Leprosy and tuberculosis concomitant infection: a poorly understood, age-old relationship

Historically, archaeological evidence, post-mortem findings and retro- spective analysis of leprosy institutions’ data demonstrates a high observed incidence of concomitant infection with leprosy and tuberculosis (TB). However, reports of concomitant infection in the modern literature remain scarce, with estimates of annual new case detection rates of concomitant infection at approximately 0·02 cases per 100,000 population. Whilst the mechanism for this apparent decline in concomitant infections remains unclear, further research on this topic has remained relatively neglected. Modelling of the interaction of the two organisms has suggested that the apparent decline in observations of concomitant infection may be due to the protective effects of cross immunity, whilst more recently others have questioned whether it is a more harmful relationship, predisposing towards increased host mortality. We review recent evidence, comparing it to previously held understanding on the epidemiological relationship and our own experience of concomitant infection. From this discussion, we highlight several under-investigated areas, which may lead to improvements in the future delivery of leprosy management and services, as well as enhance understanding in other fields of infection management. These include, a) highlighting the need for greater understanding of host immunogenetics involved in concomitant infection, b) whether prolonged courses of high dose steroids pre-dispose to TB infection? and, c) whether there is a risk of rifampicin resistance developing in leprosy patients treated in the face of undiagnosed TB and other infections? Longitudinal work is still required to characterise these temporal relationships further and add to the current paucity of literature on this subject matter

Patchy layered structure of tropical troposphere as seen by Indian MST radar

The MST radar observations at Gadanki (13.47° N, 79.18° E) show, almost every day throughout the year, stratified layers of intense reflectivity near the tropopause level (17 km) and also at a couple of levels between 4 km and 10 km. Highest individual reflectivity values occur near 17 km, but they occur for a short while. The region between 11 km and 15 km shows the lowest values of reflectivity alongwith vertical downward motion almost on all days of the year. High values of reflectivity are attributed to the existence of visible or sub-visible clouds; the layered structure of clouds is attributed to inertio-gravity waves with vertical wavelength of 2-3 km. It is suggested that each high reflectivity layer consists mainly of thin sheets and patches of visible and sub-visible cloud material. Hydrometeors inside the cloud material go up and down due to gravity, precipitation-loading, Brunt-Vaisala oscillations, and Kelvin-Helmholtz waves. In these small-scale motions, thin air sheets and patches get formed with sharp temperature and humidity discontinuities through contact cooling, melting, evaporation, condensation and freezing. Also, melting and freezing at low temperatures generate electrical charges in these thin sheets and patches. These thin sheets and patches have vertical dimensions ranging from a few centimetres to several metres and horizontal dimensions of the order of 1km. These thin sheets and patches have corresponding vertical and horizontal discontinuities and sharp gradients in refractive index for the MST radar beam. These show up as regions of high values of reflectivity

Year-round radiocarbon-based source apportionment of carbonaceous aerosols at two background sites in South Asia

Atmospheric Brown Clouds (ABC), regional-scale haze events, are a significant concern for both human cardiopulmonary health and regional climate impacts. In order to effectively mitigate this pollution-based phenomenon, it is imperative to understand the magnitude, scope and source of ABC in regions such as South Asia. Two sites in S. Asia were chosen for a 15-month field campaign focused on isotope-based source apportionment of carbonaceous aerosols in 2008-2009. Both the Maldives Climate Observatory in Hanimaadhoo (MCOH) and a mountaintop site in Sinhagad, India (SINH) act as regionally mixed receptor sites. Annual radiocarbon-based source apportionment for soot elemental carbon (SEC) at MCOH and SINH revealed 73 6 and 59 5 contribution from biomass combustion, respectively (remainder from fossil fuel). The contributions from biogenic/biomass combustion to total organic carbon were similar between MCOH and SINH (69 5 and 64 5, respectively). The biomass combustion contribution for SEC in the current study, especially the results from MCOH, shows good agreement with published black carbon emissions inventories for India. Geographic source assessment, including clustered back trajectory analysis and carbon contribution by source region, indicated that the highest SEC/TOC loads originated from the W. Indian coastal margin, including the coastal city of Mumbai, India. The winter dry season 14C-based source apportionment of the BC-tracing SEC fraction for 2006, 2008, 2009 were not statistically different (p = 0.7) and point to a near-constant two-thirds contribution from biomass combustion practices, including wood and other biofuels as well as burning of agricultural crop residues

Aerosol characteristics during winter fog at Agra, North India

Simultaneous measurements on physical, chemical and optical properties of aerosols over a tropical semi-arid location, Agra in north India, were undertaken during December 2004. The average concentration of total suspended particulates (TSP) increased by about 1.4 times during intense foggy/hazy days. Concentrations of SO4 2-, NO3 -, NH4 + and Black Carbon (BC) aerosols increased by 4, 2, 3.5 and 1.7 times, respectively during that period. Aerosols were acidic during intense foggy/hazy days but the fog water showed alkaline nature, mainly due to the neutralizing capacity of NH4 aerosols. Trajectory analyses showed that air masses were predominantly from NW direction, which might be responsible for transport of BC from distant and surrounding local sources. Diurnal variation of BC on all days showed a morning and an evening peak that were related to domestic cooking and vehicular emissions, apart from boundary layer changes. OPAC (Optical properties of aerosols and clouds) model was used to compute the optical properties of aerosols. Both OPAC-derived and observed aerosol optical depth (AOD) values showed spectral variation with high loadings in the short wavelengths (<1 μm). AOD value at 0.5 μm wavelength was significantly high during intense foggy/hazy days (1.22) than during clear sky or less foggy/hazy days (0.63). OPAC-derived Single scattering albedo (SSA) was 0.84 during the observational period, indicating significant contribution of absorbing aerosols. However, the BC mass fraction to TSP increased by only 1 during intense foggy/hazy days and thereby did not show any impact on SSA during that period. A large increase was observed in the shortwave (SW) atmospheric (ATM) forcing during intense foggy/hazy days (+75.8 W/m2) than that during clear sky or less foggy/hazy days (+38 W/m2), mainly due to increase in absorbing aerosols. Whereas SW forcing at surface (SUF) increased from -40 W/m2 during clear sky or less foggy/hazy days to -76 W/m2 during intense foggy/hazy days, mainly due to the scattering aerosols like SO4 2-

