Mycobacterium tuberculosis Responds to Chloride and pH as Synergistic Cues to the Immune Status of its Host Cell

PubMed ID: 23592993This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Rapid assessment of facilitators and barriers related to the acceptance, challenges and community perception of daily regimen for treating tuberculosis in India

Introduction: The Revised National Tuberculosis Control Program (RNTCP) is the largest tuberculosis (TB) control program in the world based on Directly Observed Treatment Short-Course (DOTS) strategy. Globally, most countries have been using a daily regimen and in India a shift towards a daily regimen for TB treatment has already begun. The daily strategy is known to improve program coverage along with compliance. Such strategic shifts have both management and operational implications. We undertook a rapid assessment to understand the facilitators and barriers in adopting the daily regimen for TB treatment in three Indian states. Methods: In-depth interviews were planned across six districts of three purposively selected states of Maharashtra, Bihar and Sikkim, among health system personnel at various levels to identify their perspectives on adoption of a daily regimen for TB. These districts were sampled on the basis of TB notification rates. Thematic analysis of the qualitative data was undertaken. Results: 62 respondents were interviewed from these 6 districts. During the analysis, it was observed that an easily accessible, patient-centred and personalized outreach is an enabling factor for adherence to treatment. Lack of transportation facilities, out-of-pocket expenses and loss of wages for accessing DOTS at institutions are major identified barriers for treatment adherence at individual level. At program level, lack of trained service providers, poor administration of treatment protocols and inadequate supervision by health care providers and program managers are key factors that influence program outcomes. Conclusion: A major observation that emerged from the interviews is that the key to achieve a relapse-free cure is ensuring that a patient receives all doses of the prescribed treatment regimen. However, switching to a daily regimen makes adherence difficult and thus new strategies are needed for its implementation at patient and health provider levels. Most stakeholders appreciate the reasons for switching to a daily regimen. The stakeholders recognised the efforts of the Ministry of Health & Family Welfare (MoHFW) in spearheading the program. Strategies like the 99 DOTS call-centre approach may also further ensure treatment adherence

A fluid model for a relay node in an ad-hoc network: the case of heavy-tailed input

Relay nodes in an ad hoc network can be modelled as fluid queues, in which the available service capacity is shared by the input and output. In this paper such a relay node is considered; jobs arrive according to a Poisson process and bring along a random amount of work. The total transmission capacity is fairly shared, meaning that, when n jobs are present, each job transmits traffic into the queue at rate 1/(n + 1) while the queue is drained at the same rate of 1/(n + 1). Where previous studies mainly concentrated on the case of exponentially distributed job sizes, the present paper addresses regularly varying jobs. The focus lies on the tail asymptotics of the sojourn time S. Using sample-path arguments, it is proven that P {S > x} behaves roughly as the residual job size, i.e., if the job sizes are regularly varying of index -nu, the tail of S is regularly varying of index 1 - nu. In addition, we address the tail asymptotics of other performance metrics, such as the workload in the queue, the flow transfer time and the queueing delay

malERA: An updated research agenda for insecticide and drug resistance in malaria elimination and eradication

Resistance to first-line treatments for Plasmodium falciparum malaria and the insecticides used for Anopheles vector control are threatening malaria elimination efforts. Suboptimal responses to drugs and insecticides are both spreading geographically and emerging independently and are being seen at increasing intensities. Whilst resistance is unavoidable, its effects can be mitigated through resistance management practices, such as exposing the parasite or vector to more than one selective agent. Resistance contributed to the failure of the 20th century Global Malaria Eradication Programme, and yet the global response to this issue continues to be slow and poorly coordinated—too often, too little, too late. The Malaria Eradication Research Agenda (malERA) Refresh process convened a panel on resistance of both insecticides and antimalarial drugs. This paper outlines developments in the field over the past 5 years, highlights gaps in knowledge, and proposes a research agenda focused on managing resistance. A deeper understanding of the complex biological processes involved and how resistance is selected is needed, together with evidence of its public health impact. Resistance management will require improved use of entomological and parasitological data in decision making, and optimisation of the useful life of new and existing products through careful implementation, combination, and evaluation. A proactive, collaborative approach is needed from basic science and the development of new tools to programme and policy interventions that will ensure that the armamentarium of drugs and insecticides is sufficient to deal with the challenges of malaria control and its elimination

Annexin A2 antibodies but not inhibitors of the annexin A2 heterotetramer impair productive HIV-1 infection of macrophages in vitro

During sexual transmission of human immunodeficiency virus (HIV), macrophages are initial targets for HIV infection. Secretory leukocyte protease inhibitor (SLPI) has been shown to protect against HIV infection of macrophages through interactions with annexin A2 (A2), which is found on the macrophage cell surface as a heterotetramer (A2t) consisting of A2 and S100A10. Therefore, we investigated potential protein-protein interactions between A2 and HIV-1 gp120 through a series of co-immunoprecipitation assays and a single molecule pulldown (SiMPull) technique. Additionally, inhibitors of A2t (A2ti) that target the interaction between A2 and S100A10 were tested for their ability to impair productive HIV-1 infection of macrophages. Our data suggest that interactions between HIV-1 gp120 and A2 exist, though this interaction may be indirect. Furthermore, an anti-A2 antibody impaired HIV-1 particle production in macrophages in vitro, whereas A2ti did not indicating that annexin A2 may promote HIV-1 infection of macrophages in its monomeric rather than tetrameric form

IMG/VR: a database of cultured and uncultured DNA Viruses and retroviruses.

