Subtractive CRISPR screen identifies the ATG16L1/vacuolar ATPase axis as required for non-canonical LC3 lipidation

Although commonly associated with autophagosomes, LC3 can also be recruited to membranes by covalent lipidation in a variety of non-canonical contexts. These include responses to ionophores such as the M2 proton channel of influenza A virus. We report a subtractive CRISPR screen that identifies factors required for non-canonical LC3 lipidation. As well as the enzyme complexes directly responsible for LC3 lipidation in all contexts, we show the RALGAP complex is important for M2-induced, but not ionophore drug-induced, LC3 lipidation. In contrast, ATG4D is responsible for LC3 recycling in M2-induced and basal LC3 lipidation. Identification of a vacuolar ATPase subunit in the screen suggests a common mechanism for non-canonical LC3 recruitment. Influenza-induced and ionophore drug-induced LC3 lipidation lead to association of the vacuolar ATPase and ATG16L1 and can be antagonized by Salmonella SopF. LC3 recruitment to erroneously neutral compartments may therefore represent a response to damage caused by diverse invasive pathogens

The Evolving Landscape of the Economics of HIV Treatment and Prevention

Bohdan Nosyk and Julio Montaner argue that the cost-effectiveness of HAART roll out has been significantly underestimated because economic analyses haven't yet taken into account the beneficial impact of HAART on HIV transmission

How can we get close to zero? The potential contribution of biomedical prevention and the investment framework towards an effective response to HIV.

BACKGROUND: In 2011 an Investment Framework was proposed that described how the scale-up of key HIV interventions could dramatically reduce new HIV infections and deaths in low and middle income countries by 2015. This framework included ambitious coverage goals for prevention and treatment services resulting in a reduction of new HIV infections by more than half. However, it also estimated a leveling in the number of new infections at about 1 million annually after 2015. METHODS: We modeled how the response to AIDS can be further expanded by scaling up antiretroviral treatment (ART) within the framework provided by the 2013 WHO treatment guidelines. We further explored the potential contributions of new prevention technologies: 'Test and Treat', pre-exposure prophylaxis and an HIV vaccine. FINDINGS: Immediate aggressive scale up of existing approaches including the 2013 WHO guidelines could reduce new infections by 80%. A 'Test and Treat' approach could further reduce new infections. This could be further enhanced by a future highly effective pre-exposure prophylaxis and an HIV vaccine, so that a combination of all four approaches could reduce new infections to as low as 80,000 per year by 2050 and annual AIDS deaths to 260,000. INTERPRETATION: In a set of ambitious scenarios, we find that immediate implementation of the 2013 WHO antiretroviral therapy guidelines could reduce new HIV infections by 80%. Further reductions may be achieved by moving to a 'Test and Treat' approach, and eventually by adding a highly effective pre-exposure prophylaxis and an HIV vaccine, if they become available

Machine-learning-corrected quantum dynamics calculations

Quantum scattering calculations for all but low-dimensional systems at low energies must rely on approximations. All approximations introduce errors. The impact of these errors is often difficult to assess because they depend on the Hamiltonian parameters and the particular observable under study. Here, we illustrate a general, system and approximation-independent, approach to improve the accuracy of quantum dynamics approximations. The method is based on a Bayesian machine learning (BML) algorithm that is trained by a small number of rigorous results and a large number of approximate calculations, resulting in ML models that accurately capture the dependence of the dynamics results on the quantum dynamics parameters. Most importantly, the present work demonstrates that the BML models can generalize quantum results to different dynamical processes. Thus, a ML model trained by a combination of approximate and rigorous results for a certain inelastic transition can make accurate predictions for different transitions without rigorous calculations. This opens the possibility of improving the accuracy of approximate calculations for quantum transitions that are out of reach of rigorous scattering calculations.Comment: 6 pages, 4 figure

AT514, a cyclic depsipeptide from Serratia marcescens, induces apoptosis of B-chronic lymphocytic leukemia cells. Interference with the Akt/NF-kB survival pathway

8 páginas, 5 figuras -- PAGS nros. 572-579Clinical treatment of B-cell chronic lymphocytic leukemia (B-CLL) is limited by the progressive drug resistance and nonselectivity of most drugs towards malignant cells. Depsipeptides are present in certain bacteria and display potent antitumor activity. We have studied the effect of the novel cyclodepsipeptide AT514 (serratamolide) from Serratia marcescens on B-CLL cell viability. AT514 induced apoptosis of B-CLL cells from the 21 patients studied, as confirmed by Annexin-V binding and nuclei condensation, with an average IC50 of 13 M. AT514 was effective in those B-CLL cases resistant to fludarabine, but had no effect on normal PBL. AT514 preferentially activated the intrinsic apoptotic pathway, as evidenced by loss of mitochondrial membrane potential, release of cytochrome c and activation of caspase-9 and -3, but not of caspase-8. Importantly, AT514 interfered with phosphatidylinositol-3 kinase and protein kinase C survival signals since it increased the apoptotic effect of LY294002 and BisI inhibitors, and induced Akt dephosphorylation at Ser 473. AT514 also decreased NF-B activity by dramatically reducing the levels of p65 in B-CLL. This was confirmed on functional assays using NF-B-luc-transfected Raji cells and transgenic mice. Our results establish that AT514 induces apoptosis of primary B-CLL cells and could be useful for clinical treatment of this malignancyThis work was supported by grants 08.3/0030.1/2003 from the Comunidad Autónoma de Madrid, SAF2003-00824 from the Ministerio de Ciencia y Tecnología (MCyT), and 01/1183 from Fondo de Investigación Sanitaria (to AGP); and CIDEM Grant 301888 (Generalitat de Catalunya)/Fundació Bosch i Gimpera, to RPT). E Escobar and E López-Martín were supported by fellowships from MCyTPeer reviewe

