Exploring the relationship between heavy metals and diabetic retinopathy: a machine learning modeling approach.

Diabetic retinopathy (DR) is one of the leading causes of adult blindness in the United States. Although studies applying traditional statistical methods have revealed that heavy metals may be essential environmental risk factors for diabetic retinopathy, there is a lack of analyses based on machine learning (ML) methods to adequately explain the complex relationship between heavy metals and DR and the interactions between variables. Based on characteristic variables of participants with and without DR and heavy metal exposure data obtained from the NHANES database (2003-2010), a ML model was developed for effective prediction of DR. The best predictive model for DR was selected from 11 models by receiver operating characteristic curve (ROC) analysis. Further permutation feature importance (PFI) analysis, partial dependence plots (PDP) analysis, and SHapley Additive exPlanations (SHAP) analysis were used to assess the model capability and key influencing factors. A total of 1042 eligible individuals were randomly assigned to two groups for training and testing set of the prediction model. ROC analysis showed that the k-nearest neighbour (KNN) model had the highest prediction performance, achieving close to 100% accuracy in the testing set. Urinary Sb level was identified as the critical heavy metal affecting the predicted risk of DR, with a contribution weight of 1.730632 ± 1.791722, which was much higher than that of other heavy metals and baseline variables. The results of the PDP analysis and the SHAP analysis also indicated that antimony (Sb) had a more significant effect on DR. The interaction between age and Sb was more significant compared to other variables and metal pairs. We found that Sb could serve as a potential predictor of DR and that Sb may influence the development of DR by mediating cellular and systemic senescence. The study revealed that monitoring urinary Sb levels can be useful for early non-invasive screening and intervention in DR development, and also highlighted the important role of constructed ML models in explaining the effects of heavy metal exposure on DR.

Association of retinopathy with risk of all-cause and specific-cause mortality in the National Health and Nutrition Examination Survey, 2005 to 2008.

Objective: This study aimed to elucidate the relationship between retinopathy status or severity and the all-cause and specific-cause mortality risk based on the updated National Health and Nutrition Examination Survey (NHANES) database and 2019 Public Access Link mortality file. Methods: In this prospective cohort study, a total of 6,797 participants aged over 40 years based on NHANES 2005-2008 were analyzed. The severity of retinopathy was classified into 4 grades-no retinopathy, mild non-proliferative retinopathy (NPR), moderate to severe NPR, and proliferative retinopathy (PR). Multiple covariate-adjusted Cox proportional hazards regression models and Fine and Gray competing risk regression models were used to assess the all-cause and cause-specific mortality risks, respectively. The propensity score matching (PSM) approach was also applied additionally to adequately balance between-group covariates to validate our findings. Results: A final total of 4,808 participants representing 18,282,772 United States (US) non-hospitalized participants were included for analysis, 50.27% were male (n = 2,417), 55.32% were non-hispanic white (n = 2,660), and mean [SE] age, 56.10 [0.40] years. After a median follow-up of 12.24 years (interquartile range, 11.16-13.49 years), 1,164 participants died of all-cause mortality, of which 941 (80.84%) died without retinopathy and 223 (19.16%) died with retinopathy at baseline. The presence of retinopathy was associated with increased all-cause mortality, cardiovascular disease (CVD), and diabetes mellitus (DM)-specific mortality, and the results remain consistent after PSM. Severity analysis showed that only mild NPR was associated with an increased all-cause mortality risk (hazard ratio (HR) = 2.01; 95% confidence interval (CI), 1.00-4.03), while increased CVD and DM-specific mortality risk were associated with all grades of retinopathy and were exponentially greater with increasing retinopathy severity, and the trend test was also significant (P for trend 0.004 and 0.04, respectively). Discussion: Our findings suggest that the diagnosis of retinopathy is an independent risk factor for all-cause mortality in people over 40 years old. Retinopathy grading is significantly associated with the survival risk of patients with CVD or DM, it can be a valuable predictor in the stratified management and risk warning of CVD or DM patients, as well as in the monitoring of systemic vasculopathy status.

Emerging roles of air pollution and meteorological factors in autoimmune eye diseases.

Autoimmune eye diseases (AEDs), a collection of autoimmune inflammatory ocular conditions resulting from the dysregulation of immune system at the ocular level, can target both intraocular and periorbital structures leading to severe visual deficit and blindness globally. The roles of air pollution and meteorological factors in the initiation and progression of AEDs have been increasingly attractive, among which the systemic and local mechanisms are both involved in. Exposure to excessive air pollution and extreme meteorological conditions including PM2.5/PM0.1, environmental tobacco smoke, insufficient sunshine, and high temperature, etc., can disturb Th17/Treg balance, regulate macrophage polarization, activate neutrophils, induce systemic inflammation and oxidative stress, decrease retinal blood flow, promote tissue fibrosis, activate sympathetic nervous system, adversely affect nutrients synthetization, as well as induce heat stress, therefore may together deteriorate AEDs. The crosstalk among inflammation, oxidative stress and dysregulated immune system appeared to be prominent. In the present review, we will concern and summarize the potential mechanisms underlying linkages of air pollution and meteorological factors to ocular autoimmune and inflammatory responses. Moreover, we concentrate on the specific roles of air pollutants and meteorological factors in several major AEDs including uveitis, Graves' ophthalmopathy (GO), ocular allergic disease (OAD), glaucoma, diabetic retinopathy (DR), etc.

Extensive and Differential Deterioration of Hip Muscles May Preexist in Older Adults with Hip Fractures: Evidence from a Cross-Sectional Study.

Hip muscles play an increasingly important role in lower limb function with aging. Investigating the deterioration of hip muscles and its relationship with hip fracture (HF) may help identify older adults prone to fall. In this study, patients with fall-related HF within 48 h and non-fracture controls aged ≥ 60 years were enrolled. The cross-sectional area (size) and attenuation (density) of the hip flexors, extensors, adductors, and abductors were calculated after segmentation on computed tomography images. The correlation of muscle parameters with HF and age were evaluated using logistic and multiple regression, respectively. Discrimination of HF was analyzed by receiver-operating characteristic analyses. A total of 220 patients and 91 controls were included. The size of the flexors, extensors, and abductors, and the density of the flexors, adductors, and abductors were lower in patients with HF after adjustment for sex, age, and body mass index (BMI). However, decreased muscle size was only observed in hip extensors in patients aged 60-74 years. Decreased muscle size was associated with HF independent of sex, age, BMI, and hip trabecular bone mineral density. Abductor size exhibited a significantly larger negative correlation with age in patients compared to controls. Including abductor size or all muscle size was effective for discrimination of HF in patients aged ≥ 75 years. In conclusion, older adults with HF may have sustained extensive and differential hip muscle deterioration before the injury; extensor atrophy in younger-old age and consideration of a closer relationship between abductor size and age deserve attention.

Spatial distribution of hip cortical thickness in postmenopausal women with different osteoporotic fractures.

