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N-Thiolated beta-lactams are a new family of antibacterials that inhibit the growth of Staphylococcus bacteria. Unlike other beta-lactam drugs, these compounds retain their full antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains and operate through a different mode of action. The structural features, which give these lactams their biological activity, have not yet been completely defined. Earlier efforts in our laboratory established that the N-organothio substituent is essential for antimicrobial activity while other groups at C(3) and C(4) on the lactam ring play a more subtle role. In this present study, we investigate these effects by varying the polar and steric nature of the ring substituents at these two centers. From the data presented herein, it appears that there is a need to balance the lipophilic character of the C(3)/C(4) groups to obtain an optimal anti-MRSA activity. The structure-bioactivity profiles more closely relate to the compound's ability to penetrate the bacterial cell membrane to sites of action within the cytoplasm rather than to any specific non-bonding interactions with a biological target. Based on these results, a model for the compounds' mode of action is presented.

The beneficial effect of feeding fenugreek ( Trigonella foenum graecum ) seed mucilage and spent turmeric ( Curcuma longa ) on diabetic status was studied in streptozotocin-induced diabetic rats. Diabetic rats lost weight but body weights were improved by feeding spent turmeric than fenugreek seed mucilage. In diabetic rats, a 30% improvement in urine sugar and urine volume profiles was observed with feeding fenugreek seed mucilage and spent turmeric. Fasting blood glucose showed a 26% and 18% improvement with fenugreek seed mucilage and spent turmeric feeding to diabetic rats, respectively. Fenugreek seed mucilage compared with tumeric was more effective in ameliorating diabetic state.

Bitter gourd (Momordica charantia), a commonly consumed vegetable is used as an adjunct in the management of diabetes mellitus. A study was carried out to examine the effect of edible portion of bitter gourd at 10% level in the diet in streptozotocin induced diabetic rats. To evaluate the glycaemic control of bitter gourd during diabetes, diet intake, gain in body weight, water intake, urine sugar, urine volume, glomerular filtration rate and fasting blood glucose profiles were monitored. Water consumption, urine volume and urine sugar were significantly higher in diabetic controls compared to normal rats and bitter gourd feeding alleviated this rise during diabetes by about 30%. Renal hypertrophy was higher in diabetic controls and bitter gourd supplementation, partially, but effectively prevented it (38%) during diabetes. Increased glomerular filtration rate in diabetes was significantly reduced (27%) by bitter gourd. An amelioration of about 30% in fasting blood glucose was observed with bitter gourd feeding in diabetic rats. These results clearly provided experimental evidence that dried bitter gourd powder in the diet at 10% level improved diabetic status signifying its beneficial effect during diabetes.

This paper presents an analysis using spatial moments for transport of nonreactive solutes in a single fracture-matrix system using a dual porosity framework. The velocity and dispersion obtained using the first and second spatial moments are found to have two regimes. The effect of fracture velocity, fracture dispersivity, fracture spacing, matrix diffusion coefficient, and matrix porosity on both regimes are analyzed. The first regime is characterized by a behavior wherein both velocity and dispersion are functions of time and all of the above parameters of the fracture-matrix system are found to have an influence. In the second regime, they are independent of time similar to the behavior of conservative solutes in an ideal porous media. This regime is characterized by the influence of a few parameters of the fracture-matrix system. The empirical relationships for solute velocity, macrodispersion coefficient, and dispersivity in the asymptotic stage are presented.

Synthesis of C-8 fluoroaryl substituted pyrimidine linked-PBD conjugates are described. The compounds are prepared with varying degrees of linker length in order to probe the structural requirements for optimal in vitro antitumour activity. These compounds have been tested against a panel of 60 human cancer cell lines, and it is demonstrated that compound 5b with four carbon spacer exhibited promising in vitro anticancer activity in comparison to the other analogues (5a and 5c).

An efficient and mild method for the reduction of aromatic nitro and azido groups on solid support using Al/NiCl 2 ·6H 2 O and Al/NH 4 Cl is described. This solid phase reduction technique has been applied towards the synthesis of DNA binding pyrrolo[2,1- c ][1,4]benzodiazepine antitumour antibiotics.

In the present work, the eggshell biowaste has been effectively utilized to produce flower-like hydroxyapatite nanostructure by using a simple and rapid microwave irradiation method with the help of ethylenediaminetetraacetic acid (EDTA) as a chelating agent. Conversion of eggshell into HA occurs via the formation of Ca–EDTA complex which subsequently reacted with phosphate under microwave irradiation. The obtained product is Mg containing b-type carbonated HA and it can be a potential material for biomedical applications.

Ludwig's angina is a form of severe diffuse cellulitis that presents an acute onset and spreads rapidly, bilaterally affecting the submandibular, sublingual and submental spaces resulting in a state of emergency. Early diagnosis and immediate treatment planning could be a life-saving procedure. Here we report a case of wide spread odontogenic infection extending to the neck with elevation of the floor of the mouth obstructing the airway which resulted in breathlessness and stridor for which the patient was directed to maintain his airway by elective tracheostomy and subsequent drainage of the potentially involved spaces. Late stages of the disease should be addressed immediately and given special importance towards the maintenance of airway followed by surgical decompression under antibiotic coverage. The appropriate use of parenteral antibiotics, airway protection techniques, and formal surgical drainage of the infection remains the standard protocol of treatment in advanced cases of Ludwig's angina.

The solid-phase synthesis of DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepine (PBD) imines and biologically important pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones on Wang resin using a reduction/cyclization procedure is reported.

USP7 is a deubiquitinating enzyme that plays a pivotal role in multiple oncogenic pathways and therefore is a desirable target for new anti-cancer therapies. However, the lack of structural information about the USP7-inhibitor interactions has been a critical gap in the development of potent inhibitors. USP7 is unique among USPs in that its active site is catalytically incompetent, and is postulated to rearrange into a productive conformation only upon binding to ubiquitin. Surprisingly, we found that ubiquitin alone does not induce an active conformation in solution. Using a combination of nuclear magnetic resonance, mass spectrometry, computational modeling, and cell-based assays, we found that DUB inhibitors P22077 and P50429 covalently modify the catalytic cysteine of USP7 and induce a conformational switch in the enzyme associated with active site rearrangement. This work represents the first experimental insights into USP7 activation and inhibition and provides a structural basis for rational development of potent anti-cancer therapeutics.

For wells drilled in shale gas reservoirs to be economic, hydraulic fracturing has become a common completion practice. Production from these completed wells is highly dependent on the characteristics of proppants placed in the created fractures. Fracturing leads to an interaction between the minerals of the proppants, formation and the fluids; this results in the phenomenon of proppants diagenesis. It involves mechanisms such as diffusion, dissolution, precipitation along with chemical reactions that take place at the fracture surface. Over time, this combined process results in a loss of proppant pack permeability thereby leading to a decline in well productivity. This occurs due to changes in compositional differences between proppants, fracturing fluid and the formation. A mathematical model, representing this phenomenon is developed in this paper. It inculcates the phenomenon of mass transfer along the length of the fracture coupled with associated surface chemical reactions, and mass conservation equations are solved for individual components. Further, the impact of finite difference techniques on the results is studied. This is supplemented with studies involving changes in fracture aperture as well as velocity profile of the flowing fluid. Impact of results from the developed mathematical model on typical shale gas well productivity is evaluated. [Received: April 1, 2015; Accepted: September 8, 2015]

The adaptability of in situ remediation techniques for low soluble fractions in petroleum products such as polycyclic aromatic hydrocarbon (PAH) is generally constrained due to their limited bio-availability owing to hydrophobicity. In the present study, a numerical model is developed to evaluate the effect of unsaturated hydraulic properties, equilibrium chemical partitioning as well as coupled reactions on the fate and transport of a typical PAH (phenanthrene) originating from a surface spill. Simulation of surfactant enhanced remediation using a non-ionic surfactant (Triton N-101) resulted in significant modifications in unsaturated hydraulic properties. The presence of natural organic matter (adsorption partitioning coefficient of 8.97 × 10–4 L/mg) as well as viable bacterial consortium (specific growth rate > 3.06 × 10–7 /sec) in the soil is found to be favouring the biodegradation in order to limit the reach of phenanthrene up to a depth of 200 cm. The results suggest that selection of surfactant type and dosage affected the extent of solubility enhancement of phenanthrene (from 1.27 to 11.5 mg/L); however, ultimately the typical bio-geochemical features of the subsurface seemed to control the success of remediation.

In-situ combustion (ISC) is an enhanced oil recovery method used to increase heavy oil recoveries. The present work describes the development of a predictive numerical model considering coupled thermal and fluid flow characteristics encountered during the complex ISC process. The physical model considers dynamic multi-phase fluid flow of oil, water and gas, and involves simultaneous heat and mass transfer mechanisms, while the kinetic model considers oxidation and cracking reactions resulting in generation of heat energy. The model considers capillary pressure effect and heat losses into the surroundings. The resulting coupled non-linear conservation equations have been solved iteratively using finite difference based numerical tool. The developed numerical model has been history matched with the results reported by Crookston et al. (1979) and found to be in good agreement. Sensitivity analysis on oxygen injection and kinetics of cracking reaction projected a dominant affect on the thermal and oil recovery profiles. [Received: August 4, 2015; Accepted: February 29, 2016]

