Repurposing Thioridazine (TDZ) as an anti-inflammatory agent

Nuclear factor-kB (NF-kB) is a crucial transcription factor in the signal transduction cascade of the inflammatory signaling. Activation of NF-κB depends on the phosphorylation of IκBα by IκB kinase (IKKβ) followed by subsequent ubiquitination and degradation. This leads to the nuclear translocation of the p50- p65 subunits of NF-κB, and further triggers pro-inflammatory cytokine gene expression. Thus, in the need of a more effective therapy for the treatment of inflammatory diseases, specific inhibition of IKKβ represents a rational alternative strategy to the current therapies. A computer-aided drug identification protocol was followed to identify novel IKKβ inhibitors from a database of over 1500 Food and Drug Administration (FDA) drugs. The best scoring compounds were compared with the already known high-potency IKKβ inhibitors for their ability to bind and inhibit IKKβ by evaluating their docking energy. Finally, Thioridazinehydrochloride (TDZ), a potent antipsychotic drug against Schizophrenia was selected and its efficiency in inhibiting IκBα protein degradation and NF-κB activation was experimentally validated. Our study has demonstrated that TDZ blocks IκBα protein degradation and subsequent NF-κB activation to inhibit inflammation. Thus, it is a potential repurposed drug against inflammation

Decoherence and coherent population transfer between two coupled systems

We show that an arbitrary system described by two dipole moments exhibits coherent superpositions of internal states that can be completely decoupled fi om the dissipative interactions (responsible for decoherence) and an external driving laser field. These superpositions, known as dark or trapping states, can he completely stable or can coherently interact with the remaining states. We examine the master equation describing the dissipative evolution of the system and identify conditions for population trapping and also classify processes that can transfer the population to these undriven and nondecaying states. It is shown that coherent transfers are possible only if the two systems are nonidentical, that is the transitions have different frequencies and/or decay rates. in particular, we find that the trapping conditions can involve both coherent and dissipative interactions, and depending on the energy level structure of the system, the population can be trapped in a linear superposition of two or more bare states, a dressed state corresponding to an eigenstate of the system plus external fields or, in some cases. in one of the excited states of the system. A comprehensive analysis is presented of the different processes that are responsible for population trapping, and we illustrate these ideas with three examples of two coupled systems: single V- and Lambda-type three-level atoms and two nonidentical tao-level atoms, which are known to exhibit dark states. We show that the effect of population trapping does not necessarily require decoupling of the antisymmetric superposition from the dissipative interactions. We also find that the vacuum-induced coherent coupling between the systems could be easily observed in Lambda-type atoms. Our analysis of the population trapping in two nonidentical atoms shows that the atoms can be driven into a maximally entangled state which is completely decoupled from the dissipative interaction

Hepatitis B Virus Impairs TLR9 Expression and Function in Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) play a key role in detecting pathogens by producing large amounts of type I interferon (IFN) by sensing the presence of viral infections through the Toll-Like Receptor (TLR) pathway. TLR9 is a sensor of viral and bacterial DNA motifs and activates the IRF7 transcription factor which leads to type I IFN secretion by pDCs. However, during chronic hepatitis B virus (HBV) infection, pDCs display an impaired ability to secrete IFN-α following ex vivo stimulation with TLR9 ligands. Here we highlight several strategies used by HBV to block IFN-α production through a specific impairment of the TLR9 signaling. Our results show that HBV particle internalisation could inhibit TLR9- but not TLR7-mediated secretion of IFN-α by pDCs. We observed that HBV down-regulated TLR9 transcriptional activity in pDCs and B cells in which TLR9 mRNA and protein levels were reduced. HBV can interfere with TLR9 activity by blocking the MyD88-IRAK4 axis and Sendai virus targeting IRF7 to block IFN-α production. Neutralising CpG motif sequences were identified within HBV DNA genome of genotypes A to H which displayed a suppressive effect on TLR9-immune activation. Moreover, TLR9 mRNA and protein were downregulated in PBMCs from patients with HBV-associated chronic hepatitis and hepatocellular carcinoma. Thus HBV has developed several escape mechanisms to avoid TLR9 activation in both pDCs and B lymphocytes, which may in turn contribute to the establishment and/or persistence of chronic infection

Wolbachia Symbiont Infections Induce Strong Cytoplasmic Incompatibility in the Tsetse Fly Glossina morsitans

Tsetse flies are vectors of the protozoan parasite African trypanosomes, which cause sleeping sickness disease in humans and nagana in livestock. Although there are no effective vaccines and efficacious drugs against this parasite, vector reduction methods have been successful in curbing the disease, especially for nagana. Potential vector control methods that do not involve use of chemicals is a genetic modification approach where flies engineered to be parasite resistant are allowed to replace their susceptible natural counterparts, and Sterile Insect technique (SIT) where males sterilized by chemical means are released to suppress female fecundity. The success of genetic modification approaches requires identification of strong drive systems to spread the desirable traits and the efficacy of SIT can be enhanced by identification of natural mating incompatibility. One such drive mechanism results from the cytoplasmic incompatibility (CI) phenomenon induced by the symbiont Wolbachia. CI can also be used to induce natural mating incompatibility between release males and natural populations. Although Wolbachia infections have been reported in tsetse, it has been a challenge to understand their functional biology as attempts to cure tsetse of Wolbachia infections by antibiotic treatment damages the obligate mutualistic symbiont (Wigglesworthia), without which the flies are sterile. Here, we developed aposymbiotic (symbiont-free) and fertile tsetse lines by dietary provisioning of tetracycline supplemented blood meals with yeast extract, which rescues Wigglesworthia-induced sterility. Our results reveal that Wolbachia infections confer strong CI during embryogenesis in Wolbachia-free (GmmApo) females when mated with Wolbachia-infected (GmmWt) males. These results are the first demonstration of the biological significance of Wolbachia infections in tsetse. Furthermore, when incorporated into a mathematical model, our results confirm that Wolbachia can be used successfully as a gene driver. This lays the foundation for new disease control methods including a population replacement approach with parasite resistant flies. Alternatively, the availability of males that are reproductively incompatible with natural populations can enhance the efficacy of the ongoing sterile insect technique (SIT) applications by eliminating the need for chemical irradiation

Two Sides of the Same Rupee? Comparing Demand for Microcredit and Microsaving in a Framed Field Experiment in Rural Pakistan

We use a field experiment to test whether saving and borrowing satisfy demand for lump-sum accumulation from regular deposits. Inspired by ROSCAs, we offer different credit and saving contracts to subjects. We find that individuals often accept both credit and saving contract across experimental waves. This behaviour can be rationalised by assuming that individuals seek lump-sum payments and struggle to hold savings. Structural estimation of this model accounts for the behaviour of 75% of participants. Of these, two-thirds have high demand for lump-sum accumulation but savings difficulties. These results imply that the distinction between microlending and microsaving is largely illusory

Isolation and characterization of synthetic pyrethroids-degrading bacterial strains from agricultural soil

Abstract Pyrethroid pesticides are commonly used for pest control in agriculture setup, veterinary and home garden. They are now posing increased risks to non-targeted organisms associated to human beings due to their considerable use. The present work deals with the isolation of bacteria with tolerance to high concentrations of bifenthrin and cypermethrin from contaminated soil. Enrichment culture technique (bifenthrin concentration = 50-800 mg/L) was used for bacterial isolation. Bacteria that showed growth on minimal media with bifenthrin were also sub-cultured on minimal media with cypermethrin. Bacteria showing luxurious growth on both the pyrethroid, were screened out based on their morphological, biochemical parameters and by API 20NE Kit. Phylogenetic studies revealed that, one bacterial isolate (MG04) belonging to Acinetobacter lwoffii and other five bacterial isolates (MG06, MG05, MG01, MG03 and MG02) cluster with Pseudomonas aeruginosa, Pseudomonas putida respectively. Isolated members of genera Pseudomonas and Acinetobacter could be used for further detailed degradation studies by using FTIR, HPLC-MS or GC-MS analysis

Worse outcomes associated with liver transplants: An increasing trend

Background and aim Since individuals in the early stages of liver cirrhosis are typically asymptomatic, the prevalence of liver cirrhosis may be underestimated. Liver cirrhosis has a significant morbidity and mortality rate, with 1.03 million deaths worldwide each year. For end-stage liver disease, liver transplantation is a potential therapeutic option. The goal of our research was to examine the current trend in liver transplants using data from a national database. Methods Using the International Classification of Diseases (ICD)-9 codes, we identified individuals who had a liver transplant during the index hospital admission in the Nationwide Inpatient Sample from 2007 to 2011. This national sample of patients is from the United States. We looked at the yearly trend in liver transplants and related outcomes, such as duration of hospitalization (DOH), hospital expenses, and mortality in the hospital. In order to find determinants of mortality, we used a multivariate analysis. Results There were 25,331 patients hospitalized (weighted for national estimate). Between 2007 and 2011, the number of transplants grew by 1.2%. The majority of transplant recipients were Caucasian (57%), with an average age of 54 years, had a private healthcare plan (53%), and had average earnings in the upper quartile by zip code (26%). Patients with a higher Charlson Comorbidity Index (79% had a score of four) were more likely to be admitted to a southern hospital (33%), an academic hospital (\u3e99%), and a large capacity hospital (90%). Seventy percent of liver transplant recipients received cadaver donors. Hepatitis C was the most prevalent reason for transplant (30%), followed by hepatocellular carcinoma (HCC) (29%) and alcoholic liver disease (25%). In 2011, compared to 2007, there was an upward rise in fatality (from 3.8% to 5.1%), average hospital expenditures (from $335,504 to$498,369), and DOH (from 17.4 to 22.7 days). The cost of hospitalization was two billion dollars per year. The independent variables related to an increased mortality on multivariate analysis were African American race (OR: 2.0, 95%, CI: 1.2-3.2; p=0.005) and large capacity hospitals (OR: 2.5, 95% CI: 1.6-4.1; p=0.0002). Predictors linked to lower mortality included private healthcare coverage (vs. Medicare: OR: 0.7, 95%, CI: 0.51-0.97; p=0.03), academic hospital (OR: 0.6, 95% CI: 0.4-0.8; p=0.005), cadaver donor (OR: 0.6, 95% CI: 0.5-0.8; p=0.002), HCC (OR: 0.6, 95% CI: 0.4-0.9; p=0.01), and non-alcoholic steatohepatitis (NASH) cirrhosis (OR: 0.4, 95% CI: 0.2-0.9; p=0.02). Conclusion Our study found an increasing trend in worse outcomes (increased mortality, average hospital costs, and average DOH) after a liver transplant. Patients of the African American race and large capacity hospitals were associated with a higher risk of death, whereas private healthcare plans, academic hospitals, cadaver donors, HCC, and NASH cirrhosis were associated with a lower risk