Few studies h ave discussed the association between cortical bone outside the fracture site and the fracture itself. Focusing on hip cortical thickness, this study revealed distinct distributions of the parameters for hip (trochanteric or femoral neck), vertebral, and peripheral osteoporotic fractures and suggested that the spatial distribution of hip cortical thickness was fracture-specific. PURPOSE: Cortical bone is critical for bone strength. Hip cortical thickness is reported to be closely associated with the incidence of hip fractures, but its relationship with nonhip fractures is rarely studied. As the hip is a major site for fracture risk assessment, it would be of great benefit to investigate the association between hip cortical thickness and different osteoporotic fractures. METHODS: One hundred age-matched postmenopausal women were equally assigned to 4 osteoporotic fracture groups (trochanteric, femoral neck, vertebral, and peripheral fractures) and a nonfracture group. Each subject had a clinical quantitative computed tomography scan of the bilateral hips and the lumbar spine. A cortical bone mapping algorithm was adopted to calculate hip cortical thickness. Hip and lumbar trabecular density and the hip cortical thickness distribution were compared among the groups. RESULTS: All the fracture groups presented lower lumbar trabecular density. Compared with nonfracture controls, patients with hip or vertebral fractures but not peripheral fractures showed decreased cortical thickness and trabecular density of the hip. Fracture-specific distributions of cortical thickness were revealed, including zonal defects on the neck-intertrochanter junction, greater trochanter, and the periphery of the lesser trochanter for trochanteric fractures, a focal defect on the anterosuperior neck for femoral neck fractures, a moderate and average distribution for vertebral fractures, and focally thicker cortices on the anterosuperior greater trochanter and the periphery of the lesser trochanter for peripheral fractures. CONCLUSION: The spatial distribution of hip cortical thickness was different for each type of osteoporotic fracture, and patients with centrally located fractures demonstrated more severe cortical deterioration. This finding needs to be validated in a larger sample.

Hierarchical-pore UiO-66 modified with Ag+ for π-complexation adsorption desulfurization.

Adsorption desulfurization represents an alternative technology for the effective removal of thiophenic compounds from fuels. Metal-organic frameworks have been the ideal candidates for the adsorptive desulfurization of fuel due to the high surface areas. Pristine UiO-66 is thought to be appropriate for the removal of small thiophenic compounds. This work developed a new type of hierarchical-pore (micro and mesopores) UiO-66 with a higher specific surface area and porosity for the removal of larger adsorbates using MOF-5 as the template. To enhance adsorption desulfurization performance, the Ag+-exchanged hierarchical-pore UiO-66 (HP-UiO-66-SO3Ag) with π-complexation was synthesized by the ion-exchange method. The HP-UiO-66-SO3Ag samples were characterized by FTIR, XRD, SEM, TEM, and N2 adsorption-desorption isotherms. Compared with the original UiO-66, the HP-UiO-66-SO3Ag has a higher specific surface area, pore volume, and pore size. The static adsorption experiments showed that HP-UiO-66-SO3Ag had a high adsorption capacity for thiophene and benzothiophene. Moreover, the HP-UiO-66-SO3Ag sample still exhibits high adsorptive performance in the presence of toluene. The regeneration results show that about 90% of the initial adsorption capacity of HP-UiO-66-SO3Ag can be regenerated after four cycles.

The comparison of bone mineral density of femoral head between non-hip fracture side and hip fracture side.

We aimed to analyze the associations of bone mineral density (BMD) of femoral heads, age and gender, and compare the differences in BMD between fracture side and non-fracture side by "3D Spine Exam Analysis" module in QCT Pro software. In this study, we identified patients who had undergone quantitative computed tomography (QCT) examinations between March 2016 and July 2018 and measured their trabecular volumetric BMD (vBMD) of femoral heads. This retrospective study enrolled 367 subjects. A total of 149 participants with images were randomly selected to verify the repeatability of this method. The relationship among the vBMD, age and gender was analyzed (n = 367), and the difference of vBMD between non-fracture side and fracture side were studied in subjects (n = 75) with low-energy hip fracture on one side and compared the image quality of bilateral hip joints. The intraclass correlation coefficients (ICCs) between the results measured by 2 operators and the results measured by the same operator showed excellent agreement (ICCs > 0.9). Multivariate regression equation of vBMD of femoral head, age and gender showed statistical significance (P < 0.05). vBMD showed negative correlation with age (P < 0.05), and showed no statistically significant relation with gender (P > 0.05). vBMD of non-fracture side was higher than that of fracture side, but the difference was statistically significant only at the middle layer (Pmiddle < 0.05). In conclusions, the vBMD of femoral head as measured by "3D Spine Exam Analysis" module in QCT Pro software showed good repeatability. The trabecular vBMD of femoral head was negatively correlated with age, and not related with gender. The vBMD of femoral head was higher on non-fracture side than that on the fracture side.