There are various sources of energies available worldwide and among them, crude oil plays a vital role. Oil recovery is achieved using conventional primary and secondary recovery methods. In-order to recover the remaining residual oil, technologies like Enhanced Oil Recovery (EOR) are utilized which is also known as tertiary recovery. Among EOR, Microbial enhanced oil recovery (MEOR) is a technique which enables the improvement of oil recovery by injection of bio-surfactant produced by microorganisms. Bio-surfactant can retrieve unrecoverable oil from the cap rock which is held by high capillary force. Bio-surfactant is a surface active agent which can reduce the interfacial tension and reduce viscosity of oil and thereby oil can be recovered to the surface as the mobility of the oil is increased. Research in this area has shown promising results besides the method is echo-friendly and cost effective compared with other EOR techniques. In our research, on laboratory scale we produced bio-surfactant using the strain Pseudomonas putida (MTCC 2467) and injected into designed simple sand packed column which resembles actual petroleum reservoir. The experiment was conducted in order to determine the efficiency of produced bio-surfactant in oil recovery. The column was made of plastic material with 10 cm in length. The diameter was 2.5 cm. The column was packed with fine sand material. Sand was saturated with brine initially followed by oil saturation. Water flooding followed by bio-surfactant injection was done to determine the amount of oil recovered. Further, the injection of bio-surfactant volume was varied and checked how effectively oil recovery can be achieved. A comparative study was also done by injecting Triton X 100 which is one of the chemical surfactant. Since, bio-surfactant reduced surface and interfacial tension oil can be easily recovered from the porous sand packed column., {"references":["I. Lazar, I.G. Petrisor and T.F. Yen. \"Microbial Enhanced Oil Recovery\"\n(MEOR). Petroleum Sci. Technol, 25, pp. 1353-1366, 2007.","Qingxin, Li., Congbao Kang, Hao Wang, Chunde Liu, Changkai Zhang,.\n\"Application of microbial enhanced oil recovery technique to Daqing\nOilfield\" .Biochem. Eng. J, pp. 197 – 199. 2002.","A. Fiechter, \"Biosurfactants: Moving Towards Industrial Application.\"\nTrends Biotechnol, 10, pp. 208-217. 1992.","S. Mukherjee,., P. Das, C. Sivapathasekaran and R. Sen, \"Enhanced\nproduction of biosurfactant by marine bacterium on statistical screening\nof nutritional parameters\", J. Biochem. Eng, 42: pp. 254 – 260, 2008.","V. Singh, \"Biosurfactant – Isolation, production, purification &\nsignificance\" J. Sci. Ind. Res., 2: pp. 1 – 4.2012.","R.S, Makkar and S. S, Cameotra, \"Biosurfactant production by a\nthermophilic Bacillus subtilis strain\", J. Ind. Microbiol. Biotechnol, 18:\npp. 37 – 42. 1997.","J.D, Desai and I.M Banat, \"Microbial production of surfactants and their \ncommercial Potential\", Microbiol Mol Biol Rev, 61, pp. 47 – 64. 1997.","L. Fracchia, M. Cavallo, M.G. Martinooti and I. M. Banat, \n\"Biosurfactants and bioemsulfiers biomedical and related applications – \npresent status and future potentials\", In Tech., pp: 325 – 370. 2012.","Shah, D.O, \"Fundamental aspects of surfactant–polymer flooding \nprocess\", European Symposium on Enhanced Oil Recovery, England, \npp. 1–41, 1981.\n[10] C. Zhang, Shenghui Wang and Yanchun Yan. \"Isomerization and \nbiodegradation of beta-cypermethrin by Pseudomonas aeruginosa CH7 \nwith biosurfactant production\", Bioresource Technol, 102 (14), pp. 7139 \n– 7146.2011.\n[11] Suthar, H., Hingurao, K., Desai, A., Nerurkar, A.: \"Selective plugging \nstrategy based microbial enhanced oil recovery using Bacillus \nlicheniformis TT33\". J. Microbiol. Biotechnol. 19(10), pp. 1230–\n1237.2009.\n[12] Soudmand-asli, A., Ayatollahi, S. S., Mohabatkar, H., Zareie, M., \nShariatpanahi, S. F. \"The in situ microbial enhanced oil recovery in \nfractured porous media\". J. Petrol. Sci. Eng. 58, 161 – 172. 2007.\n[13] A. Muggeridge, A. Cockin, K. Webb, H Frampton, I. Collins, Tim \nMoulds and Peter Salino. \"Recovery rates, enhanced oil recovery and \ntechnological limits\", Phil.Trans. R. Soc. A, 372, pp. 1 – 26. 2013. \n[14] R.T. Armstrong and D. Wildenschild, \"Decoupling the Mechanism of \nMicrobial Enhanced Oil Recovery\", SPE146714, paper prepared for the \nSPE Annual Technical Conference and Exhibition held in Denver, CO, \nOct30, Nov 2., 2011."]}

This paper presents an analysis of the lower order spatial moments of colloidal transport in a coupled fracture-matrix system. For this purpose, colloidal transport is numerically modeled to obtain the spatial distribution of concentration profiles along the fracture. Implicit finite-difference numerical technique has been adopted to obtain the colloidal concentration in the fracture. Subsequently, the first and second spatial moments are evaluated using the colloidal concentration. The results suggest that effective velocity of the colloid is retarded by increment in rock matrix porosity, matrix diffusion coefficient, filtration coefficient, reduction of half-fracture aperture, initial colloid velocity, and remobilization coefficient. Significant mixing of colloids occurs in the fracture due to low-fracture aperture, initial colloid velocity, and filtration coefficient. � 2013 � 2013 Indian Society for Hydraulics.

