Novel Hybrid 1,2,4- and 1,2,3-Triazoles Targeting Mycobacterium Tuberculosis Enoyl Acyl Carrier Protein Reductase (InhA): Design,Synthesis, and Molecular Docking

Tuberculosis (TB) caused by Mycobacterium tuberculosis is still a serious public health concern around the world. More treatment strategies or more specific molecular targets have been sought by researchers. One of the most important targets is M. tuberculosis’ enoyl-acyl carrier protein reductase InhA which is considered a promising, well-studied target for anti-tuberculosis medication development. Our team has made it a goal to find new lead structures that could be useful in the creation of new antitubercular drugs. In this study, a new class of 1,2,3- and 1,2,4-triazole hybrid compounds was prepared. Click synthesis was used to afford 1,2,3-triazoles scaffold linked to 1,2,4-triazole by fixable mercaptomethylene linker. The new prepared compounds have been characterized by different spectroscopic tools. The designed compounds were tested in vitro against the InhA enzyme. At 10 nM, the inhibitors 5b, 5c, 7c, 7d, 7e, and 7f successfully and totally (100%) inhibited the InhA enzyme. The IC₅₀ values were calculated using different concentrations. With IC₅₀ values of 0.074 and 0.13 nM, 7c and 7e were the most promising InhA inhibitors. Furthermore, a molecular docking investigation was carried out to support antitubercular activity as well as to analyze the binding manner of the screened compounds with the target InhA enzyme’s binding site.     

A microcomputer-based clinical trial database incorporated with an ‘audit trail’ for correction process

Multicenter clinical trials usually involve several hundred research variables with tens of thousands of records and require mainframe computers for processing. Because of recent advances in hardware and software, it has become possible to support data management and statistical analysis for a complex research project totally on a microcomputer. The Veterans Administration Cooperative Studies Program Coordinating Center (CSPCC) in Hines, IL, U.S.A. has successfully implemented three studies employing the SIR/PC Database Management System (DBMS) on an IBM PC AT. The CSPCC DBMS was designed with a method of verifying data and of updating the database, that leaves a more detailed ‘audit trail’ of the original data and subsequent modifications than provided by the SIR audit trail facility. Data validation can be done at any time throughout the study to facilitate error identification as early as possible in the data handling process. DBMS operation and maintenance are automated by a system of menus. The utility programs are prestored in a procedure file to optimize performance. The simple design speeds implementation and also reduces the cost of development.     

Testing to predict outcome after transurethral resection of the prostate

PURPOSE: We assessed the ability of routine clinical tests to predict outcome following transurethral resection of the prostate. MATERIALS AND METHODS: A total of 556 men randomized into a trial of surgery versus watchful waiting was evaluated preoperatively with symptom interview, quality of life assessment, uroflowmetry, urinalysis, standard chemistry panel, post-void residual urine determination and cystoscopy. The ability to predict avoidance of postoperative complications, and improvement in quality of life and genitourinary symptoms was assessed in the 249 men randomized to undergo transurethral resection of the prostate. RESULTS: Patients with the highest symptom scores were most likely to have symptom improvement and those most bothered by the symptoms were most likely to have improvement in quality of life. No objective tests measuring physiological parameters made clinically significant contributions toward predicting these outcomes. Lower obstructive symptom scores and larger perioperative infusions of intravenous fluids were associated with a greater chance of complications. CONCLUSIONS: Symptom analysis and quality of life assessment are most useful in selecting patients for transurethral resection of the prostate. Objective diagnostic tests are of limited additional benefit.     