Preparation of Magnetic Ni0.5Zn0.5Fe2O4/ZnO Nanocomposites and Their Photocatalytic Performances for Methylene Blue in Aqueous Solution.

Magnetic Ni0.5Zn0.5Fe2O4/ZnO-R (NZFO/ZnO-R) nanocomposites are prepared via the rapid combustion-coprecipitation process, and they are characterized by the Fourier Transform Infrared Spectroscopy (FTIR), the X-ray Diffraction (XRD), the Scanning Electron Microscopy (SEM), the Energy Dispersive X-ray Detector (EDX), the Specific Surface Area (BET), the UV-vis Diffuse Reflection Spectroscopy (DRS), and the Vibrating Sample Magnetometer (VSM). The photocatalytic activity of NZFO/ZnO-R nanocomposites is assessed in ultraviolet light (365 nm) by decoloration of methylene blue (MB). The results show that the magnetic NZFO/ZnO-0.2 nanocomposites consist of particles and rods. The size of particles is 18 nm. The width and length of rods are 66 nm and 198 nm, respectively. NZFO/ZnO-0.5 nanocomposites have better photocatalytic performance than that of NZFO, ZnO and NZFO/ZnO-R (R = 0.2, 0.3, 0.4, 0.6, or 0.7) from the results. Through careful investigation of influencing parameters (the amount of catalysts, pH and concentration of MB solution), the degradation efficiency of MB is closely connected with the transparency of solution and surface charge of catalysts. The enhanced photocatalytic activity of NZFO/ZnO-0.5 nanocomposites can be ascribed to the matching band positions between ZnO and NZFO, which results in a low recombination between the photogenerated electron-hole pairs. The possible mechanism is proposed for the improved ultraviolet photocatalytic activity of NZFO/ZnO-0.5 nanocomposites.

Systematic Differences Between Perceptually Relevant Image Statistics of Brain MRI and Natural Images.

It is well-known that the human visual system is adapted to the statistical structure of natural scenes. Yet there are important classes of images - for example, medical images - that are not natural scenes, and therefore, that are expected to have statistical properties that deviate from the class of images that shaped the evolution and development of human vision. Here, focusing on structural brain MRI images, we quantify and characterize these deviations in terms of a set of local image statistics to which human visual sensitivity has been well-characterized, and that has previously been used for natural image analysis. We analyzed MRI images in multiple databases including T1-weighted and FLAIR sequence types, and simulated MRI images based on a published image simulation procedure for T1 images, which we also modified to generate FLAIR images. We first computed the power spectra of MRI images; spectral slopes were in the range -2.6 to -3.1 for T1 sequences, and -2.2 to -2.7 for FLAIR sequences. Analysis of local image statistics was then carried out on whitened images. For all of the databases as well as for the simulated images, we found that the three-point correlations contributed substantially to the differences between the "texture" of randomly selected ROIs. The informative nature of three-point correlations for brain MRI was greater than for natural images, and also disproportionate to human visual sensitivity. As this finding was consistent across databases, it is likely to result from brain geometry at the scale of brain MRI resolution, rather than characteristics of specific imaging and reconstruction methods.

Structural basis for the recognition of MucA by MucB and AlgU in Pseudomonas aeruginosa.

