Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay

Objectives: Lead antituberculosis (anti-TB) molecules with novel mechanisms of action are urgently required to fuel the anti-TB drug discovery pipeline. The aim of this study was to validate the use of the high-throughput spot culture growth inhibition (HT-SPOTi) assay for screening libraries of compounds against Mycobacterium tuberculosis and to study the inhibitory effect of ibuprofen (IBP) and the other 2-arylpropanoic acids on the growth inhibition of M tuberculosis and other mycobacterial species. Methods: The HT-SPOTi method was validated not only with known drugs but also with a library of 47 confirmed anti-TB active compounds published in the ChEMBL database. Three over-the-counter non-steroidal anti-inflammatory drugs were also included in the screening. The 2-arylpropanoic acids, including IBP, were comprehensively evaluated against phenotypically and physiologically different strains of mycobacteria, and their cytotoxicity was determined against murine RAW264.7 macrophages. Furthermore, a comparative bioinformatic analysis was employed to propose a potential mycobacterial target. Results: IBP showed antitubercular properties while carprofen was the most potent among the 2-arylpropanoic class. A 3,5-dinitro-IBP derivative was found to be more potent than IBP but equally selective. Other synthetic derivatives of IBP were less active, and the free carboxylic acid of IBP seems to be essential for its anti-TB activity. IBP, carprofen and the 3,5-dinitro-IBP derivative exhibited activity against multidrug-resistant isolates and stationary phase bacilli. On the basis of the human targets of the 2-arylpropanoic analgesics, the protein initiation factor infB (Rv2839c) of M tuberculosis was proposed as a potential molecular target. Conclusions: The HT-SPOTi method can be employed reliably and reproducibly to screen the antimicrobial potency of different compounds. IBP demonstrated specific antitubercular activity, while carprofen was the most selective agent among the 2-arylpropanoic class. Activity against stationary phase bacilli and multidrug-resistant isolates permits us to speculate a novel mechanism of antimycobacterial action. Further medicinal chemistry and target elucidation studies could potentially lead to new therapies against TB

A Tutorial on Empirical ICT4D Research in Developing Countries: Processes, Challenges, and Lessons

Humanitarian operations research holds a considerable allure for researchers, often promising interesting contexts to develop and extend current theory, large pools of data to validate theory and generate new insights, and, more generally, the opportunity to conduct “research that matters”. For many of these reasons, we embarked on several research initiatives over the past several years with mixed results. In this tutorial, we draw on several studies (some abandoned) to explore the use of information and communication technologies for humanitarian purposes, and we synthesize and highlight the distinct features of humanitarian operations research. Specifically, we draw attention to differences between “the process” of conducting these studies relative to traditional research and focus on challenges and opportunities for researchers

YHR150w and YDR479c encode peroxisomal integral membrane proteins involved in the regulation of peroxisome number, size, and distribution in Saccharomyces cerevisiae

The peroxin Pex24p of the yeast Yarrowia lipolytica exhibits high sequence similarity to two hypothetical proteins, Yhr150p and Ydr479p, encoded by the Saccharomyces cerevisiae genome. Like YlPex24p, both Yhr150p and Ydr479p have been shown to be integral to the peroxisomal membrane, but unlike YlPex24p, their levels of synthesis are not increased upon a shift of cells from glucose- to oleic acid–containing medium. Peroxisomes of cells deleted for either or both of the YHR150w and YDR479c genes are increased in number, exhibit extensive clustering, are smaller in area than peroxisomes of wild-type cells, and often exhibit membrane thickening between adjacent peroxisomes in a cluster. Peroxisomes isolated from cells deleted for both genes have a decreased buoyant density compared with peroxisomes isolated from wild-type cells and still exhibit clustering and peroxisomal membrane thickening. Overexpression of the genes PEX25 or VPS1, but not the gene PEX11, restored the wild-type phenotype to cells deleted for one or both of the YHR150w and YDR479c genes. Together, our data suggest a role for Yhr150p and Ydr479p, together with Pex25p and Vps1p, in regulating peroxisome number, size, and distribution in S. cerevisiae. Because of their role in peroxisome dynamics, YHR150w and YDR479c have been designated as PEX28 and PEX29, respectively, and their encoded peroxins as Pex28p and Pex29p

