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Résumé La latence du virus de l'immunodéficience humaine (VIH) est actuellement un obstacle majeur à l'éradication des cellules infectées. En effet, en état de latence, le VIH se réplique peu et produit une faible quantité de protéines virales ; il est donc hors d'atteinte des traitements antirétroviraux ciblant les enzymes essentielles du cycle viral et invisible pour le système immunitaire qui ne peut détecter les protéines virales à la surface des cellules infectées. De plus, la latence étant un état réversible maintenu principalement par la pression exercée par les traitements antirétroviraux sur le virus qui peut se réactiver lorsque ces traitements sont interrompus.

Cat and Mouse: HIV Transcription in Latency, Immune Evasion and Cure/Remission Strategies.

There is broad scientific and societal consensus that finding a cure for HIV infection must be pursued. The major barrier to achieving a cure for HIV/AIDS is the capacity of the HIV virus to avoid both immune surveillance and current antiretroviral therapy (ART) by rapidly establishing latently infected cell populations, termed latent reservoirs. Here, we provide an overview of the rapidly evolving field of HIV cure/remission research, highlighting recent progress and ongoing challenges in the understanding of HIV reservoirs, the role of HIV transcription in latency and immune evasion.

Inhibition of NF-κB-dependent HIV-1 replication by the marine natural product bengamide A.

HIV-1 inhibitors that act by mechanisms distinct from existing antiretrovirals can provide novel insights into viral replication and potentially inform development of new therapeutics. Using a multi-cycle HIV-1 replication assay, we screened 252 pure compounds derived from marine invertebrates and microorganisms and identified 6 (actinomycin Z, bastadin 6, bengamide A, haliclonacyclamine A + B, keramamine C, neopetrosiamide B) that inhibited HIV-1 with 50% effective concentrations (ECs) of 3.8 μM or less.

BIM and NOXA are mitochondrial effectors of TAF6δ-driven apoptosis.

TAF6δ is a pro-apoptotic splice variant of the RNA polymerase II general transcription factor, TAF6, that can dictate life vs. death decisions in animal cells. TAF6δ stands out from classical pro-apoptotic proteins because it is encoded by a gene that is essential at the cellular level, and because it functions as a component of the basal transcription machinery.

Mortality in acute non-invasive ventilation.

A prospective study of non-invasive ventilation at The Prince Charles Hospital outside of the intensive care unit from March 2015 to March 2016 was performed. Overall 69 patients were included. Acute hypercapnic respiratory failure was the most common indication (n = 59; 85%).

Precise manipulation of biophysical particle parameters enables control of proinflammatory cytokine production in presence of TLR 3 and 4 ligands.

Unlabelled: The biophysical parameters governing nanoparticle (NP)-cell interactions significantly affect biological responses, particularly in the application of NP-based immunotherapeutics. Modulation of the surface biophysical character of NPs can be achieved via introduction of amino acids, which offer the ability to fine tune a range of biophysical parameters of interest. We employed this approach using monodisperse silica NPs coated with numerous poly(amino acid)s (PAAs).

Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication.

We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying strong anti-HIV-1 potency against a variety of clinical strains in vitro. Here we show that 1C8 decreases the expression of HIV-1 and alters splicing events involved in the production of HIV-1 mRNAs. Although 1C8 was designed to be a structural mimic of the fused tetracyclic indole compound IDC16 that targets SRSF1, it did not affect the splice site shifting activity of SRSF1.

Alternative splicing of TAF6: downstream transcriptome impacts and upstream RNA splice control elements.

The TAF6δ pathway of apoptosis can dictate life versus death decisions independently of the status of p53 tumor suppressor. TAF6δ is an inducible pro-apoptotic subunit of the general RNA polymerase II (Pol II) transcription factor TFIID. Alternative splice site choice of TAF6δ has been shown to be a pivotal event in triggering death via the TAF6δ pathway, yet nothing is currently known about the mechanisms that promote TAF6δ splicing.

Cancer-Associated Perturbations in Alternative Pre-messenger RNA Splicing.