Carbonate substituted nanohydroxyapatite (CHA) was synthesized and utilized for the removal of reactive red and reactive blue dye from aqueous solution, as it mimics the composition of conventional adsorbent animal bone charcoal. Also ionic substitution seems to alter the surface nature of the apatite structure. Physicochemical nature of adsorbent was characterized by XRD, FT-IR and SEM analysis. Adsorption as a function of contact time, adsorbent dosage and pH were studied by batch mode adsorption technique. Kinetic studies were performed to correlate the experimental kinetic data with theoretical models in order to understand the adsorption mechanism and the reaction rate.

Molecular oncology has the potential to revolutionize cancer treatment owing to its focus on discrete, cancer-selective targets, as evident in the recent success of kinase inhibitors and antibody-based therapies. Because of the heterogeneous nature of cancer, however, not every tumor type can be addressed with an appropriately selective therapy and some respond best to drug combinations that include classical “toxic” agents. The ubiquitin-proteasome pathway, recently harnessed for cancer treatment with the clinical use of “toxic” proteasome inhibitors bortezomib and carfilzomib, affords targets that intuitively are highly selective, exemplified by inhibitors of E3 ligases, the ubiquitin-conjugating enzymes, as well as those that are intuitively nonselective, exemplified by the proteasomal proteases. In the last two decades, anticancer drug development based on these two target classes has proceeded in parallel, with the early results suggesting that the nonselective proteasome is the better target. Lately, however, it has become clear that (1) the “nonselective” proteasome target may be addressed in selective ways and (2) a clearer understanding of the E3 ligase reaction can lead to the design or discovery of efficacious inhibitors. Evidence supporting these notions and implications for cancer treatment going forward will be discussed.

Este articulo se enfoca en obtener condiciones necesarias y suficientes para la existencia de la menos una solucion Ψ-acotada para la ecuacion lineal en diferencias matricial X (n + 1) = A (n) X (n) B (n) + F (n), donde F (n) es una funcion Ψ-sumable con valores matriciales en Z+.Finalmente, probamos un resultado relacionado al comportamiento asintotico de las soluciones Ψ-acotadas de esta ecuacion en Z+.

The contaminant transport mechanism in fractured clay porous media has been analysed using numerical modelling. Implicit finite difference has been used to develop the numerical model. A constant continuous source of contaminants has been assumed at the inlet of the fracture. The domain is considered to be saturated. A varying grid is considered in the fracture skin to account for the flux transfer at the interface of the fracture and the skin. The effect of constant dispersion as well as distance-dependent dispersion on the contaminant transport mechanism has been analysed in the presence of fracture skin. The contaminants are assumed to follow Freundlich non-linear sorption isotherm. Sensitivity analysis has been conducted to study the effect of different fracture-skin porosities, skin diffusion coefficients, half fracture apertures, fluid velocities and skin thicknesses on the solute transport mechanism within the fractured clay porous media. Results suggest that amount of solute diffusion into the clay matrix is directly proportional to the fracture-skin porosity and fracture-skin diffusion coefficient and inversely proportional to thickness of the half fracture aperture and the fluid velocity. The role of non-linear sorption is insignificant and scale-dependent dispersivity results in enhanced mass diffusion from the fracture. � 2014 Indian Society for Hydraulics.

2,7-Diaminomitosene (2,7-DAM), the major metabolite of the antitumor antibiotic mitomycin C, forms DNA adducts in tumor cells. 2,7-DAM was reacted with the deoxyoligonucleotide d(GTGGTATACCAC) under reductive alkylation conditions. The resulting DNA adduct was characterized as d(G-T-G-[M]G-T-A-T-A-C-C-A-C) (5), where [M]G stands for a covalently modified guanine, linked at its N7-position to C10 of the mitosene. The adducted oligonucleotide complements with itself, retaining 2-fold symmetry in the 2:1 drug-duplex complex, and provides well-resolved NMR spectra, amenable for structure determination. Adduction at the N7-position of G4 ([M]G, 4) is characterized by a downfield shift of the G4(H8) proton and separate resonances for G4(NH(2)) protons. We assigned the exchangeable and nonexchangeable proton resonances of the mitosene and the deoxyoligonucleotide in adduct duplex 5 and identified intermolecular proton-proton NOEs necessary for structural characterization. Molecular dynamics computations guided by 126 intramolecular and 48 intermolecular distance restraints were performed to define the solution structure of the 2,7-DAM-DNA complex 5. A total of 12 structures were computed which exhibited pairwise rmsd values in the 0.54-1.42 A range. The 2,7-DAM molecule is anchored in the major groove of DNA by its C10 covalently linked to G4(N7) and is oriented 3' to the adducted guanine. The presence of 2,7-DAM in the major groove does not alter the overall B-DNA helical structure. Alignment in the major groove is a novel feature of the complexation of 2,7-DAM with DNA; other known major groove alkylators such as aflatoxin, possessing aromatic structural elements, form intercalated complexes. Thermal stability properties of the 2,7-DAM-DNA complex 5 were characteristic of nonintercalating guanine-N7 alkylating agents. Marked sequence selectivity of the alkylation by 2,7-DAM was observed, using a series of oligonucleotides incorporating variations of the 5'-TGGN sequence as substrates. The selectivity correlated with the sequence specificity of the negative molecular electrostatic potential of the major groove, suggesting that the alkylation selectivity of 2,7-DAM is determined by sequence-specific variation of the reactivity of the DNA. The unusual, major groove-aligned structure of the adduct 5 may account for the low cytotoxicity of 2,7-DAM.

