Discovery of novel antitubercular 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues

In the present investigation, a series of 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues were synthesized and were evaluated for antitubercular activity by two fold serial dilution technique. All the newly synthesized compounds showed low to high inhibitory activities against Mycobacterium tuberculosis H(37)Rv and INH resistant M. tuberculosis. The compound 3-(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carbothioamide (4o) was found to be the most promising compound active against M. tuberculosis H(37)Rv and isoniazid resistant M. tuberculosis with minimum inhibitory concentration 3.12 μM and 6.25 μM, respectively.     

How does storage affect the quality and quantity of organic carbon in sewage for use in the bioremediation of acidic mine waters?

Pit lakes (abandoned flooded mine pits) represent a potentially valuable water resource. However, acid mine drainage (AMD) generation due to mining activities often results in pit lake waters with low pH, high sulphate and dissolved metal concentrations. Sulphate reduction-based bioremediation offers tremendous scope for removal of acidity and metals from pit lake water. In this study, the effect of storing sewage on its carbon quality for bioremediation of acidic pit lake water was studied. In addition, the effectiveness of labile organic carbon (lactic acid and ethanol) on SRB activity was tested. Bioremediation experiments were performed in controlled and replicated microcosms with acidic (pH 2.2) water from a pit lake by addition of stored (3 years at 4 °C) sewage for stimulation of sulphate reducing bacteria (SRB) activity. This sewage had been previously used successfully in remediating to pH 7 water from this pit lake. The initial aim was to test the sewage at lower doses (18 and 28 g/L) and in a pulsed addition (over 5 weeks). Bioremediation efficacy was evaluated by measuring pit lake water pH increase, redox potential decrease, and acidity and sulphate removal. Though the stored sewage had retained a very similar high total organic carbon (TOC) equivalent to prior to storage, it failed to increase dissolved organic carbon (DOC) levels in pit lake water. Microcosms amended with doubled doses of sewage and an extended remediation time still failed to demonstrate any substantial improvement in water quality, other than a small amount of sulphate reduction and direct neutralisation by the sewage. In order to determine if low DOC concentrations in sewage were the cause of the bioremediation failure, labile organic carbon (LOC), consisting of 50:50 (w/w) lactic acid and ethanol, was added to all microcosm treatments at concentrations of 3000, 6000 and 9000 mg/L. After LOC addition, water quality improved with effective removal of acidity, sulphate and metals in the lowest carbon concentration (3000 mg/L). However, 6000 and 9000 mg/L LOC concentrations showed a delay in response due to the increased acidity associated with the lactic acid addition. The experiments showed that pulsed dosing of carbon simply slowed the commencement of remediation but it was ultimately able to reach the same effectiveness as the equivalent quantity added all at once. Prolonged storage of sewage leads to loss of LOC. In situ pit lake remediations which aim to make use of sewage as the main carbon source will need to factor in the storage time required to obtain sufficient sewage for the treatment into the design. Pulsing may help reduce issues with storage or supplementation with LOC may need to be considered. Results highlight that LOC is a more useful indicator of material effectiveness compared to a simple measures of TOC.     

Multimodel ensembles of wheat growth: many models are better than one

Crop models of crop growth are increasingly used to quantify the impact of global changes due to climate or crop management. Therefore, accuracy of simulation results is a major concern. Studies with ensembles of crop models can give valuable information about model accuracy and uncertainty, but such studies are difficult to organize and have only recently begun. We report on the largest ensemble study to date, of 27 wheat models tested in four contrasting locations for their accuracy in simulating multiple crop growth and yield variables. The relative error averaged over models was 24–38% for the different end‐of‐season variables including grain yield (GY) and grain protein concentration (GPC). There was little relation between error of a model for GY or GPC and error for in‐season variables. Thus, most models did not arrive at accurate simulations of GY and GPC by accurately simulating preceding growth dynamics. Ensemble simulations, taking either the mean (e‐mean) or median (e‐median) of simulated values, gave better estimates than any individual model when all variables were considered. Compared to individual models, e‐median ranked first in simulating measured GY and third in GPC. The error of e‐mean and e‐median declined with an increasing number of ensemble members, with little decrease beyond 10 models. We conclude that multimodel ensembles can be used to create new estimators with improved accuracy and consistency in simulating growth dynamics. We argue that these results are applicable to other crop species, and hypothesize that they apply more generally to ecological system models.     

Association of TLR5 Gene Polymorphisms in Ulcerative Colitis Patients of North India and Their Role in Cytokine Homeostasis

Background and Aim

In health, TLR signaling protects the intestinal epithelial barrier and in disease, aberrant TLR signaling stimulates diverse inflammatory responses. Association of TLR polymorphisms is ethnicity dependent but how they impact the complex pathogenesis of IBD is not clearly defined. So we propose to study the status of polymorphisms in TLR family of genes and their effect on cytokines level in UC patients.