For most of our 25,000 genes, the removal of introns by pre-messenger RNA (pre-mRNA) splicing represents an essential step toward the production of functional messenger RNAs (mRNAs). Alternative splicing of a single pre-mRNA results in the production of different mRNAs. Although complex organisms use alternative splicing to expand protein function and phenotypic diversity, patterns of alternative splicing are often altered in cancer cells.

Selective recognition of viral promoters by host cell transcription complexes: challenges and opportunities to control latency.

The rate of transcription driven by the HIV promoter defines both the entry into and reactivation from viral latency. The HIV core promoter plays a pivotal role in HIV latency by recruiting host cell RNA polymerase II pre-initiation complexes essential for viral transcription. Pioneering studies on the HIV core promoter revealed that the architecture of the HIV core promoter is specifically required for the amplification of transcription in response to the viral trans-activator Tat, and provided the proof-of-concept that the HIV core promoter represents a tractable drug target.

A rare mechanism of very late bare metal stent thrombosis--role of optical coherence imaging in its evaluation and management.

Very late stent thrombosis is an uncommon event following implantation with bare metal stents (BMS) in coronary arteries. Long term follow up studies have shown that a small number of BMS develop very late thrombosis following years of stability. Atherosclerotic transformation of neointimal tissue is increasingly being recognised as the cause of these adverse events.

HMGA1 directly interacts with TAR to modulate basal and Tat-dependent HIV transcription.

The transactivating response element (TAR) of human immunodeficiency virus 1 (HIV-1) is essential for promoter transactivation by the viral transactivator of transcription (Tat). The Tat-TAR interaction thereby recruits active positive transcription elongation factor b (P-TEFb) from its inactive, 7SK/HEXIM1-bound form, leading to efficient viral transcription. Here, we show that the 7SK RNA-associating chromatin regulator HMGA1 can specifically bind to the HIV-1 TAR element and that 7SK RNA can thereby compete with TAR.

Anterior ECG changes following iatrogenic dissection of the right coronary artery into the aortic root: exclusion of left coronary obstruction with transoesophageal echocardiography.

One of the most troublesome complications of percutaneous coronary intervention (PCI) or angiography is retrograde dissection of the artery into the aortic root. We report a case involving the right coronary artery (RCA) which was treated with prompt deployment of stents. Recurrent chest pain and ST segment elevation in V(2-4) mimicked the ECG appearance of acute anterior infarction and prompted concern that the dissection had extended to impair flow in the left coronary artery (LCA).

CTGC motifs within the HIV core promoter specify Tat-responsive pre-initiation complexes.

Background: HIV latency is an obstacle for the eradication of HIV from infected individuals. Stable post-integration latency is controlled principally at the level of transcription. The HIV trans-activating protein, Tat, plays a key function in enhancing HIV transcriptional elongation.

Probing endogenous RNA polymerase II pre-initiation complexes by electrophoretic mobility shift assay.

RNA polymerase II (Pol II) plays a crucial role in eukaryotic biology since it is necessary for the expression of all protein-coding genes as well as most microRNAs and several small nuclear RNAs. Pol II is specifically recruited to core promoter DNA via its association with general transcription factors (GTFs) that possess DNA binding activity such as TFIID, TFIIA, and TFIIB. The large multi-protein assemblies of Pol II together with the GTFs required for productive transcription are termed pre-initiation complexes (PICs).

Impella assisted transradial coronary intervention in patients with acute coronary syndromes and cardiogenic shock: case series.

Operators may feel apprehension when considering the transradial approach in patients with cardiogenic shock due to concerns of the need for femoral access for mechanical support. There is however potential benefit of transradial approach in this setting by reducing bleeding complications in patients on potent anticoagulant and antiplatelet agents. We report three cases of patients with cardiogenic shock with successful transradial intervention (TRI) whilst using unilateral femoral access for Impella (ABIOMED, Danvers, MA) mechanical support.

Focused clinical review: periprocedural management of antiplatelet therapy in patients with coronary stents.

Coronary stent implantation, particularly drug eluting stents, is now the major method of coronary revascularisation. Following drug-eluting stent implantation dual antiplatelet therapy with aspirin and thienopyridine is recommended for at least 12 months. Premature discontinuation, often at the time of noncardiac surgery, has been associated with stent thrombosis which has a significant risk of death and myocardial infarction.