Eye lens alpha-crystallin is a member of the small heat shock protein (sHSP) family and forms large multimeric structures. Earlier studies have shown that it can act like a molecular chaperone and form a stable complex with partially unfolded proteins. We have observed that prior binding of the hydrophobic protein melittin to alpha-crystallin diminishes its chaperone-like activity toward denaturing alcohol dehydrogenase, suggesting the presence of mutually exclusive sites for these proteins in alpha-crystallin. To investigate the mechanism of the interaction between alpha-crystallin and substrate proteins, we determined the melittin-binding sites in alpha-crystallin by cross-linking studies. Localization of melittin-binding sites in alpha-crystallin resulted in the identification of RTLGPFYPSR and FVIFLDVKHFSPEDLTVK of alphaA-crystallin and FSVNLDVK of alphaB-crystallin as the chaperone sites. Of these sites, FVIFLDVKHFSPEDLTVK and FSVNLDVK were identified earlier as 1,1'-bi(4-anilino) naphthalene-5,5'-disulfonic acid (bis-ANS)-binding hydrophobic sites. Here we also report the synthesis and characterization of the peptide, KFVIFLDVKHFSPEDLTVK, having the melittin as well as bis-ANS-binding sequence of alphaA-crystallin. We show that this peptide has characteristics similar to that of alphaA-crystallin by in vitro thermal aggregation assay, gel filtration study, CD spectroscopy, and bis-ANS interaction studies. The peptide sequence corresponds to the beta3 and beta4 region present in the alpha-crystallin domain of sHSP 16.5. We hypothesize that the alpha-crystallin domain in other sHSPs may have a similar function and would likely possess the anti-aggregation property even when separated from the native protein.

The hydrophobic binding sites in alpha-crystallin were evaluated using fluorescent probes 1,1'-bi(4-anilino)naphthalenesulfonic acid (bis-ANS), 8-anilino-1-naphthalene sulfonate (ANS), and 1-azidonaphthalene 5-sulfonate (1,5-AZNS). The photolysis of bis-ANS-alpha-crystallin complex resulted in incorporation of the probe to both alphaA- and alphaB-subunits. Prior binding of denatured alcohol dehydrogenase to alpha-crystallin significantly decreased the photoincorporation of bis-ANS to alpha-crystallin. Localization of bis-ANS incorporated into alphaA-crystallin resulted in the identification of residues QSLFR and HFSPEDLTVK as the fluorophore binding regions. In alphaB-crystallin, sequences DRFSVNLNVK and VLGDVIEVHGK were found to be the bis-ANS binding regions. Of the bis-ANS binding sequences, HFSPEDLTVK of alphaA-crystallin and DRFSVNLNVK and VLGDVIEVHGK of alphaB-crystallin were earlier identified as part of the sequences involved in their interaction with target proteins during the molecular chaperone-like action. The hydrophobic probe, 1,5-AZNS, also interacted with both subunits of alpha-crystallin. Localization of 1,5-AZNS binding site in alphaB-crystallin lead to the identification of HFSPEEK sequence as the interacting site in this subunit of alpha-crystallin. Glycated alpha-crystallin displayed decreased ANS fluorescence and loss of chaperone-like function, suggesting the involvement of glycation site as well as ANS binding site in chaperone-like activity display.

The hydrophobic sites in alpha-crystallin were evaluated using a fluorescent probe 1,1'-bi(4-anilino)naphthalenesulfonic acid (bis-ANS). Approximately one binding site/subunit of alpha-crystallin at 25 degrees C was estimated by equilibrium binding and Scatchard analysis (Kd = 1.1 microM). Based on fluorescence titration, the dissociation constant was 0.95 microM. The number of bis-ANS binding sites nearly doubled upon heat treatment of the protein at 60 degrees C. Likewise, the exposure of alpha-crystallin to 2-3 M urea resulted in increased binding of bis-ANS. Above 3 M urea there was a rapid loss in the fluorescence indicating the loss of interaction between bis-ANS and protein. The alpha-crystallin refolded from 6 M urea showed tryptophan fluorescence emission similar to the native alpha-crystallin. However, the refolded alpha-crystallin showed a 60% increase in bis-ANS binding, suggesting distinct changes on the protein surface resulting from exposure to urea similar to the changes occurring due to heat treatment. The fluorescence of tryptophan in native alpha-crystallin was quenched by the addition of bis-ANS. The quenching was inversely related to the amount of bis-ANS bound to alpha-crystallin. Additionally, the binding of bis-ANS reduced the chaperone-like activity of the protein. Photolysis of bis-ANS-alpha-crystallin complex resulted in incorporation of the probe to both A- and B-subunits, indicating that both subunits in native alpha-crystallin contribute to the surface hydrophobicity of the protein.

