Modulation of HIV-1 macrophage-tropism among R5 envelopes occurs before detection of neutralizing antibodies

HIV-1 R5 viruses vary widely in their capacity to infect primary macrophages. R5 macrophage-tropism is associated with an increased envelope:CD4 affinity that partly results from an increased exposure of CD4 contact residues on gp120 and allows the use of low levels of CD4 for infection. The selective pressures in vivo that modulate R5 macrophage-tropism are not understood. It is possible that different R5 variants adapt for replication in either T-cells (high CD4) or in macrophages (low CD4). However, other selective pressures in vivo (e.g. neutralizing antibodies) may also impact R5 tropism. Here, we measured macrophage infectivity conferred by gp120 sequences amplified sequentially from subjects in London followed from the acute stage of infection. We report wide variation in the capacity of these envelopes to confer macrophage infection in the complete absence of both autologous and heterologous neutralizing antibodies. Our data show that the variation in macrophage tropism observed at early times cannot have been influenced by neutralizing antibodies

Wind Profile Characteristics and Turbine Performance Analysis in Kano, North-western Nigeria

This study analyzed the electricity generation potential from wind at Kano, Nigeria (12.05°N; 08.2°E; altitude 472.5 m; air density 1.1705 kg/m3). Twenty one years (1987 to 2007) monthly mean wind speed data at a height of 10 m were assessed from the Nigeria Meteorological Department, Oshodi. The data were subjected to different statistical tests and also compared with the two-parameter Weibull probability density function. The outcome shows that the average monthly wind speed ranged from 6.6 to 9.5 m/s. Seasonally, average wind speeds ranged between 6.6 to 8.5 m/s and 7.4 to 9.5 m/s for dry (October to March) and wet (April to September) seasons, respectively. Also, estimated monthly wind power ranged between 3.6 and 12.5 MWh/m2. The most probable and maximum energy carrying wind speeds were also determined and the two parameters of the Weibull statistics were found to lie between 2.1 ≤ k ≤ 4.9 and 7.3 ≤ c ≤ 10.7, respectively. These results indicate that wind speeds at Kano may be economically viable for wind-to-electricity at and above the height of 10 m. In addition, five practical turbine models were assessed for the site’s wind profile, with results suggesting strong economic viabilit

A phase I, randomized study of combined IL-2 and therapeutic immunisation with antiretroviral therapy

BACKGROUND: Fully functional HIV-1-specific CD8 and CD4 effector T-cell responses are vital to the containment of viral activity and disease progression. These responses are lacking in HIV-1-infected patients with progressive disease. We attempted to augment fully functional HIV-1-specific CD8 and CD4 effector T-cell responses in patients with advanced chronic HIV-1 infection. DESIGN: Chronically infected patients with low CD4 counts T-cell counts who commenced antiretroviral therapy (ART) were subsequently treated with combined interleukin-2 and therapeutic vaccination. METHODS: Thirty six anti-retroviral naive patients were recruited and initiated on combination ART for 17 weeks before randomization to: A) ongoing ART alone; B) ART with IL-2 twice daily for 5 days every four weeks starting at week 17 for 3 cycles; C) ART with IL-2 as in group B and Remune HIV-1 vaccine administered once every 3 months, starting at week 17; and D) ART with Remune vaccine as in group C. Patients were studied for 65 weeks following commencement of ART, with an additional prior 6 week lead-in observation period. CD4 and CD8 T-cell counts, evaluations of HIV-1 RNA levels and proliferative responses to recall and HIV-1 antigens were complemented with assessment of IL-4-secretion alongside quantification of anti-HIV-1 CD8 T-cell responses and neutralizing antibody titres. RESULTS: Neither IL-2 nor Remune™ vaccination induced sustained HIV-1-specific T-cell responses. However, we report an inverse relationship between HIV-1-specific proliferative responses and IL-4 production which continuously increased in patients receiving immunotherapy, but not patients receiving ART alone. CONCLUSION: Induction of HIV-1-specific cell-mediated responses is a major challenge in chronically HIV-1-infected patients even when combining immunisation with IL-2 therapy. An antigen-specific IL-4-associated suppressive response may play a role in attenuating HIV-specific responses

The transcriptional repressor protein NsrR senses nitric oxide directly via a [2Fe-2S] cluster

The regulatory protein NsrR, a member of the Rrf2 family of transcription repressors, is specifically dedicated to sensing nitric oxide (NO) in a variety of pathogenic and non-pathogenic bacteria. It has been proposed that NO directly modulates NsrR activity by interacting with a predicted [Fe-S] cluster in the NsrR protein, but no experimental evidence has been published to support this hypothesis. Here we report the purification of NsrR from the obligate aerobe Streptomyces coelicolor. We demonstrate using UV-visible, near UV CD and EPR spectroscopy that the protein contains an NO-sensitive [2Fe-2S] cluster when purified from E. coli. Upon exposure of NsrR to NO, the cluster is nitrosylated, which results in the loss of DNA binding activity as detected by bandshift assays. Removal of the [2Fe-2S] cluster to generate apo-NsrR also resulted in loss of DNA binding activity. This is the first demonstration that NsrR contains an NO-sensitive [2Fe-2S] cluster that is required for DNA binding activity

