Influence of model assumptions about HIV disease progression after initiating or stopping treatment on estimates of infections and deaths averted by scaling up antiretroviral therapy

Background Many mathematical models have investigated the population-level impact of expanding antiretroviral therapy (ART), using different assumptions about HIV disease progression on ART and among ART dropouts. We evaluated the influence of these assumptions on model projections of the number of infections and deaths prevented by expanded ART. Methods A new dynamic model of HIV transmission among men who have sex with men (MSM) was developed, which incorporated each of four alternative assumptions about disease progression used in previous models: (A) ART slows disease progression; (B) ART halts disease progression; (C) ART reverses disease progression by increasing CD4 count; (D) ART reverses disease progression, but disease progresses rapidly once treatment is stopped. The model was independently calibrated to HIV prevalence and ART coverage data from the United States under each progression assumption in turn. New HIV infections and HIV-related deaths averted over 10 years were compared for fixed ART coverage increases. Results Little absolute difference (<7 percentage points (pp)) in HIV infections averted over 10 years was seen between progression assumptions for the same increases in ART coverage (varied between 33% and 90%) if ART dropouts reinitiated ART at the same rate as ART-naïve MSM. Larger differences in the predicted fraction of HIV-related deaths averted were observed (up to 15pp). However, if ART dropouts could only reinitiate ART at CD4<200 cells/μl, assumption C predicted substantially larger fractions of HIV infections and deaths averted than other assumptions (up to 20pp and 37pp larger, respectively). Conclusion Different disease progression assumptions on and post-ART interruption did not affect the fraction of HIV infections averted with expanded ART, unless ART dropouts only re-initiated ART at low CD4 counts. Different disease progression assumptions had a larger influence on the fraction of HIV-related deaths averted with expanded ART

A Flavin-dependent Monooxygenase from Mycobacterium tuberculosis Involved in Cholesterol Catabolism

Mycobacterium tuberculosis (Mtb) and Rhodococcus jostii RHA1 have similar cholesterol catabolic pathways. This pathway contributes to the pathogenicity of Mtb. The hsaAB cholesterol catabolic genes have been predicted to encode the oxygenase and reductase, respectively, of a flavin-dependent mono-oxygenase that hydroxylates 3-hydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione (3-HSA) to a catechol. An hsaA deletion mutant of RHA1 did not grow on cholesterol but transformed the latter to 3-HSA and related metabolites in which each of the two keto groups was reduced: 3,9-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-17-one (3,9-DHSA) and 3,17-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-9-one (3,17-DHSA). Purified 3-hydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione 4-hydroxylase (HsaAB) from Mtb had higher specificity for 3-HSA than for 3,17-DHSA (apparent k_(cat)/K_m = 1000 ± 100 M^(−1) s^(−1) versus 700 ± 100 M^(−1) s^(−1)). However, 3,9-DHSA was a poorer substrate than 3-hydroxybiphenyl (apparent k_(cat)/K_m = 80 ± 40 M^(−1) s^(−1)). In the presence of 3-HSA the K_(mapp) for O_2 was 100 ± 10 μM. The crystal structure of HsaA to 2.5-Å resolution revealed that the enzyme has the same fold, flavin-binding site, and catalytic residues as p-hydroxyphenyl acetate hydroxylase. However, HsaA has a much larger phenol-binding site, consistent with the enzyme's substrate specificity. In addition, a second crystal form of HsaA revealed that a C-terminal flap (Val^(367)–Val^(394)) could adopt two conformations differing by a rigid body rotation of 25° around Arg^(366). This rotation appears to gate the likely flavin entrance to the active site. In docking studies with 3-HSA and flavin, the closed conformation provided a rationale for the enzyme's substrate specificity. Overall, the structural and functional data establish the physiological role of HsaAB and provide a basis to further investigate an important class of monooxygenases as well as the bacterial catabolism of steroids

Kinetic Mechanism of L-α-Glycerophosphate Oxidase from Mycoplasma pneumoniae

L-α-glycerophosphate oxidase is an FAD-dependent enzyme that catalyzes the oxidation of L-α-glycerophosphate (Glp) by molecular oxygen to generate dihydroxyacetone phosphate (DHAP) and hydrogen peroxide (H₂O₂). The catalytic properties of the recombinant His₆-GlpO from Mycoplasma pneumoniae (His₆-MpGlpO) were investigated with transient and steady-state kinetics and ligand binding. The results indicate that the reaction mechanism of His₆-MpGlpO follows a ping-pong model. Double-mixing stopped-flow experiments show that after flavin-mediate substrate oxidation, DHAP leaves rapidly prior to the oxygen reaction. The values of the individual rate constants and k [subscript]cat (4.2 s⁻¹ at 4 °C) determined, in addition to the finding that H₂O₂ can bind to the oxidized enzyme suggest that H₂O₂ release is the rate-limiting step for the overall reaction. Results indicate that His₆-MpGlpO contains mixed populations of fast and slow reacting species. Only the fast reacting species predominantly participates in turnovers. Different from other GlpO enzymes previously reported, His₆-MpGlpO can catalyze the reverse reaction of reduced enzyme and DHAP. This result can be explained by the standard reduction potential value of His₆-MpGlpO (-167 ± 1 mV), which is lower than those of GlpO from other species. We found that DL-glyceraldehyde 3-phosphate (GAP) can be used as a substrate in the His₆-MpGlpO reaction, although it exhibited a ~100-fold lower k[subscript]cat value in comparison to the reaction of Glp. These results also imply the involvement of GlpO in glycolysis, as well as in lipid and glycerol metabolism. The kinetic models and distinctive properties of His₆-MpGlpO reported here should be useful for future studies of drug development against Mycoplasma pneumoniae infection