The role of intraseasonal oscillations (ISOs) in modulating synoptic and interannual variations of surface winds over the Indian monsoon region is studied using daily averaged National Centers for Environmental Prediction/National Centre for Atmospheric Research (NCEP/NCAR) reanalyses for the period 1987-1996. Two dominant ISOs are found in all years, with a period between 30-60 days and 10-20 days respectively. Although the ISOs themselves explain only about 10-25% of the daily variance, the spatial structure of variance of the ISOs is found to be nearly identical to that of high frequency activity (synoptic disturbances), indicating a significant control by the ISOs in determining the synoptic variations. Zonal and meridional propagation characteristics of the two modes and their interannual variability are studied in detail. The synoptic structure of the 30-60 day mode is similar in all years and is shown to be intimately related to the strong ('active') or weak ('break') phases of the Indian summer monsoon circulation. The peak (trough) phase of the mode in the north Bay of Bengal corresponds to the 'active' ('break') phase of monsoon strengthening (weakening) the entire large scale monsoon circulation. The ISOs modulate synoptic activity through the intensification or weakening of the large scale monsoon flow (monsoon trough). The peak wind anomalies associated with these ISOs could be as large as 30% of the seasonal mean winds in many regions. The vorticity pattern associated with the 30-60 day mode has a bi-modal meridional structure similar to the one associated with the seasonal mean winds but with a smaller meridional scale. The spatial structure of the 30-60 day mode is consistent with fluctuations of the tropical convergence zone (TCZ) between one continental and an equatorial Indian Ocean position. The 10-20 day mode has maximum amplitude in the north Bay of Bengal, where it is comparable to that of the 30-60 day mode. Elsewhere in the Indian Ocean, this mode is almost always weaker than the 30-60 day mode. In the Bay of Bengal region, the wind curl anomalies associated with the peak phases of the ISOs could be as large as 50% of the seasonal mean wind curl. Hence, ISOs in this region could drive significant ISOs in the ocean and might influence the seasonal mean currents in the Bay. On the interannual time scale, the NCEP/NCAR reanalysed wind stress is compared with the Florida State University monthly mean stress. The seasonal mean stress as well as interannual standard deviation of monthly stress from the two analyses agree well, indicating absence of any serious systematic bias in the NCEP/NCAR reanalysed winds. It is also found that the composite structure of the 30-60 day mode is strikingly similar to the dominant mode of interannual variability of the seasonal mean winds indicating a strong link between the ISOs and the seasonal mean. The ISO influences the seasonal mean and its interannual variability either through increased/decreased residence time of the TCZ in the continental position or through occurrence of stronger/weaker active/break spells. Thus, the ISOs seem to modulate all variability in this region from synoptic to interannual scales.

The photochemical properties of the alkanolamine form of sanguinarine, a benzophenanthridine plant alkaloid, were studied using absorption, fluorescence and high pressure liquid chromatography techniques. An excitation time dependent decrease in the fluorescence intensity of its emission maximum, along with changes in the emission and absorption spectral pattern was observed when the solution of alkanolamine form was excited under stirring. The rate of the reaction was dependent on the number of photons and the process was found to be irreversible. The irreversibility of the fluorescence excitation, emission and absorption spectra of the alkanolamine solution on excitation confirmed that this form of the alkaloid was undergoing a photochemical conversion in the excited singlet state. Further evidence for a photo-oxidation reaction was obtained from the experiments performed in the absence of molecular oxygen. On saturation of the solution with nitrogen gas, the photochemical conversion was not found occur indicating an absolute requirement of molecular oxygen in the reaction. The photoproduct was isolated and identified as oxysanguinarine. On the basis of these observations, it is concluded that the sanguinarine alkanolamine form undergoes an irreversible photo-oxidation in the excited singlet state to produce oxysanguinarine.

Nutraceuticals availability in heat-processed foods is considered to be the index for healthy food. This study has made an attempt to optimize the temperature to retain nutraceuticals in wheat bran (WB) and wheat germ (WG). Heated WG (130 °C140 °C) and WB (140 °C150 °C) were analyzed for sensory profiles. Extracted oils were subjected to physicochemical parameter as well as its nutraceuticals. Increased oil yield, color values and reduced free fatty acids were found with varied temperatures. Fat-soluble compounds total tocols, steryl ferulates and carotenoids found in WG (0.316, 0.058 and 0.011%) and WB (0.228, 0.595 and 0.015%) and maximum reductions started in WG (0.183%, 0.034% and 0.004%) at 130 °C. The free radical-scavenging activities of control samples showed high EC50 values than processed samples; however, no differences were observed between two temperatures. Study may clearly spell out that the reduced nutraceuticals observed after subjecting food raw materials to optimum temperature eventually lead to its quality.

Fat-soluble nutraceuticals of cereals are known for number of disease preventive activities. Hence wheat bran oil (WBO) and wheat germ oil (WGO) were extracted from wheat bran and germ which yielded 3.35 % and 7.35 % of oil, containing polyunsaturated fatty acids (PUFA) (64 %, 61.2 %) respectively. Both oils contained tocopherols and carotenoids, which were higher in wheat germ oil (273 mg/100 g, 12.23 mg/100 g) than wheat bran oil (190 mg/100 g, 2.21 mg/100 g). Steryl ferulates were also present in both the oils, but their content was eight-fold higher in WBO than in WGO. Three major steryl ferulates identified by HPLC were campesteryl ferulate and sitostenyl ferulate, campestanyl ferulate and β-sitosteryl ferulate as in γ-oryzanol and another ferulate, viz., sitostanyl ferulate. A strong IC50 value of 7.5 mg/mL and 21.6 mg/mL DPPH free radicals scavenging for wheat germ oil for wheat bran oil was observed. NMR ((13)C and (1)H) profile explored the evidence of distribution of antioxidant molecules in the unsaponifiable matter of wheat derived oil. Since oils rich in PUFA and minor components are required for the normal physiological activities, blending such oils with other edible oils of the diet in wheat growing countries like India may be useful to provide health benefits.