Molecular characterization and phylogenetic distribution of the streptococcal superantigen gene (ssa) from Streptococcus pyogenes

A striking increase in the frequency and severity of invasive infections caused by Streptococcus pyogenes has occurred in recent years. Among these diseases is streptococcal toxic-shock-like syndrome (TSLS), a condition characterized by fulminant soft-tissue destruction and multiorgan failure. Streptococcal superantigen (SSA), a superantigen isolated from a TSLS-inducing, serotype M3 S. pyogenes strain, has recently been identified. We here describe the cloning, sequencing, and phylogenetic distribution of the SSA structural gene. The 783-bp open reading frame encodes a predicted 260-amino-acid protein that is similar in size to several other bacterial superantigens. The deduced sequence of the mature protein is 60.2% identical to that of staphylococcal enterotoxin B but only 49% identical to that of streptococcal pyrogenic exotoxin A. Southern blot and PCR analysis of 138 group A streptococcal strains representing 65 M protein serotypes and 15 nontypeable isolates identified ssa in 68 strains from 10 distinct clonal lineages. All ssa-positive clones expressed SSA. Of the two clones associated with TSLS, the ET 2-M3 lineage, but not the ET 1-M1 lineage, carried the SSA gene. Further analysis of the ET 2-M3 lineage found evidence for temporal variation in ssa association. Contemporary ET 2-M3 disease isolates had ssa, but two older isolates of this clone recovered in 1910 and 1920 lacked the gene. The clonal and temporal distribution patterns of ssa suggest a relatively recent acquisition of this superantigen-encoding gene by the ET 2-M3 lineage, perhaps by horizontal transfer and recombination.     

Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients

BACKGROUND: Several studies have suggested that if recombinant human erythropoietin (epoetin) is administered subcutaneously rather than intravenously, a lower dose may be sufficient to maintain the hematocrit at a given level. METHODS: In a randomized, unblinded trial conducted at 24 hemodialysis units at Veterans Affairs medical centers, we assigned 208 patients who were receiving long-term hemodialysis and epoetin therapy to treatment with either subcutaneous or intravenous epoetin. The dose was initially reduced until the hematocrit was below 30 percent and then was gradually increased to a level that would maintain the hematocrit in the range of 30 to 33 percent for 26 weeks. We compared the average doses in the 26-week maintenance phase and the discomfort associated with the two routes of administration. RESULTS: For the 107 patients treated by the subcutaneous route, the average weekly dose of epoetin during the maintenance phase was 32 percent less than that for the 101 patients treated by the intravenous route (mean [+/-SD], 95.1+/-75.0 vs. 140.3+/-88.5 U per kilogram of body weight per week; P<0.001). Only one patient in the subcutaneous-therapy group withdrew from the study because of pain at the injection site, and 86 percent rated the pain associated with subcutaneous administration as ranging from absent to mild. CONCLUSIONS: In patients receiving hemodialysis, subcutaneous administration of epoetin can maintain the hematocrit in a desired target range, with an average weekly dose of epoetin that is lower than with intravenous administration.     

Effect of close-fit sliplining on the hydraulic capacity of a pressurized pipeline

A full-scale laboratory testing setup was used to examine the flow conditions through a new steel pipe with relatively smooth interior (no tubercles, encrustations, holes, scales, etc.) before and after sliplining with a high density polyethylene (HDPE) liner. Results of the tests indicate that the relative roughness of the lined pipe section was generally lower than that of the new steel pipe at Reynolds Numbers of 200,000 to 500,000. The average friction factor (Swamee–Jain) for the lined pipe was 0.0180 compared to 0.0185 for the original steel pipe. The minimum and maximum friction coefficients were 0.0146 and 0.0208 for the lined pipe and 0.0148 and 0.0241 for the new steel pipe, respectively. This indicates that a deteriorated pipe with significant roughness could be restored back to its original condition using close-fit sliplining. Meanwhile, installation of the 6.35 mm (1/4 in.) thick liner in the 152.4 mm (6 in.) pipe reduced its cross-sectional flow area by about 16% and, accordingly, would decrease the flow by about 20% under the same head loss. To further explore this condition, two design parameters, the liner thickness and its buckling resistance, were examined analytically using a practical application of 152.4 mm (6 in.) pipeline with an internal negative pressure due to a water hammer. Results of the analysis indicate that a 3.4 mm (1/8 in.) thick HDPE liner with average quality installation would provide about 100 kPa ( 10 m or 33 ft water column) of buckling resistance, but would also reduce the flow capacity by about 12.7%. While the laboratory tests were only performed on one type of liner material (i.e., HDPE), the general concepts and findings of this study would apply to other types of polymeric liners.     

