TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis.

TNFα-related apoptosis-inducing ligand (TRAIL), specifically initiates programmed cell death, but often fails to eradicate all cells, making it an ineffective therapy for cancer. This fractional killing is linked to cellular variation that bulk assays cannot capture. Here, we quantify the diversity in cellular signaling responses to TRAIL, linking it to apoptotic frequency across numerous cell systems with single-cell mass cytometry (CyTOF). Although all cells respond to TRAIL, a variable fraction persists without apoptotic progression. This cell-specific behavior is nonheritable where both the TRAIL-induced signaling responses and frequency of apoptotic resistance remain unaffected by prior exposure. The diversity of signaling states upon exposure is correlated to TRAIL resistance. Concomitantly, constricting the variation in signaling response with kinase inhibitors proportionally decreases TRAIL resistance. Simultaneously, TRAIL-induced de novo translation in resistant cells, when blocked by cycloheximide, abrogated all TRAIL resistance. This work highlights how cell signaling diversity, and subsequent translation response, relates to nonheritable fractional escape from TRAIL-induced apoptosis. This refined view of TRAIL resistance provides new avenues to study death ligands in general

ETHNOMEDICINAL PLANTS USED BY TRIBES OF CHITTOOR DISTRICT OF ANDHRA PRADESH TO CURE MUSCULAR PAIN AND INFLAMMATION

An ethnobotanical survey was carried out to collect the first-hand information on medicinal plants used by the inhabited and traditionally rich tribal communities (Chenchus, Yanadis and Nakkalas) in Chittoor district of Andhra Pradesh (AP) for the treatment of muscular pain and inflammation. The information was gathered by an integrated approach of botanical collections, group discussions and questionnaire. The survey revealed thirty forty (34) ethno-medicinal plants belonging to twenty one (21) angiospermic families specifically used for the preparation of medicinal remedies. The tribal claims on the medicinal plants are listed with Latin name, family, local name, part used, method of preparation, dose and its use in pain and inflammation conditions. The habit of frequently used plant were recorded includes tree species (44 %) followed by herbs (35 %) climbers (12 %), under shrubs (6 %) and shrub (3%). Most frequently utilized plant parts were leaves, followed by root, latex, whole plant, bark, fruits, rhizome and seeds. In this particular study the most dominant family was found to be Euphorbiaceae. The result clearly indicates that people living around Chittoor forest area hold valuable traditional knowledge of the use of medicinal plants for their primary health care need related to muscular injury and inflammation. These plant resources are important component in their local livelihood and to control overexploitation of these resources sustainable management approach and proper conservation strategy for the area is also highly recommended by bringing the involvement of local communities and forest department. More in-depth investigations on these claims through phytochemical and pharmacological parameters are required to explore their activities to deal with the conditions of pain and inflammation

Diabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages

People with type 2 diabetes mellitus (T2DM) have a 25-fold higher risk of limb loss than non-diabetics due in large part to impaired wound healing. Here, we show that the impaired wound healing phenotype found in T2D mice is recapitulated in lethally irradiated wild type recipients, whose hematopoiesis is reconstituted with hematopoietic stem cells (HSCs) from T2D mice, indicating an HSC-autonomous mechanism. This impaired wound healing phenotype of T2D mice is due to a Nox-2-dependent increase in HSC oxidant stress that decreases microRNA let-7d-3p, which, in turn, directly upregulates Dnmt1, leading to the hypermethylation of Notch1, PU.1, and Klf4. This HSC-autonomous mechanism reduces the number of wound macrophages and skews their polarization towards M1 macrophages. These findings reveal a novel inflammatory mechanism by which a metabolic disorder induces an epigenetic mechanism in HSCs, which predetermines the gene expression of terminally differentiated inflammatory cells that controls their number and function

Application of random amplified polymorphic DNA (RAPD) analysis and plasmid profiles to the differentiation of Vibrio parahaemolyticus isolated from coastal waters

Plasmid profiles and random amplified polymorphic DNA (RAPD) techniques were used to analyse the genetic differentiation of 57 isolates of Vibrio parahaemolyticus isolated from coastal water. Among the isolates, 16 plasmid patterns were observed, with plasmid sizes ranging from 1.5 to 7.6 megadalton. The two primers (Gen1-50-01, 5'-GTGCAATGAG-3' and Gen1-50-02, 5'-CAATGCGTCT-3') generated reproducible profiles of genomic DNA fingerprints producing bands ranging from 0.25 to 5.0 kb. The RAPD types profiles revealed a high level of DNA sequence diversity within the Vibrio parahaemolyticus isolates tested, as 48 RAPD types were observed for each primer respectively. Hence, plasmid profiles and RAPD-PCR analysis proved useful in discriminating the isolates. The later method proved to be more sensitive. Our data show that Vibrio parahaemolyticus isolates can be divided into at least 56 epidemiological subgroups on the basis of the plasmid profiles and RAPD-PCR results

A Dissipative-Particle-Dynamics Model for Simulating Dynamics of Charged Colloid

A mesoscopic colloid model is developed in which a spherical colloid is represented by many interacting sites on its surface. The hydrodynamic interactions with thermal fluctuations are taken accounts in full using Dissipative Particle Dynamics, and the electrostatic interactions are simulated using Particle-Particle-Particle Mesh method. This new model is applied to investigate the electrophoretic mobility of a charged colloid under an external electric field, and the influence of salt concentration and colloid charge are systematically studied. The simulation results show good agreement with predictions from the electrokinetic theory.Comment: 17 pages, 8 figures, submitted to the proceedings of High Performance Computing in Science & Engineering '1

Simulation of natural convective boundary layer flow of a nanofluid past a convectively heated inclined plate in the presence of magnetic field