Cover Crops and Returning Residue Impact on Soil Organic Carbon, Bulk Density, Penetration Resistance, Water Retention, Infiltration, and Soybean Yield

Residue management with cover crops (CC) can conserve soil moisture and thus has a potential to increase crop yield, but its effectiveness varies significantly by region and cropping system management. A study was conducted at Brookings, SD, on finesilty, mixed, superactive, frigid, Calcic/Pachic Hapludolls soils to understand the impact of CC and crop residue on soil properties and soil-water dynamics for soybean (Glycine max L.) crop grown after corn (Zea mays L.). The site had two crop residue treatments (residue returned [RR] and residue not returned [RNR]) under a no-till corn–soybean rotation. Each residue returned treatment was later subdivided to include CC and no CC (NCC) treatments. Results from this 3 yr (2014, 2015, and 2016) study showed that RR (1.30 Mg m–3) had 7% lower bulk density (BD) compared to the RNR (1.40 Mg m–3). Soil organic carbon (SOC) was 22% higher under RR (26.2 g kg–1) compared to RNR (21.5 g kg–1). Soil water infiltration was 66% higher under RR (108 mm h–1) compared to RNR (64.8 mm h–1). Similarly, soil water infiltration in CC treatment (111 mm h–1) was 80% higher compared to NCC (61.7 mm h–1). The RR with CC treatment increased soil volumetric water content and soil water storage. Overall, the CC increased soybean yield by 14% compared to NCC. Data from this study suggest that the use of CC with RR are beneficial for improving soil properties, conserving soil moisture and enhancing crop yield

Liquid crystal relaxation in three dimensions: the effect of hydrodynamic interactions

We investigate the relaxation of two line defects of opposite strength in a confined nematic liquidcrystal by solving the coupled tensor order parameter evolution and momentum balance equations in three dimensions. The inclusion of hydrodynamic interactions causes the defects to move at different velocities and slows the overall relaxation process, but this effect is suppressed by increasing the degree of confinement. The most notable flow features that develop in the system are large vortices that surround and follow the defects as they approach each other

Risks Involved in the Use of Enrofloxacin for Salmonella Enteritidis or Salmonella Heidelberg in Commercial Poultry

The objectives of the present study were to evaluate the risks involved in the use of Enrofloxacin for Salmonella Enteritidis (SE) or Salmonella Heidelberg (SH) in commercial poultry and determine the effects of a probiotic as an antibiotic alternative. Two experiments were conducted to evaluate the risks involved in the use of Enrofloxacin for SE or SH in commercial poultry. Exp 1 consisted of 2 trials. In each trial, chickens were assigned to one of three groups; control + SE challenged; Enrofloxacin 25 mg/kg + SE; Enrofloxacin 50 mg/kg + SE. Chickens received Enrofloxacin in the drinking water from days 1 to 5 of age. On day 6, all groups received fresh water without any treatment. All chickens were orally gavaged with 107 cfu/chick of SE at 7 days of age and euthanized on 8 days of age. In Exp 2, turkey poults were assigned to one of the three groups; control + SH; probiotic + SH; Enrofloxacin 50 mg/kg + SH. Poults received probiotic or Enrofloxacin in the drinking water from days 1 to 5 of age. On day 6, poults received fresh water without any treatment. Poults were orally gavaged with 107 cfu/poult of SH at 7 days of age. Poults were weighted and humanely killed 24 h post-SH challenge to evaluate serum concentration of FITC-D to evaluate intestinal permeability, metagenomics and SH infection. In both trials of Exp 1, chickens treated with Enrofloxacin were more susceptible to SE organ invasion and intestinal colonization when compared with control non-treated chickens (P < 0.05). In Exp 2, poults treated with 50 mg/kg of Enrofloxacin showed an increase in body weight, however, this group also showed an increase in SH susceptibility, intestinal permeability and lower proportion of Firmicutes and Bacteroidetes, but with control group had the highest proportion of Proteobacteria. In contrast, poults that received the probiotic had the highest proportion of Firmicutes and Bacteroidetes, but lowest Proteobacteria. The results of the present study suggest that prophylactic utilization of Enrofloxacin at 5 times the recommended dose in poultry, increases the susceptibility to salmonellae infections, and confirms probiotics may be a