Alginate production in Pseudomonas aeruginosa is regulated by the alternate σ factor AlgU, which in turn is regulated by the MucABCD system. The anti-σ factor MucA binds AlgU in the cytoplasm and prevents AlgU from binding to the RNA polymerase for transcription. MucB binds MucA in the periplasm and inhibits proteolysis of MucA and subsequent release of AlgU. In this work, we report crystal structures of MucA in complex with AlgU and MucB. A structure of MucB alone reveals the structural changes required for MucA recognition. A unique disulfide bond is identified in MucB, and mutation of this disulfide bond results in a shift from monomer to MucB dimers or tetramers. As MucB tetramers have previously been shown to be unable to bind MucA, this suggests a redox-sensitive stress response mechanism in MucB. The AlgU-MucA structure reveals a conserved σ factor/anti-σ factor complex, but AlgU lacks a disulfide bond conserved in many other σ factors. Our structures reveal the molecular basis for MucA recognition by MucB in the periplasm and AlgU in the cytoplasm, thus providing an important step in understanding the mechanisms that regulate a key signal transduction pathway involved in P. aeruginosa pathogenesis. DATABASE: The atomic coordinates and structure factors for MucAcyto -AlgU, MucB, and MucAperi -MucB have been deposited in the Protein Data Bank (PDB) with the accession code 6IN7, 6IN8, and 6IN9, respectively.

Structural analysis of activating mutants of YfiB from Pseudomonas aeruginosa PAO1.

Bacterial cyclic-di-GMP (c-di-GMP) is an important messenger molecule that influences diverse cellular processes including motility, virulence and cytotoxicity systems, polysaccharide synthesis and biofilm formation. The YfiBNR tripartite signalling system in P. aeruginosa modulates the cellular c-di-GMP levels in response to signals received from the periplasm. In this study, we analyse the structures of activating mutants of the outer membrane protein YfiB that give rise to increased surface attachment and biofilm formation. The F48S and W55L mutants of YfiB(27-168) crystallize in the same dimeric arrangement as our previously reported YfiB structures that preclude complex formation with YfiR. The L43P mutant of YfiB(27-168) is monomeric and forms a stable complex with YfiR. The YfiB(L43P)-YfiR crystal structure reveals a dramatic rearrangement of the N-terminal fragment, which is implicated in increased YfiB activation and membrane attachment, upon YfiR binding. Comparison with our previous complex structure between YfiB(59-168) and YfiR reveals extensive interactions between the N-terminal fragment of YfiB (residues 35-55) and YfiR.

Synthesis of a MnO2/Fe3O4/diatomite nanocomposite as an efficient heterogeneous Fenton-like catalyst for methylene blue degradation.

Heterogeneous Fenton-like catalysts with the activation of peroxymonosulfate (PMS), which offer the advantages of fast reaction rate, wide functional pH range and cost efficiency, have attracted great interest in wastewater treatment. In this study, a novel magnetic MnO2/Fe3O4/diatomite nanocomposite is synthesized and then used as heterogeneous Fenton-like catalyst to degrade the organic pollutant methylene blue (MB) with the activation of PMS. The characterization results show that the Fe3O4 nanoparticles and nanoflower-like MnO2 are evenly distributed layer-by-layer on the surface of diatomite, which can be readily magnetically separated from the solution. The as-prepared catalyst, compared with other Fenton-like catalysts, shows a superb MB degradation rate of nearly 100% in 45 min in the pH range of 4 to 8 and temperature range of 25 to 55 °C. Moreover, the nanocomposite shows a good mineralization rate of about 60% in 60 min and great recyclability with a recycle efficiency of 86.78% after five runs for MB. The probable mechanism of this catalytic system is also proposed as a synergistic effect between MnO2 and Fe3O4.

Crystal structure of a glutamate-1-semialdehyde-aminomutase from Pseudomonas aeruginosa PAO1.

The C5 pathway in bacteria is responsible for the synthesis of 5-aminolevulinic acid, which forms the core skeleton of cofactors required for metabolism. One of the key actors in this pathway is a pyridoxamine-5'-phosphate (PMP)/pyridoxal-5'-phosphate (PLP) dependent enzyme called glutamate-1-semialdehyde aminomutase (GSAM). In this study, we crystallized the expression product of the uncharacterized pa4088 gene from the opportunistic pathogen Pseudomonas aeruginosa PAO1. The resulting high-resolution structure confirms it to be a member of the GSAM family. Continuous electron density indicates the presence of a PLP cofactor with a Schiff base linkage between the PLP cofactor and the ε-amino group of Lys286. A crystal structure of a K286A mutant in complex with PMP is also reported. As GSAM enzymes are not present in mammalian cells, this work provides a starting point for the investigation of GSAM as a target for drug development against P. aeruginosa infection.