Biocompatible luminescent materials have received much attention for the development of novel bioprobes. In the present work, we have synthesized the flower-like hydroxyapatite (HA) nanostructure from eggshell biowaste via a simple and rapid microwave conversion process. The synthesized product is identified as Mg containing B-type carbonated HA. It showed an intense blue emission between 360 nm to 550 nm with maximum around 430 nm under UV light excitation (λex= 344 nm). This blue emission might result from the carbonate related impurities present in the structure of HA and it can be a potential luminescent material for the development biocompatible probes.

Following myocardial infarction, extracellular matrix (ECM) is disrupted, which leads to the generation of collagen- and elastin-derived peptides (CDPs and EDPs, respectively). To investigate whether ECM-derived peptides (i.e., CDPs and EDPs) induce extracellular proteinases in human heart fibroblast (HHF) cells, we isolated CDP and EDP using gelfiltration and antibody affinity column chromatography. The CDP and EDP were characterized by their intrinsic fluorescence due to cross-link structure (pyridinoline and desmosine, respectively) and by immunoblot analysis using anti-desmosine antibody. Neutrophil elastase and cathepsin G were identified using selective chromogenic substrates and by their specific inhibition with α1-proteinase inhibitor and α1-antichymotrypsin, respectively. Elastase and cathepsin G were elevated in the infarcted tissue. Selective inhibition of matrix metalloproteinase (MMP) by a higher concentration of tetracycline or doxycycline in zymographic gels elicited an inhibition constant (IC50) of 278 ± 10 μM and indicated that majority of MMP in the infarcted tissue is from fibroblast cells. The HHF proliferation was measured using an acid-phosphatase assay. The EDP and CDP induce HHF cell proliferation. After EDP treatment phenotypic (formation of pseudopodia) changes were observed in HHF cells. To measure whether phenotypic changes by EDP or CDP are associated with MMP and tissue inhibitor of metalloproteinase (TIMP) expression in HHF cells, we measured MMP and TIMP expression by zymographic and Northern blot (mRNA) analyses. The expression of MMP and TIMP were upregulated at both the protein and gene transcription levels. These results suggested that during ischemic cardiomyopathy, initially neutrophil proteinase activates latent myocardial MMP which can degrade ECM, which continuously degrades if not controlled by TIMP, leading to ventricular dilatation and dysfunction. © 1996 Wiley-Liss, Inc.

Latent matrix metalloproteinases (MMPs) in normal myocardium are activated in end-stage heart failure. In vitro oxidized glutathione (GSSG) activates myocardial MMPs which contains a cysteine residue. In vivo GSSG induce the collagen lysis and cardiac dilatation. To assess whether thiol and non-thiol reducing agents have direct effect on the interstitial human heart fibroblast (HHF) proliferation and MMP expression, HHF and polyoma virus transformed fibroblast cells were cultured with or without the thiol-containing reduced (GSH) or oxidized (GSSG) glutathiones, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), and non-thiol ascorbic acid. After 100 micrograms/ml (approximately 0.3 mM) GSH or PDTC treatment the proliferative (synthetic) phenotype of transformed fibroblast cells was changed to quiescent (contractile) phenotype. Also, after GSH, PDTC, and ascorbic acid treatment the medium was then analyzed for MMP activity by zymography. The results indicate reduction in MMP expression in transformed fibroblast cells after GSH and PDTC treatments and no effect after ascorbic acid treatment. Based on reverse zymography, we observed the level of tissue inhibitor of metalloproteinase (TIMP) at a decreased level in transformed cells. The effect of the reducing agent at the gene transcription was measured by estimating mRNA (Northern blot analysis) of MMP and of TIMP in the cells that were cultured in medium in the presence and absence of GSH. These results indicate that GSH induces MMP-2 and MMP-1 expression in normal HHF and that GSH reduces MMP-2 and MMP-1 in transformed fibroblast cells. After the treatment, the TIMP-2 level was repressed in normal HHF and TIMP-2 level increased in transformed fibroblast cells. These events are dependent on the nuclear transcription factor activity on the collagenase promoter in normal HHF cells. On the other hand, in polyoma transform fibroblast cells these events are not dependent on this collagenase promoter. These results suggest that oxidative environment induces normal HHF cell proliferation, and the reducing agent decreases normal HHF cell proliferation by inducing MMP and repressing TIMP gene transcription. In transformed cells reducing agents inhibit MMP expression and increase TIMP levels, which suggests a role of antioxidants in preventing tumorigenesis.