Microstructure control in functionally graded Al-Si castings

Al-Si functionally graded castings (FGCs) were prepared under centrifugal force. Three compositions were selected; 356, 413 and 390 representing hypoeutectic, eutectic and hypereutectic alloys, respectively. The microstructure and the mechanical properties of the FGCs at different positions were dependent on the centrifugal force. This was more pronounced in 390 FGCs, where the hardness and wear resistance increased towards the inner surface containing the highest volume fraction of primary Si. Grain refining of α-Al was observed in the inner section of 356-FGCs. In 413FGCs, Fe-intermetallics were refined gradually towards the outer surface. Heat treatment spherodized the eutectic Si in case of 356FGCs and increased the hardness from ~60 to 83 (HV). In 390FGCs, precipitation hardening raised the hardness by 20 % while no improvement was observed in 413FGCs. These results emphasize the role of centrifugal force and heat treatment in controlling the microstructure and the mechanical properties of Al-Si FGCs.     

A method to calibrate a solar pyranometer for measuring reference diffuse irradiance

Accurate pyranometer calibrations, traceable to internationally recognized standards, are critical for solar irradiance measurements. One calibration method is the component summation, where the pyranometers are calibrated outdoors under clear sky conditions, and the reference global solar irradiance is calculated as the sum of two reference components, the diffuse and subtended beam solar irradiances. The beam component is measured with pyrheliometers traceable to the World Radiometric Reference, while there is no internationally recognized reference for the diffuse component. In the absence of such a reference, we present a method to consistently calibrate pyranometers for measuring the diffuse component with an estimated uncertainty of ±(3% of reading+1 W/m²). The method is based on using a modified shade/unshade method, and pyranometers with less than 1 W/m² thermal offset errors. We evaluated the consistency of our method by calibrating three pyranometers four times. Calibration results show that the responsivity change is within ±0.52% for the three pyranometers. We also evaluated the effect of calibrating pyranometers unshaded, then using them shaded to measure diffuse irradiance. We calibrated three unshaded pyranometers using the component summation method. Their outdoor measurements of clear sky diffuse irradiance, from sunrise to sundown, showed that the three calibrated pyranometers can be used to measure the diffuse irradiance to within ±1.4 W/m² variation from the reference irradiance.     

Rheological modeling and finite element simulation of epoxy adhesive creep in FRP-strengthened RC beams

We have shown that a significant creep occurs at the concrete–fiber reinforced polymer (FRP) interface based on double shear long-term test. The primary test parameters were the shear stress to ultimate shear strength ratio, the epoxy curing time before loading as well as the epoxy thickness. The test results showed that when the epoxy curing time before loading was earlier than seven days the shear stress level significantly affected the long-term behavior of epoxy at the interfaces, and in particular the combined effect of high shear stress and thick epoxy adhesive can result in interfacial failure if subjected to high-sustained stresses. In this paper, based on the previous experimental observations, an improved rheological model was developed to simulate the long-term behavior of epoxy adhesive at the concrete–FRP interfaces. Furthermore, the newly developed rheological creep model was incorporated in finite element (FE) modeling of a reinforced concrete (RC) beam strengthened with FRP sheets. The use of rheological model in FE setting provides the opportunity to conduct a parametric investigation on the behavior of RC beams strengthened with FRP. It is demonstrated that creep of epoxy at the concrete–FRP interfaces increases the beam deflection. It is also shown that consideration of creep of epoxy is essential if part or the entire load supported by FRP is to be sustained.