NH3-SCR performance and the resistance to SO2 for Nb doped vanadium based catalyst at low temperatures.

Niobium oxide as the promoter was doped in the V/WTi catalyst for the selective catalytic reduction (SCR) of NO. The results showed that the addition of Nb2O5 could improve the SCR activity at low temperatures and the 6wt.% additive was an appropriate dosage. The enhanced reaction activity of adsorbed ammonia species and the improved dispersion of vanadium oxide might be the reasons for the elevation of SCR activity at low temperatures. The resistances to SO2 of 3V6Nb/WTi catalyst at different temperatures were investigated. FTIR spectrum and TG-FTIR result indicated that the deposition of ammonium sulfate species was the main deactivation reason at low temperatures, which still exhibited the reactivity with NO above 200°C on the catalyst surface. There was a synergistic effect among NH3, H2O and SO2 that NH3 and H2O both accelerated the catalyst deactivation in the presence of SO2 at 175°C. The thermal treatment at 400°C could regenerate the deactivated catalyst and get SCR activity recovered. The particle and monolith catalysts both kept stable NOx conversion at 225°C with high concentration of H2O and SO2 during the long time tests.

Crystal structure of the apurinic/apyrimidinic endonuclease IV from Mycobacterium tuberculosis.

Endonuclease IV is a typical endonuclease of the apurinic-apyrimidinic (AP) or abasic endonuclease superfamily. It repairs damaged DNA through base excision repair by cleaving the DNA backbone immediately 5' of an AP site. In Mycobacterium tuberculosis, endonuclease IV is the major AP endonuclease. This enzyme is absent from mammalian cells, making it an attractive target for anti-tuberculosis drug development. In this study, the structure of the recombinant endonuclease IV from M. tuberculosis (MtbEndo IV) was determined at a high resolution of 1.18 Å. MtbEndo IV was found to have a classical α8ß8-fold TIM barrel with loops on its surface connecting the α-helices and ß-strands that constitute a groove for DNA binding. Three zinc ions were identified at the active site. A comparison between the structures of MtbEndo IV and Escherichia coli End IV suggested that Gln32 of MtbEndo IV may plays a role in regulating substrate binding.

Structure and characterization of a NAD(P)H-dependent carbonyl reductase from Pseudomonas aeruginosa PAO1.

To investigate the function of the pa4079 gene from the opportunistic pathogen Pseudomonas aeruginosa PAO1, we determined its crystal structure and confirmed it to be a NAD(P)-dependent short-chain dehydrogenase/reductase. Structural similarity and activity for a broad range of substrates indicate that PA4079 functions as a carbonyl reductase. Comparison of apo- and holo-PA4079 shows that NADP stabilizes the active site specificity loop, and small molecule binding induces rotation of the Tyr183 side chain by approximately 90° out of the active site. Quantitative real-time PCR results show that pa4079 maintains high expression levels during antibiotic exposure. This work provides a starting point for understanding substrate recognition and selectivity by PA4079, as well as its possible reduction of antimicrobial drugs. DATABASE: Structural data are available in the Protein Data Bank (PDB) under the following accession numbers: apo PA4079 (condition I), 5WQM; apo PA4079 (condition II), 5WQN; PA4079 + NADP (condition I), 5WQO; PA4079 + NADP (condition II), 5WQP.

Structural insights into YfiR sequestering by YfiB in Pseudomonas aeruginosa PAO1.

YfiBNR is a tripartite signalling system in Pseudomonas aeruginosa that modulates intracellular c-di-GMP levels in response to signals received in the periplasm. YfiB is an outer membrane lipoprotein and presumed sensor protein that sequesters the repressor protein YfiR. To provide insights into YfiBNR function, we have determined three-dimensional crystal structures of YfiB and YfiR from P. aeruginosa PAO1 alone and as a 1:1 complex. A YfiB(27-168) construct is predominantly dimeric, whereas a YfiB(59-168) is monomeric, indicating that YfiB can dimerize via its N-terminal region. YfiR forms a stable complex with YfiB(59-168), while the YfiR binding interface is obstructed by the N-terminal region in YfiB(27-168). The YfiB-YfiR complex reveals a conserved interaction surface on YfiR that overlaps with residues predicted to interact with the periplasmic PAS domain of YfiN. Comparison of native and YfiR-bound structures of YfiB suggests unwinding of the N-terminal linker region for attachment to the outer membrane. A model is thus proposed for YfiR sequestration at the outer membrane by YfiB. Our work provides the first detailed insights into the interaction between YfiB and YfiR at the molecular level and is a valuable starting point for further functional and mechanistic studies of the YfiBNR signalling system.

Molecular basis for the inhibition of ß-hydroxyacyl-ACP dehydratase HadAB complex from Mycobacterium tuberculosis by flavonoid inhibitors.

Dehydration is one of the key steps in the biosynthesis of mycolic acids and is vital to the growth of Mycobacterium tuberculosis (Mtb). Consequently, stalling dehydration cures tuberculosis (TB). Clinically used anti-TB drugs like thiacetazone (TAC) and isoxyl (ISO) as well as flavonoids inhibit the enzyme activity of the ß-hydroxyacyl-ACP dehydratase HadAB complex. How this inhibition is exerted, has remained an enigma for years. Here, we describe the first crystal structures of the MtbHadAB complex bound with flavonoid inhibitor butein, 2',4,4'-trihydroxychalcone or fisetin. Despite sharing no sequence identity from Blast, HadA and HadB adopt a very similar hotdog fold. HadA forms a tight dimer with HadB in which the proteins are sitting side-by-side, but are oriented anti-parallel. While HadB contributes the catalytically critical His-Asp dyad, HadA binds the fatty acid substrate in a long channel. The atypical double hotdog fold with a single active site formed by MtbHadAB gives rise to a long, narrow cavity that vertically traverses the fatty acid binding channel. At the base of this cavity lies Cys61, which upon mutation to Ser confers drug-resistance in TB patients. We show that inhibitors bind in this cavity and protrude into the substrate binding channel. Thus, inhibitors of MtbHadAB exert their effect by occluding substrate from the active site. The unveiling of this mechanism of inhibition paves the way for accelerating development of next generation of anti-TB drugs.

Structural Properties and Dynamics of Thiophene in Sub/Supercritical Carbon Dioxide from Car-Parrinello Molecular Dynamics Simulations.

Structrual and dynamic properties of thiophene (C4H4S) in supercritical carbon dioxide were studied using Car-Parrinello molecular dynamics simulations. The geometries and energies optimized for the thiophene-CO2 complex show a stable C-H···O hydrogen bond interactions both in gas phase and in supercritical CO2. The radial distribution functions of CO2 around thiophene in the supercritical phase state show a correlation suggesting C-H···O hydrogen bond and S···C interaction. Local structural properties of the mixtures were investigated by angular-radial distributions and spatial distribution functions. The results show a mutually parallel arrangement between the thiophene plane and CO2 molecules at short distances and a high probability of the thiophene being located in the radial directions of the CO2 molecules. The decay of orientational correlations at 318.15 K shows slower relaxation compared to those of 298.15 K for first and second rank correlations. The vibrations of CO2 and thiophene molecules have been examined through an analysis of the velocity autocorrelation functions of the atoms. The C-H stretching modes of thiophene in the isolated configuration are less red-shifted and have a much narrower frequency range than that in the mixtures.