Characterization of Shewanella oneidensis MtrC: a cell-surface decaheme cytochrome involved in respiratory electron transport to extracellular electron acceptors

MtrC is a decaheme c-type cytochrome associated with the outer cell membrane of Fe(III)-respiring species of the Shewanella genus. It is proposed to play a role in anaerobic respiration by mediating electron transfer to extracellular mineral oxides that can serve as terminal electron acceptors. The present work presents the first spectropotentiometric and voltammetric characterization of MtrC, using protein purified from Shewanella oneidensis MR-1. Potentiometric titrations, monitored by UV–vis absorption and electron paramagnetic resonance (EPR) spectroscopy, reveal that the hemes within MtrC titrate over a broad potential range spanning between approximately +100 and approximately -500 mV (vs. the standard hydrogen electrode). Across this potential window the UV–vis absorption spectra are characteristic of low-spin c-type hemes and the EPR spectra reveal broad, complex features that suggest the presence of magnetically spin-coupled low-spin c-hemes. Non-catalytic protein film voltammetry of MtrC demonstrates reversible electrochemistry over a potential window similar to that disclosed spectroscopically. The voltammetry also allows definition of kinetic properties of MtrC in direct electron exchange with a solid electrode surface and during reduction of a model Fe(III) substrate. Taken together, the data provide quantitative information on the potential domain in which MtrC can operate

Long-term changes in drought indices in eastern and central Europe

This study analyses long-term changes in drought indices (Standardised Precipitation Index—SPI, Standardised Precipitation–Evapotranspiration Index—SPEI) at 1 and 3 months scales at 182 stations in 11 central and eastern European countries during 1949–2018. For comparative purposes, the necessary atmospheric evaporative demand (AED) to obtain SPEI was calculated using two methods, Hargreaves-Samani (SPEIH) and Penman-Monteith (SPEIP). The results show some relevant changes and tendencies in the drought indices. Statistically significant increase in SPI and SPEI during the cold season (November–March), reflecting precipitation increase, was found in the northern part of the study region, in Estonia, Latvia, Lithuania, northern Belarus and northern Poland. In the rest of study domain, a weak and mostly insignificant decrease prevailed in winter. Summer season (June–August) is characterized by changes in the opposite sign. An increase was observed in the north, while a clear decrease in SPEI, reflecting a drying trend, was typical for the southern regions: the Czech Republic, Slovakia, Hungary, Romania, Moldova and southern Poland. A general drying tendency revealed also in April, which was statistically significant over a wide area in the Czech Republic and Poland. Increasing trends in SPI and SPEI for September and October were detected in Romania, Moldova and Hungary. The use of SPEI instead of SPI generally enhances drying trends

Economic evaluation of complete revascularization for patients with multivessel disease undergoing primary percutaneous coronary intervention

Objective: To determine the cost-effectiveness of complete revascularisation at index admission compared to infarct-related artery (IRA) treatment only, in patients with multi-vessel disease undergoing Primary percutaneous coronary intervention (P-PCI) for ST-segment elevation Myocardial Infarction (STEMI). Methods: Economic evaluation of a multi-centre randomised trial comparing complete revascularisation at index admission to IRA-only P-PCI in patients with multi-vessel disease (12 month follow-up). Overall hospital costs (costs for P-PCI procedure(s), hospital stay and any subsequent readmissions) were estimated. Outcomes were major adverse cardiac events (MACE, a composite of all-cause death, recurrent myocardial infarction, heart failure, and ischemia-driven revascularisation) and quality-adjusted life years (QALYs) derived from the EQ-5D-3L. Multiple imputation was undertaken. The mean incremental cost and effects, with associated 95% confidence intervals (95%CI), the incremental cost-effectiveness ratio (ICER) and the cost-effectiveness acceptability curve (CEAC) were estimated. Results: Based on 296 patients, the mean incremental overall hospital cost for complete revascularisation was estimated to be –£215.96 (–£1,390.20 to £958.29), compared to IRA-only, with a per-patient mean reduction in MACE events of 0.170 (0.044 to 0.296) and a QALY gain of 0.011 (-0.019 to 0.041). According to the CEAC, the probability of complete revascularisation being cost-effective was estimated to be 72.0% at willingness to pay of £20,000 per QALY. Conclusions: Complete revascularisation at index admission was estimated to be more effective (in terms of MACE and QALYs) and cost-effective (overall costs were estimated to be lower and complete revascularisation thereby dominated IRA-only). There was, however, some uncertainty associated with this decision