High electron mobility, quantum Hall effect and anomalous optical response in atomically thin InSe

A decade of intense research on two-dimensional (2D) atomic crystals has revealed that their properties can differ greatly from those of the parent compound. These differences are governed by changes in the band structure due to quantum confinement and are most profound if the underlying lattice symmetry changes. Here we report a high-quality 2D electron gas in few-layer InSe encapsulated in hexagonal boron nitride under an inert atmosphere. Carrier mobilities are found to exceed 103cm2V-1s-1and 104cm2V-1s-1at room and liquid-helium temperatures, respectively, allowing the observation of the fully developed quantum Hall effect. The conduction electrons occupy a single 2D subband and have a small effective mass. Photoluminescence spectroscopy reveals that the bandgap increases by more than 0.5eV with decreasing the thickness from bulk to bilayer InSe. The band-edge optical response vanishes in monolayer InSe, which is attributed to the monolayer's mirror-plane symmetry. Encapsulated 2D InSe expands the family of graphene-like semiconductors and, in terms of quality, is competitive with atomically thin dichalcogenides and black phosphorus.EU, EPSRC. The Royal Societ

Performance evaluation of premixed burner fueled with biomass derived producer gas

Energy consumption of liquefied petroleum gas (LPG) in ceramic firing process accounts for about 15–40% of production cost. Biomass derived producer gas may be used to replace LPG. In this work, a premixed burner originally designed for LPG was modified for producer gas. Its thermal performance in terms of axial and radial flame temperature distribution, thermal efficiency and emissions was investigated. The experiment was conducted at various gas production rates with equivalence ratios between 0.8 and 1.2. Flame temperatures of over 1200 °C can be achieved, with maximum value of 1260 °C. It was also shown that the burner can be operated at 30.5–39.4 kWth with thermal efficiency in the range of 84 – 91%. The maximum efficiency of this burner was obtained at producer gas flow rate of 24.3 Nm3/h and equivalence ratio of 0.84

Effect of Annealing Temperature on ECD Grown Hexagonal-Plane Zinc Oxide

Zinc oxide (ZnO) offers a great potential in several applications from sensors to Photovoltaic cells thanks to the material&rsquo;s dependency, to its optical and electrical properties and crystalline structure architypes. Typically, ZnO powder tends to be grown in the form of a wurtzite structure allowing versatility in the phase of material growths; albeit, whereas in this work we introduce an alternative in scalable yet relatively simple 2D hexagonal planed ZnO nanoflakes via the electrochemical deposition of commercially purchased Zn(NO3)2 and KCl salts in an electrochemical process. The resulting grown materials were analyzed and characterized via a series of techniques prior to thermal annealing to increase the grain size and improve the crystal quality. Through observation via scanning electron microscope (SEM) images, we have analyzed the statistics of the grown flakes&rsquo; hexagonal plane&rsquo;s size showing a non-monotonal strong dependency of the average flake&rsquo;s hexagonal flakes&rsquo; on the annealing temperature, whereas at 300 &deg;C annealing temperature, average flake size was found to be in the order of 300 &mu;m2. The flakes were further analyzed via transmission electron microscopy (TEM) to confirm its hexagonal planes and spectroscopy techniques, such as Raman Spectroscopy and photo luminescence were applied to analyze and confirm the ZnO crystal signatures. The grown materials also underwent further characterization to gain insights on the material, electrical, and optical properties and, hence, verify the quality of the material for Photovoltaic cells&rsquo; electron collection layer application. The role of KCl in aiding the growth of the less preferable (0001) ZnO is also investigated via various prospects discussed in our work. Our method offers a relatively simple and mass-producible method for synthesizing a high quality 2D form of ZnO that is, otherwise, technically difficult to grow or control

Crystallization and preliminary X-ray crystallographic analysis of 2-methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) oxygenase from Pseudomonas sp. MA-1

This paper describes the first crystallization study of a flavoprotein monooxygenase that can cleave an aromatic compound without requiring a metal-ion cofactor