A NOVEL INDEX OF ABUNDANCE OF JUVENILE YELLOWFIN TUNA IN THE ATLANTIC OCEAN DERIVED FROM ECHOSOUNDER BUOYS

The collaboration with the Spanish vessel-owners associations and the buoy-providers companies, has made it possible the recovery of the information recorded by the satellite linked GPS tracking echosounder buoys used by the Spanish tropical tuna purse seiners and associated fleet in the Atlantic since 2010. These instrumental buoys inform fishers remotely in real-time about the accurate geolocation of the FAD and the presence and abundance of fish aggregations underneath them. Apart from its unquestionable impact in the conception of a reliable CPUE index from the tropical purse seine tuna fisheries fishing on FADs, echosounder buoys have also the potential of being a privileged observation platform to evaluate abundances of tunas and accompanying species using catch-independent data. Current echosounder buoys provide a single acoustic value without discriminating species or size composition of the fish underneath the FAD. Therefore, it has been necessary to combine the echosounder buoys data with fishery data, species composition and average size, to obtain a specific indicator. This paper presents a novel index of abundance of juvenile yellowfin tuna in the Atlantic Ocean derived from echosounder buoys for the period 2010-2018

CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells

The persistence of HIV reservoirs, including latently infected, resting CD4+ T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to mark CD4+ T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4+ T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV+ or SIV+ subjects, we found that most of the circulating memory CD32+ CD4+ T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a TH2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4+ T cells in peripheral blood or lymphoid tissue; isolated CD32+ resting CD4+ T cells accounted for less than 3% of the total HIV DNA in CD4+ T cells. Cell-associated HIV DNA and RNA loads in CD4+ T cells positively correlated with the frequency of CD32+ CD69+ CD4+ T cells but not with CD32 expression on resting CD4+ T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4+ T cells or of enriched HIV DNA–positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4+ T cells enriched for transcriptionally active HIV after long-term ART

Factors Associated With the Frequency of Monitoring of Liver Enzymes, Renal Function and Lipid Laboratory Markers Among Individuals Initiating Combination Antiretroviral Therapy: A Cohort Study

Background As the average age of the HIV-positive population increases, there is increasing need to monitor patients for the development of comorbidities as well as for drug toxicities. Methods We examined factors associated with the frequency of measurement of liver enzymes, renal function tests, and lipid levels among participants of the Canadian Observational Cohort (CANOC) collaboration which follows people who initiated HIV antiretroviral therapy in 2000 or later. We used zero-inflated negative binomial regression models to examine the associations of demographic and clinical characteristics with the rates of measurement during follow-up. Generalized estimating equations with a logit link were used to examine factors associated with gaps of 12 months or more between measurements. Results Electronic laboratory data were available for 3940 of 7718 CANOC participants. The median duration of electronic follow-up was 3.5 years. The median (interquartile) rates of tests per year were 2.76 (1.60, 3.73), 2.55 (1.44, 3.38) and 1.42 (0.50, 2.52) for liver, renal and lipid parameters, respectively. In multivariable zero-inflated negative binomial regression models, individuals infected through injection drug use (IDU) were significantly less likely to have any measurements. Among participants with at least one measurement, rates of measurement of liver, renal and lipid tests were significantly lower for younger individuals and Aboriginal Peoples. Hepatitis C co-infected individuals with a history of IDU had lower rates of measurement and were at greater risk of having 12 month gaps between measurements. Conclusions Hepatitis C co-infected participants infected through IDU were at increased risk of gaps in testing, despite publicly funded health care and increased risk of comorbid conditions. This should be taken into consideration in analyses examining factors associated with outcomes based on laboratory parameters

Expert consensus statement on the science of HIV in the context of criminal law

INTRODUCTION: Globally, prosecutions for non-disclosure, exposure or transmission of HIV frequently relate to sexual activity, biting, or spitting. This includes instances in which no harm was intended, HIV transmission did not occur, and HIV transmission was extremely unlikely or not possible. This suggests prosecutions are not always guided by the best available scientific and medical evidence. DISCUSSION: Twenty scientists from regions across the world developed this Expert Consensus Statement to address the use of HIV science by the criminal justice system. A detailed analysis of the best available scientific and medical research data on HIV transmission, treatment effectiveness and forensic phylogenetic evidence was performed and described so it may be better understood in criminal law contexts. Description of the possibility of HIV transmission was limited to acts most often at issue in criminal cases. The possibility of HIV transmission during a single, specific act was positioned along a continuum of risk, noting that the possibility of HIV transmission varies according to a range of intersecting factors including viral load, condom use, and other risk reduction practices. Current evidence suggests the possibility of HIV transmission during a single episode of sex, biting or spitting ranges from no possibility to low possibility. Further research considered the positive health impact of modern antiretroviral therapies that have improved the life expectancy of most people living with HIV to a point similar to their HIV-negative counterparts, transforming HIV infection into a chronic, manageable health condition. Lastly, consideration of the use of scientific evidence in court found that phylogenetic analysis alone cannot prove beyond reasonable doubt that one person infected another although it can be used to exonerate a defendant. CONCLUSIONS: The application of up-to-date scientific evidence in criminal cases has the potential to limit unjust prosecutions and convictions. The authors recommend that caution be exercised when considering prosecution, and encourage governments and those working in legal and judicial systems to pay close attention to the significant advances in HIV science that have occurred over the last three decades to ensure current scientific knowledge informs application of the law in cases related to HIV.publishersversionpublishe