Effectiveness of a cardiovascular risk management program in the incidence of cardiovascular events in a low-income population from the caribbean region of Colombia

Methods This was a retrospective cohort study. Patients with 20 to 76 years affiliated to insurer company and enrolled to the DTC program were considered as the study population. The data source was an administrative database of all 128,263 patients between Jan 2015 and Dec 2018. The main outcome was the reduction in the risk of a CVE (stroke, AMI or CHF) based in the time-person exposed to the intervention. Four different time thresholds were considered for stablishing exposure status: six months, one year, two years and four years. Propensity score-weighted Cox regression models were used to evaluate the association between exposure to the program and the incidence of CVE

Identification of Serum Biomarkers for Intestinal Integrity in a Broiler Chicken Malabsorption Model

Intestinal health is essential for feed efficiency and growth in animal agriculture and is dependent on barrier function, inflammation and dysbiosis. Our laboratory has published a nutritional model to induce gut inflammation using rye as a source of energy in poultry. More recently, we have used this model as an assessment of a nutritional rehabilitation model for better understanding of childhood undernutrition. The objective of this brief research report was to use a well-establish malabsorption model in broiler chickens using corn and rye as an energy source to identify several intestinal health biomarkers in the serum. To screen for inflammatory biomarkers, seven commercially available tests were used including Griess, superoxide dismutase, thiobarbituric acid reactive substances, Total antioxidant capacity, extracellular-signal-regulated kinase, Citrulline, and Interferon-ɤ; total IgA from cloacal swab was also measured. In the present study, chickens fed rye had a significant (P &lt; 0.05) reduction in body weight and body weight gain at 10 day when compared with chickens that received the corn diet. In the second phase of the experiment, chickens that remain with the corn diet had significant differences in body weight and body weight gain. No significant differences were observed for any of the four antioxidant biomarkers evaluated in the sera (P &gt; 0.05). However, significant differences were observed in serum citrulline and IFN-ɤ, as well as in cloacal IgA, in broiler chickens fed with rye, suggesting their potential use as biomarkers to study intestinal inflammation

Coevolved mutations reveal distinct architectures for two core proteins in the bacterial flagellar motor

Switching of bacterial flagellar rotation is caused by large domain movements of the FliG protein triggered by binding of the signal protein CheY to FliM. FliG and FliM form adjacent multi-subunit arrays within the basal body C-ring. The movements alter the interaction of the FliG C-terminal (FliGC) "torque" helix with the stator complexes. Atomic models based on the Salmonella entrovar C-ring electron microscopy reconstruction have implications for switching, but lack consensus on the relative locations of the FliG armadillo (ARM) domains (amino-terminal (FliGN), middle (FliGM) and FliGC) as well as changes during chemotaxis. The generality of the Salmonella model is challenged by the variation in motor morphology and response between species. We studied coevolved residue mutations to determine the unifying elements of switch architecture. Residue interactions, measured by their coevolution, were formalized as a network, guided by structural data. Our measurements reveal a common design with dedicated switch and motor modules. The FliM middle domain (FliMM) has extensive connectivity most simply explained by conserved intra and inter-subunit contacts. In contrast, FliG has patchy, complex architecture. Conserved structural motifs form interacting nodes in the coevolution network that wire FliMM to the FliGC C-terminal, four-helix motor module (C3-6). FliG C3-6 coevolution is organized around the torque helix, differently from other ARM domains. The nodes form separated, surface-proximal patches that are targeted by deleterious mutations as in other allosteric systems. The dominant node is formed by the EHPQ motif at the FliMMFliGM contact interface and adjacent helix residues at a central location within FliGM. The node interacts with nodes in the N-terminal FliGc α-helix triad (ARM-C) and FliGN. ARM-C, separated from C3-6 by the MFVF motif, has poor intra-network connectivity consistent with its variable orientation revealed by structural data. ARM-C could be the convertor element that provides mechanistic and species diversity.JK was supported by Medical Research Council grant U117581331. SK was supported by seed funds from Lahore University of Managment Sciences (LUMS) and the Molecular Biology Consortium