Vitamin D Inhibits Human Immunodeficiency Virus Type 1 and Mycobacterium tuberculosis Infection in Macrophages through the Induction of Autophagy

Low vitamin D levels in human immunodeficiency virus type-1 (HIV) infected persons are associated with more rapid disease progression and increased risk for Mycobacterium tuberculosis infection. We have previously shown that 1α,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D, inhibits HIV replication in human macrophages through the induction of autophagy. In this study, we report that physiological concentrations of 1,25D3 induce the production of the human cathelicidin microbial peptide (CAMP) and autophagic flux in HIV and M. tuberculosis co-infected human macrophages which inhibits mycobacterial growth and the replication of HIV. Using RNA interference for Beclin-1 and the autophagy-related 5 homologue, combined with the chemical inhibitors of autophagic flux, bafilomycin A1, an inhibitor of autophagosome-lysosome fusion and subsequent acidification, and SID 26681509 an inhibitor of the lysosome hydrolase cathepsin L, we show that the 1,25D3-mediated inhibition of HIV replication and mycobacterial growth during single infection or dual infection is dependent not only upon the induction of autophagy, but also through phagosomal maturation. Moreover, through the use of RNA interference for CAMP, we demonstrate that cathelicidin is essential for the 1,25D3 induced autophagic flux and inhibition of HIV replication and mycobacterial growth. The present findings provide a biological explanation for the benefits and importance of vitamin D sufficiency in HIV and M. tuberculosis-infected persons, and provide new insights into novel approaches to prevent and treat HIV infection and related opportunistic infections

Selective cell death of latently HIV-infected CD4+ T cells mediated by autosis inducing nanopeptides.

Despite significant advances in the treatment of human immunodeficiency virus type-1 (HIV) infection, antiretroviral therapy only suppresses viral replication but is unable to eliminate infection. Thus, discontinuation of antiretrovirals results in viral reactivation and disease progression. A major reservoir of HIV latent infection resides in resting central memory CD4+ T cells (TCM) that escape clearance by current therapeutic regimens and will require novel strategies for elimination. Here, we evaluated the therapeutic potential of autophagy-inducing peptides, Tat-Beclin 1 and Tat-vFLIP-α2, which can induce a novel Na+/K+-ATPase dependent form of cell death (autosis), to kill latently HIV-infected TCM while preventing virologic rebound. In this study, we encapsulated autophagy inducing peptides into biodegradable lipid-coated hybrid PLGA (poly lactic-co-glycolic acid) nanoparticles for controlled intracellular delivery. A single dose of nanopeptides was found to eliminate latent HIV infection in an in vitro primary model of HIV latency and ex vivo using resting CD4+ T cells obtained from peripheral blood mononuclear cells of HIV-infected patients on antiretroviral with fully suppressed virus for greater than 12 months. Notably, increased LC3B lipidation, SQSTM1/p62 degradation and Na+/K+-ATPase activity characteristic of autosis, were detected in nanopeptide treated latently HIV-infected cells compared to untreated uninfected or infected cells. Nanopeptide-induced cell death could be reversed by knockdown of autophagy proteins, ATG5 and ATG7, and inhibition or knockdown of Na+/K+-ATPase. Importantly, viral rebound was not detected following the induction of the Na+/K+-ATPase dependent form of cell death induced by the Tat-Beclin 1 and Tat-vFLIP-α2 nanopeptides. These findings provide a novel strategy to eradicate HIV latently infected resting memory CD4+ T cells, the major reservoir of HIV latency, through the induction of Na+/K+-ATPase dependent autophagy, while preventing reactivation of virus and new infection of uninfected bystander cells

Minimal access surgery compared with medical management for gastro-oesophageal reflux disease : five year follow-up of a randomised controlled trial (REFLUX)

Peer reviewedPublisher PD

Are existing soils data meeting the needs of stakeholders in Europe? An analysis of practical use from policy to field

Soils form a major component of the natural system and their functions underpin many key ecosystem goods and services. The fundamental importance of soils in the environment means that many different organisations and stakeholders make extensive use of soils data and information in their everyday working practices. For many reasons, stakeholders are not always aware that they are reliant upon soil data and information to support their activities. Various reviews of stakeholder needs and how soil information could be improved have been carried out in recent years. However, to date, there has been little consideration of user needs from a non-expert perspective. The aim of this study was to explore the use of explicit and hidden soil information in different organisations across Europe and gain a better understanding of improvements needed in soil data and information to assist in practical use by non-expert stakeholders. An on-line questionnaire was used to investigate different uses of soils data and information with 310 responses obtained from 77 organisations across Europe. Results illustrate the widespread use of soil data and information across diverse organisations within Europe, particularly spatial products and soil functional assessments and tools. A wide range of improvements were expressed with a prevalence for finer scale resolution, trends over time, future scenarios, improved accuracy, non-technical supporting information and better capacity to use GIS. An underlying message is that existing legacy soils data need to be supplemented by new up-to-date data to meet stakeholder needs and information gaps

Clinical and economic evaluation of laparoscopic surgery compared with medical management for gastro-oesophageal reflux disease : 5-year follow-up of multicentre randomised trial (the REFLUX trial)

Peer reviewedPublisher PD

Occupational Therapy for Adults With Cancer: Why It Matters

Adults with cancer may be at risk for limitations in functional status and quality of life (QOL). Occupational therapy is a supportive service with the specific mission to help people functionally engage in life as safely and independently as possible with the primary goal of improving QOL. Unfortunately, for people with cancer, occupational therapy remains underused. The overall purpose of this review is to provide an understanding of what occupational therapy is and its relevance to patients with cancer, highlight the reasons to refer, and, last, provide general advice on how to access services

Planet Four: Terrains - Discovery of Araneiforms Outside of the South Polar Layered Deposits

We present the results of a systematic mapping of seasonally sculpted terrains on the South Polar region of Mars with the Planet Four: Terrains (P4T) online citizen science project. P4T enlists members of the general public to visually identify features in the publicly released Mars Reconnaissance Orbiter CTX images. In particular, P4T volunteers are asked to identify: 1) araneiforms (including features with a central pit and radiating channels known as 'spiders'); 2) erosional depressions, troughs, mesas, ridges, and quasi-circular pits characteristic of the South Polar Residual Cap (SPRC) which we collectively refer to as 'Swiss cheese terrain', and 3) craters. In this work we present the distributions of our high confidence classic spider araneiforms and Swiss cheese terrain identifications. We find no locations within our high confidence spider sample that also have confident Swiss cheese terrain identifications. Previously spiders were reported as being confined to the South Polar Layered Deposits (SPLD). Our work has provided the first identification of spiders at locations outside of the SPLD, confirmed with high resolution HiRISE imaging. We find araneiforms on the Amazonian and Hesperian polar units and the Early Noachian highland units, with 75% of the identified araneiform locations in our high confidence sample residing on the SPLD. With our current coverage, we cannot confirm whether these are the only geologic units conducive to araneiform formation on the Martian South Polar region. Our results are consistent with the current CO2 jet formation scenario with the process exploiting weaknesses in the surface below the seasonal CO2 ice sheet to carve araneiform channels into the regolith over many seasons. These new regions serve as additional probes of the conditions required for channel creation in the CO2 jet process. (Abridged)Comment: accepted to Icarus - Supplemental data files are available at https://www.zooniverse.org/projects/mschwamb/planet-four-terrains/about/results - Icarus print version available at http://www.sciencedirect.com/science/article/pii/S001910351730055

Quantitative changes in soil organic C over 37 years under conventional tillage - effect of crop rotations and fertilizers

Non-Peer Reviewe