Methods

The genotypes of the six loci TLR1-R80T, TLR2-R753Q, TLR3-S258G, TLR5-R392X, TLR5-N592S and TLR6-S249P were determined in 350 controls and 328 UC patients by PCR-RFLP and sequencing. Cytokine levels were measured by ELISA in blood plasma samples. Data were analyzed statistically by SPSS software.

Results

TLR5 variants R392X and N592S showed significant association (p = 0.007, 0.021) with UC patients but TLR 1, 2, 3, 6 variants did not show any association. Unlike other studies carried out in different ethnic groups, TLR 6 (S249P) SNP was universally present in our population irrespective of disease. Genotype-phenotype correlation analysis revealed that the patients having combination of multiple SNPs both in TLR5 and TLR4 gene suffered from severe disease condition and diagnosed at an early age. The level of TNFα (p = 0.004), IL-6 (p = 0.0001) and IFNγ (p = 0.006) significantly increased in patients as compared to controls having wild genotypes for the studied SNPs. However, there was decreased level of TNFα (p = 0.014), IL-6 (p = 0.028) and IFNγ (p = 0.001) in patients carrying TLR5-R392X variant as compared to wild type patients. Patients carrying two simultaneous SNPs D299G in TLR4 gene and N592S in TLR5 gene showed significant decrease in the levels of TNFα (p = 0.011) and IFNγ (p = 0.016).

Conclusion

Polymorphisms in TLR 5 genes were significantly associated with the UC in North Indian population. The cytokine level was significantly modulated in patients with different genotypes of TLR4 and TLR5 SNPs.     

Batch and fed-batch fermentation of optically pure D (-) lactic acid from Kodo millet (Paspalum scrobiculatum) bran residue hydrolysate: growth and inhibition kinetic modeling

Abstract

A low-cost Kodo millet bran residue was utilized as feedstock for the production of D (?) lactic acid (DLA) using Lactobacillus delbrueckii NBRC3202 under anaerobic condition. Data culled from a series of batch fermentation processes with different initial Kodo millet bran residue hydrolysate (KMBRH) and DLA concentrations were used for kinetic model development. Both simulated and experimental data were in good agreement for cell growth, KMBRH utilization, and DLA formation. The values of kinetic constants specific growth rate, (μ_m = 0.17?h^?1); growth (α_P = 0.96?g.g^?1) and non-growth (β_P = 1.19?g.g^?1.h^?1) associated constant for DLA production and the maximum specific KMBRH utilization rate, (q_{G, max} = 1.18?g.g^?1.h^?1) were in good agreement with the literature reports. Kinetic analysis elucidated that L. delbrueckii growth was predominantly influenced by KMBRH limitation and highly sensitive to DLA inhibition. Fed-batch fermentation studies demonstrated the existence of substrate and product inhibition paving the scope for process intensification.     

Ameliorative role of atorvastatin on methionine-induced hyperhomocysteinemia and hematological changes in albino rats

Methionine (1g/kg, po) administration to pathogenic control rats for 30 days significantly increased the levels of homocysteine, total cholesterol (TC), low density lipoprotein (LDL-C), very low density lipoprotein (VLDL-C) and triglycerides (TGs) and decreased the levels of high density lipoprotein (HDL-C) in serum. Hematological observations of the peripheral blood smears of pathogenic rats fed with methionine also showed crenation of RBCs cell membrane and significant increase in total leukocyte count, differential leukocyte count and platelet counts with significant decrease in the mean hemoglobin levels as compared to vehicle control rats. Administration of atorvastatin (0.2 mg/kg/po) to hyperhomocysteinemic rats significantly decreased the levels of homocysteine, TC, TGs, LDL-C and VLDL-C and increased the levels of HDL-C in serum. The present results provide clear evidence that oral treatment with atorvastatin exhibit homocysteine and lipid lowering activity and also reversal of hematological changes induced by methionine in albino rats.     

Comparison of temperature and moisture requirements for sporulation of Aspergillus flavus sclerotia on natural and artificial substrates

A key step in the infection cycle by Aspergillus flavus in maize is sporulation of sclerotia present in soil or in crop debris. However, little information is available on this critical and important phase. This study included experiments on artificial (Czapek Dox Agar (CZ)) and natural (maize stalks) substrates under different conditions of temperature (T; from 5 to 45 °C) and water activity (a(w); from 0.50 to 0.99) levels to quantify sporulation from sclerotia. The mean numbers of spores were higher on defined nutritional medium in vitro on CZ agar than on maize stalks (4.5×10(6) spores/sclerotium versus 4.2×10(4) spores/sclerotium) with production initiated after 6 and 24h, respectively. Surprisingly, the optimal temperature was found at 30-35 °C for CZ agar (9.23×10(6) spores/sclerotium) and to be 20-25 °C for maize stalks (6.26×10(4) spores/sclerotium). Water stress imposition only reduced sporulation at ≤0.90 a(w.) With more available water no significant differences were found between 0.90 and 0.99 a(w). This type of data is critical in the development of a mechanistic model to predict the infection cycle of A. flavus in maize in relation to meteorological conditions.