AbstractThis paper deals with the numerical simulation of transient magnetohydrodynamics natural convective boundary layer flow of a nanofluid over an inclined plate. In the modeling of nanofluids, dynamic effects including the Brownian motion and thermophoresis are taken into account. Numerical solutions have been computed via the Galerkin-finite element method. The effects of angle of inclination, buoyancy-ratio parameter, Brownian motion, thermophoresis and magnetic field are taken into account and controlled by non-dimensional parameters. To compute the rate of convergence and error of the computed numerical solution, the double mesh principle is used. Similarity solutions are calculated and presented graphically for non-dimensional velocity, temperature, local rate of heat and mass transfer with pertinent parameters. The modified Nusselt number decreases with increasing inclination angle, buoyancy-ratio parameter, Brownian motion and thermophoresis parameter, whereas it increases with increasing Prandtl number. Validation of the results is achieved with earlier results for forced convective flow and non-magnetic studies. Such problems have several applications in engineering and petroleum industries such as electroplating, chemical processing of heavy metals and solar water heaters. External magnetic fields play an important role in electrical power generation, inclination/acceleration sensors, fine-tuning of the final materials to industrial specification because of their controlling behaviour on the flow characteristics of nanofluids

Efficacy and safety of telithromycin 800 mg once daily for 7 days in community-acquired pneumonia: an open-label, multicenter study

BACKGROUND: Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality throughout the world. Telithromycin (a new ketolide) has shown good in vitro activity against the key causative pathogens of CAP, including S pneumoniae resistant to penicillin and/or macrolides. METHODS: The efficacy and safety of telithromycin 800 mg orally once daily for 7 days in the treatment of CAP were assessed in an open-label, multicenter study of 442 adults. RESULTS: Of 149 microbiologically evaluable patients, 57 (9 bacteremic) had Streptococcus pneumoniae. Of the 57 S pneumoniae pathogens isolated in these patients, 9 (2 bacteremic) were penicillin- or erythromycin-resistant; all 57 were susceptible to telithromycin and were eradicated. Other pathogens and their eradication rates were: Haemophilus influenzae (96%), Moraxella catarrhalis (100%), Staphylococcus aureus (80%), and Legionella spp. (100%). The overall bacteriologic eradication rate was 91.9%. Of the 357 clinically evaluable patients, clinical cure was achieved in 332 (93%). In the 430 patients evaluable for safety, the most common drug-related adverse events were diarrhea (8.1%) and nausea (5.8%). CONCLUSION: Telithromycin 800 mg once daily for 7 days is an effective and well-tolerated oral monotherapy and offers a new treatment option for CAP patients, including those with resistant S pneumoniae

Klinische Bedeutung der Bestimmung der Bindung von Trijodthyronin an Serumproteine mittels Dextran-Gel-Filtration

Neben den bewährten älteren Verfahren zur Bestimmung des proteingebundenen127Jods und des Radiojodumsatzes hat sich die gleichzeitige Bestimmung des sog. freien und des proteingebundenen Anteils an in vitro mit Serum inkubiertem L-Trijodthyronin-131Jod mittels Dextran-Gel-Filtration klinisch zur Differentialdiagnose von Hyperthyreose und Euthyreose bewährt. Bei Ausnützung der Verdrängung von proteingebundenem L-Trijodthyronin-131Jod durch nichtmarkiertes Hormon und bei Variation der Dextran-Gel-Menge in der Säule bietet die Methode gute Differenzierungsmöglichkeiten auch für die Schilddrüsenfunktionszustände Euthyreose und Hypothyreose. Bei dem Verfahren wird der Patient nicht mit radioaktivem Jod belastet, ein für die Kinderklinik wichtiger Gesichtspunkt. Manche Störfaktoren, die den131Jodspeicherungstest und die Bestimmung des proteingebundenen Jods (PB127I) verfälschen, haben keinen Einfluß auf die mit der Dextran-Gel-Filtration untersuchten Proteinbindungsverhältnisse für L-Trijodthyronin-131Jod. So hat sich das Verfahren für die Untersuchung von Patienten mit operativ oder durch131Jodbehandlung verkleinerten Schilddrüsen, mit endokrinem Exophthalmus und in Fällen mit vorausgegangener Jodgabe, z. B. in Form von Kontrastmitteln, besonders bewährt. Mit der Bestimmung des sog. freien L-Trijodthyronin-131Jods wird ein physiologisch und pathogenetisch wichtiger Parameter der Schilddrüsenfunktion ermittelt. Die klinische Bedeutung der Bestimmung der Bindungs-und Transportverhältnisse für Trijodthyronin mittels Dextran-Gel-Filtration wird diskutiert.In addition to conventional methods of assay of protein bound iodine (PB127I) and of131iodine turnover in the thyroid, the simultaneous determination of socalled free and protein bound 1-triiodothyronine-131I, added in vitro to serum, using dextran gel filtration was found to be clinically helpful for diagnosis of euthyroidism and hyperthyroidism. Employing discharge effects of non-labelled triiodothyronine on protein bound 1-triiodothyronine-131I and varying the amount of dextran gel in the columns, the method provides reasonably good differentiation of euthyroid and hypothyroid states. No radioactive iodine is given to patients during this procedure, a fact of importance for pediatriciens. Some factors, that influence131iodine uptake or PB127I levels, do not disturb protein binding of 1-triiodothyronine-131I as determined by dextran gel filtration. The latter method was found to be especially useful for the examination of patients with surgically, or by therapy with131iodine dissected thyroid glands, with endocrine exophthalmos, and in cases of previous iodine administration (e.g. X-ray procedures). Determination of socalled free 1-triiodothyronine-131I provides information about a factor of physiological and pathogenetical significance, its clinical meaning is discussed