Viruses represent the most abundant life forms on the planet. Recent experimental and computational improvements have led to a dramatic increase in the number of viral genome sequences identified primarily from metagenomic samples. As a result of the expanding catalog of metagenomic viral sequences, there exists a need for a comprehensive computational platform integrating all these sequences with associated metadata and analytical tools. Here we present IMG/VR (https://img.jgi.doe.gov/vr/), the largest publicly available database of 3908 isolate reference DNA viruses with 264 413 computationally identified viral contigs from >6000 ecologically diverse metagenomic samples. Approximately half of the viral contigs are grouped into genetically distinct quasi-species clusters. Microbial hosts are predicted for 20 000 viral sequences, revealing nine microbial phyla previously unreported to be infected by viruses. Viral sequences can be queried using a variety of associated metadata, including habitat type and geographic location of the samples, or taxonomic classification according to hallmark viral genes. IMG/VR has a user-friendly interface that allows users to interrogate all integrated data and interact by comparing with external sequences, thus serving as an essential resource in the viral genomics community

Association between high-dose erythropoiesis-stimulating agents, inflammatory biomarkers, and soluble erythropoietin receptors

<p>Abstract</p> <p>Background</p> <p>High-dose erythropoiesis-stimulating agents (ESA) for anemia of chronic kidney disease (CKD) have been associated with adverse clinical outcomes and do not always improve erythropoiesis. We hypothesized that high-dose ESA requirement would be associated with elevated inflammatory biomarkers, decreased adipokines, and increased circulating, endogenous soluble erythropoietin receptors (sEpoR).</p> <p>Methods</p> <p>A cross-sectional cohort of anemic 32 CKD participants receiving ESA were enrolled at a single center and cytokine profiles, adipokines, and sEpoR were compared between participants stratified by ESA dose requirement (usual-dose darbepoetin-α (< 1 μg/kg/week) and high-dose (≥1 μg/kg/week)).</p> <p>Results</p> <p>Baseline characteristics were similar between groups; however, hemoglobin was lower among participants on high-dose (1.4 μg/kg/week) vs usual-dose (0.5 μg/kg/week) ESA.</p> <p>In adjusted analyses, high-dose ESA was associated with an increased odds for elevations in c-reactive protein and interleukin-6 (p < 0.05 for both). There was no correlation between high-dose ESA and adipokines. Higher ESA dose correlated with higher levels of sEpoR (r_s= 0.39, p = 0.03). In adjusted analyses, higher ESA dose (per μcg/kg/week) was associated with a 53% greater odds of sEpoR being above the median (p < 0.05).</p> <p>Conclusion</p> <p>High-dose ESA requirement among anemic CKD participants was associated with elevated inflammatory biomarkers and higher levels of circulating sEpoR, an inhibitor of erythropoiesis. Further research confirming these findings is warranted.</p> <p>Trial registration</p> <p>Clinicaltrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00526747">NCT00526747</a></p

Myofibrillogenesis regulator 1 induces hypertrophy by promoting sarcomere organization in neonatal rat cardiomyocytes

Human myofibrillogenesis regulator 1, a novel 17-kDa protein, is closely involved in cardiac hypertrophy. We studied the molecular mechanism that links MR-1 to hypertrophic response. Hypertrophic hallmarks such as cell size and [3H]-leucine incorporation were significantly increased when MR-1 was transfected into cardiomyocytes for 48 h. However, sarcomere organization was promoted when MR-1 was transfected for 8 h. The finding that cardiac hypertrophy was induced long after increase of sarcomere organization indicates that the promoted sarcomere organization may be one of the crucial factors causing hypertrophy. Furthermore, when MR-1 was transfected into cardiomyocytes, the nuclear localization of myomesin-1 was shifted to the cytoplasm. Transfection with small ubiquitin-like modifier-1 (SUMO-1) mimicked the effect of MR-1 inducing translocation of myomesin-1. However, transfection with SUMO-1 in MR-1-silenced cardiomyocytes failed to induce translocation and sarcomere organization, even though SUMO-1 expression was at the same level. Overexpression of MR-1 may induce cardiomyocyte hypertrophy via myomesin-1-mediated sarcomere organization

PS18kh: A New Tidal Disruption Event with a Non-axisymmetric Accretion Disk

We present the discovery of PS18kh, a tidal disruption event discovered at the center of SDSS J075654.53+341543.6 (d ≃ 322 Mpc) by the Pan-STARRS Survey for Transients. Our data set includes pre-discovery survey data from Pan-STARRS, the All-sky Automated Survey for Supernovae, and the Asteroid Terrestrial-impact Last Alert System as well as high-cadence, multiwavelength follow-up data from ground-based telescopes and Swift, spanning from 56 days before peak light until 75 days after. The optical/UV emission from PS18kh is well-fit as a blackbody with temperatures ranging from T ≃ 12,000 K to T ≃ 25,000 K and it peaked at a luminosity of L ≃ 8.8 × 10 erg s . PS18kh radiated E = (3.45 ± 0.22) × 10 erg over the period of observation, with (1.42 ± 0.20) × 10 erg being released during the rise to peak. Spectra of PS18kh show a changing, boxy/double-peaked Hα emission feature, which becomes more prominent over time. We use models of non-axisymmetric accretion disks to describe the profile of the Hα line and its evolution. We find that at early times the high accretion rate leads the disk to emit a wind which modifies the shape of the line profile and makes it bell-shaped. At late times, the wind becomes optically thin, allowing the non-axisymmetric perturbations to show up in the line profile. The line-emitting portion of the disk extends from r ∼ 60r to an outer radius of r ∼ 1400r and the perturbations can be represented either as an eccentricity in the outer rings of the disk or as a spiral arm in the inner disk. 43 -1 50 50 in g out