Bianchi Type-II String Cosmological Models in Normal Gauge for Lyra's Manifold with Constant Deceleration Parameter

The present study deals with a spatially homogeneous and anisotropic Bianchi-II cosmological models representing massive strings in normal gauge for Lyra's manifold by applying the variation law for generalized Hubble's parameter that yields a constant value of deceleration parameter. The variation law for Hubble's parameter generates two types of solutions for the average scale factor, one is of power-law type and other is of the exponential form. Using these two forms, Einstein's modified field equations are solved separately that correspond to expanding singular and non-singular models of the universe respectively. The energy-momentum tensor for such string as formulated by Letelier (1983) is used to construct massive string cosmological models for which we assume that the expansion ($\theta$) in the model is proportional to the component $\sigma^{1}_{~1}$ of the shear tensor $\sigma^{j}_{i}$. This condition leads to $A = (BC)^{m}$, where A, B and C are the metric coefficients and m is proportionality constant. Our models are in accelerating phase which is consistent to the recent observations. It has been found that the displacement vector $\beta$ behaves like cosmological term $\Lambda$ in the normal gauge treatment and the solutions are consistent with recent observations of SNe Ia. It has been found that massive strings dominate in the decelerating universe whereas strings dominate in the accelerating universe. Some physical and geometric behaviour of these models are also discussed.Comment: 24 pages, 10 figure

Studies on the effect of doxorubicin on MDA, NO2, NO3, Se-GSH peroxidase and SOD levels in albino rat tissues

Doxorubicin, a highly effective anticancer drug, produces cardiotoxicity, which limits its therapeutic potential. The mechanism of this cardiotoxicity has remained elusive. The use of this drug, however,continues to be limited by its dose-related and time interval toxicity. Reactive oxygen species are hypothesized to be a major factor in the toxicity of doxorubicin. The aim of this work was to investigate theeffect of doxorubicin on dose-related and time interval in rat. The study utilized adult albino rats (120 ± 5 g). They were divided into 8 groups of 7 animals each and were kept under standard laboratory conditions.They had free access to commercial pellet diet and water. The room temperature was maintained at 20 ± 5°C. The study measured rat tissue MDA, NO2, NO3, Se-GSH peroxidase and SOD under Dox stress, and the results indicate that MDA and NO generated in Dox treated samples cause neuro, myo, hepato and renal toxicity. Since SOD and Peroxidase are scavenging molecules, increase in their levels in Dox treated samples may be one of mechanism to overcome Dox caused oxidative stress in Dox treated albino rat

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

Integrating transposable elements in the 3D genome

Chromosome organisation is increasingly recognised as an essential component of genome regulation, cell fate and cell health. Within the realm of transposable elements (TEs) however, the spatial information of how genomes are folded is still only rarely integrated in experimental studies or accounted for in modelling. Whilst polymer physics is recognised as an important tool to understand the mechanisms of genome folding, in this commentary we discuss its potential applicability to aspects of TE biology. Based on recent works on the relationship between genome organisation and TE integration, we argue that existing polymer models may be extended to create a predictive framework for the study of TE integration patterns. We suggest that these models may offer orthogonal and generic insights into the integration profiles (or "topography") of TEs across organisms. In addition, we provide simple polymer physics arguments and preliminary molecular dynamics simulations of TEs inserting into heterogeneously flexible polymers. By considering this simple model, we show how polymer folding and local flexibility may generically affect TE integration patterns. The preliminary discussion reported in this commentary is aimed to lay the foundations for a large-scale analysis of TE integration dynamics and topography as a function of the three-dimensional host genome

The Goldbeter-Koshland switch in the first-order region and its response to dynamic disorder

In their classical work (Proc. Natl. Acad. Sci. USA, 1981, 78:6840-6844), Goldbeter and Koshland mathematically analyzed a reversible covalent modification system which is highly sensitive to the concentration of effectors. Its signal-response curve appears sigmoidal, constituting a biochemical switch. However, the switch behavior only emerges in the "zero-order region", i.e. when the signal molecule concentration is much lower than that of the substrate it modifies. In this work we showed that the switching behavior can also occur under comparable concentrations of signals and substrates, provided that the signal molecules catalyze the modification reaction in cooperation. We also studied the effect of dynamic disorders on the proposed biochemical switch, in which the enzymatic reaction rates, instead of constant, appear as stochastic functions of time. We showed that the system is robust to dynamic disorder at bulk concentration. But if the dynamic disorder is quasi-static, large fluctuations of the switch response behavior may be observed at low concentrations. Such fluctuation is relevant to many biological functions. It can be reduced by either increasing the conformation interconversion rate of the protein, or correlating the enzymatic reaction rates in the network.Comment: 23 pages, 4 figures, accepted by PLOS ON

Genetic determinants of co-accessible chromatin regions in activated T cells across humans.

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression