The action of mimetic peptides on connexins protects fibroblasts from the negative effects of ischemia reperfusion

Connexins have been proposed as a target for therapeutic treatment of a variety of conditions. The main approaches have been by antisense or small peptides specific against connexins. Some of these peptides enhance communication while others interfere with connexin binding partners or bind to the intracellular and extracellular loops of connexins. Here, we explored the mechanism of action of a connexin mimetic peptide by evaluating its effect on gap junction channels, connexin protein levels and hemichannel activity in fibroblast cells under normal conditions and following ischemia reperfusion injury which elevates Cx43 levels, increases hemichannel activity and causes cell death. Our results showed that the effects of the mimetic peptide were concentration-dependent. High concentrations (100-300 μM) significantly reduced Cx43 protein levels and GJIC within 2 h, while these effects did not appear until 6 h when using lower concentrations (10-30 μM). Cell death can be reduced when hemichannel opening and GJIC were minimised

A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro.

OBJECTIVES: Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states. METHODS: The natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time-kill curves from log-phase (0.25-16 mg/L) and stationary-phase (0.5-64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure-response relationships. RESULTS: The final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R(2) = 0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively. CONCLUSIONS: The model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro

Arabic Quranic Search Tool Based on Ontology

This paper reviews and classifies most of the common types of search techniques that have been applied on the Holy Quran. Then, it addresses the limitations of these methods. Additionally, this paper surveys most existing Quranic ontologies and what are their deficiencies. Finally, it explains a new search tool called: a semantic search tool for Al-Quran based on Qur’anic on-tologies. This tool will overcome all limitations in the existing Quranic search applications

Moxifloxacin Replacement in Contemporary Tuberculosis Drug Regimens Is Ineffective against Persistent Mycobacterium tuberculosis in the Cornell Mouse Model

Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a leading killer worldwide, and disease control is hampered by ineffective control of persistent infections. Substitution of moxifloxacin for isoniazid or ethambutol in standard TB regimens reduces treatment duration and relapse rates in animal studies and four-month regimens were not non-inferior in clinical trials. Resuscitation promoting factor (RPF) dependent bacilli have recently been implicated in M. tuberculosis persistence. We aimed to investigate the therapeutic effects of moxifloxacin substitution in the standard drug regimen for eradicating colony forming count (CFU) positive and RPF-dependent persistent M. tuberculosis using the Cornell murine model. M. tuberculosis infected mice were treated with regimens in which either isoniazid or ethambutol were replaced by moxifloxacin to the standard regimen. The efficacy of the regimens was compared to the standard regimen for bacterial CFU count elimination and removal of persistent tubercle bacilli evaluated using culture filtrate (CF) derived from M. tuberculosis strain H37Rv. We also measured disease relapse rates. Moxifloxacin-isoniazid substituted regimen achieved total organ CFU count clearance at 11 weeks post-treatment, faster than standard regimen (14 weeks), and with a 34% lower relapse rate. Moxifloxacin-ethambutol substituted regimen was similar to standard regimens in these regards. Importantly, neither moxifloxacin-substituted regimens nor the standard regimen could remove CF-dependent persistent bacilli. Evaluation of CF-dependent persistent M. tuberculosis requires confirmation in human studies, and has implications in future drug design, testing and clinical applications

Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide

BACKGROUND: For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option. METHODS: Fruit juices were screened for inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor; and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates. RESULTS: HIV-1 entry inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O. CONCLUSION: These results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored

Enhanced Power Conversion Efficiency via Hybrid Ligand Exchange Treatment of p-Type PbS Quantum Dots.

PbS quantum dot solar cells (QDSCs) have emerged as a promising low-cost, solution-processable solar energy harvesting device and demonstrated good air stability and potential for large-scale commercial implementation. PbS QDSCs achieved a record certified efficiency of 12% in 2018 by utilizing an n+-n-p device structure. However, the p-type layer has generally suffered from low carrier mobility due to the organic ligand 1,2-ethanedithiol (EDT) that is used to modify the quantum dot (QD) surface. The low carrier mobility of EDT naturally limits the device thickness as the carrier diffusion length is limited by the low mobility. Herein, we improve the properties of the p-type layer through a two-step hybrid organic ligand treatment. By treating the p-type layer with two types of ligands, 3-mercaptopropionic acid (MPA) and EDT, the PbS QD surface was passivated by a combination of the two ligands, resulting in an overall improvement in open-circuit voltage, fill factor, and current density, leading to an improvement in the cell efficiency from 7.0 to 10.4% for the champion device. This achievement was a result of the improved QD passivation and a reduction in the interdot distance, improving charge transport through the p-type PbS quantum dot film

Dynamics of one-dimensional tight-binding models with arbitrary time-dependent external homogeneous fields

The exact propagators of two one-dimensional systems with time-dependent external fields are presented by following the path-integral method. It is shown that the Bloch acceleration theorem can be generalized to the impulse-momentum theorem in quantum version. We demonstrate that an evolved Gaussian wave packet always keeps its shape in an arbitrary time-dependent homogeneous driven field. Moreover, that stopping and accelerating of a wave packet can be achieved by the pulsed field in a diabatic way.Comment: 8 pages, 6 figure

Domain State Diagnosis in Rock Magnetism: Evaluation of Potential Alternatives to the Day Diagram

The Day diagram is used extensively in rock magnetism for domain state diagnosis. It has been shown recently to be fundamentally ambiguous for ten sets of reasons. This ambiguity highlights the urgency for adopting suitable alternative approaches to identify the domain state of magnetic mineral components in rock magnetic studies. We evaluate ten potential alternative approaches here and conclude that four have value for identifying data trends, but, like the Day diagram, they are affected by use of bulk parameters that compromise domain state diagnosis in complex samples. Three approaches based on remanence curve and hysteresis loop unmixing, when “supervised” by independent data to avoid non-uniqueness of solutions provide valuable component-specific information that can be linked by inference to domain state. Three further approaches based on first-order reversal curve (FORC) diagrams provide direct domain state diagnosis with varying effectiveness. Environmentally important high coercivity hematite and goethite are represented with variable effectiveness in the evaluated candidate approaches. These minerals occur predominantly in non-interacting single domain particle assemblages in paleomagnetic contexts, so domain state diagnosis is more critical for ferrimagnetic minerals. Treating the high-coercivity component separately following normal rock magnetic procedures allows focus on the more vexing problem of diagnosing domain state in ferrimagnetic mineral assemblages. We suggest a move away from non-diagnostic methods based on bulk parameters and adoption of approaches that provide unambiguous component-specific domain state identification, among which various FORC-based approaches provide diagnostic information.European Research Council (ERC) Australian Research Council (ARC