Nanoparticles have attracted remarkable recent interest for drug delivery application and control of protein structure and activity. The interaction of gold nanoparteicles (GNP), thionine (TH), two complexes of GNP-TH, namely S1 and S2 with the transport protein Human Serum Albumin (HSA) was studied. GNP was prepared by citrate reduction method, while S1 and S2 were synthesized by mixing GNP and TH at different ratios - at room temperature and at 80oC, respectively. GNP, S1 and S2 were characterized by strong plasmon resonance absorption in 500-600 nm region. The adsorption of TH on GNP surfaces was characterized by FTIR spectroscopy. In order to understand the particle size domains of the synthesized GNP, S1 and S2, dynamic light scattering technique was used. Absorbance and fluorescence quenching experiments revealed the formation of strong complexes of S2 and HSA, and comparatively weaker complex between S1 and HSA. Spectroscopic analysis suggested the binding affinity of S1-HSA to be of the order of 104 M−1 and that of GNP-HSA, TH-HSA, S2-HSA to be of the order 105 M−1. Synchronous fluorescence confirmed alteration in the microenvironment of the Trp residues of HSA while practically no shift in the maximum emission wavelength reflected little transformation around Tyr residues. Circular dichroism studies revealed that binding, in all cases, altered the protein conformation by reducing the α-helical content. The binding also caused perturbation of the tertiary structure leading to unfolding of the protein and induced optical activity in the bound molecules, but to varying extents. The present study through multifaceted biophysical experiments is an effort to use GNPs as delivery vehicles for multiple therapeutic purposes.

The present experimental and numerical study aims to study the effect of transverse forces on the velocity of nanoparticles through a single fracture. The velocity of nanoparticles is computed with the effect of van der Waals and gravity force through a single fracture based on the parallel plate model for a fixed half fracture aperture and temperature, a selected nanofluid (type of nanoparticles and dispersing medium) over a range of particles sizes. Particle size limit is identified as the particle size beyond which the nanoparticles have negligible velocity through the fracture. Effect of half fracture aperture and temperature on particle size limit is studied. Finally, the numerical model is applied to experimental data obtained for a range of silane coated silica and alumina nanofluids prepared in distilled water and formation water of an Indian carbonate reservoir to screen the nanofluids for flooding applications. [Received: July 31, 2014; Accepted: March 2, 2015]

The polymorphic behaviour on the conformation of a alternating GC polymer and its methylated analogue has been studied under the influence of low pH, low temperature and low ionic strength from the measurements of UV-absorption and circular dichroic spectroscopy. Studies indicate that both the polymers isomerize to a stable left handed type conformations. The duplex nature of these conformations were inferred from thermal denaturation curves and the temperature dependence of the CD spectra. In natural DNA, the influence of low pH and low temperature also shows a defined conformational change, characterized by two positive CD bands. This conformational status is achieved in all DNAs irrespective of base composition or sequence of base pairs. Further evidence to this altered polymorphic state of natural DNAs is inferred from ethidium binding study.

Increasing oil prices and depleting domestic resources have generated interest in Enhanced Oil Recovery (EOR) methods. Many EOR methods are currently being used, and CO2 flooding is of great interest, particularly in fractured reservoirs as it not only increases the ultimate recovery but also reduces greenhouse emissions allowing companies to earn carbon credits. In general, primary recovery based on the natural energy of reservoir can produce only 33% of original oil in place (OOIP), while secondary recovery methods based on gas and water flooding can enhance it to 66% in non-fractured reservoirs. However, in fractured reservoirs, gas/water bypass the resident fluid residing within the low-permeability rock-matrix due to the marked difference in porosity and permeability between fracture and its associated rock matrix, and eventually, provides poor sweep efficiency. Thus, fractured reservoirs have always been considered as poor candidates for EOR as these high permeability fractures provide a preferential pathway for injected fluids to channel through directly from injection to production wells without significant fracture-matrix interaction. In the present study, Computer Modeling Group (CMG - GEM) and WINPRO reservoir simulators are used to perform CO2 injection experiments numerically using the concept of "dual-porosity" with different CO2 injection rates and eventually to determine the optimal peak oil production rate during CO2 fluid injection within a fractured reservoir process in a single fracture. Through simulation, sensitivity analysis is conducted to determine the effect of parameters like fracture permeability, matrix porosity, matrix permeability, fracture spacing and fluid velocity on oil recovery factor. Results suggest that oil recovery in case of fractured reservoir is significantly greater than that in a non fractured reservoir or porous reservoir.

Progressive muscle wasting, also known as myopathy or muscle atrophy is a debilitating and life-threatening disorder. Myopathy is a pathological condition of many diseases including cancer, diabetes, COPD, and AIDS and is a natural consequence of inactivity and aging (sarcopenia). Muscle atrophy occurs when there is a net loss of muscle mass resulting in a change in the balance between protein synthesis and protein degradation. The ubiquitin pathway and specific ubiquitin pathway enzymes have been directly implicated in the progression of atrophy. The ubiquitin E3 ligase Muscle-specific RING Finger E3 ligase (MuRF1) is upregulated and increases protein degradation and muscle wasting in numerous muscle atrophy models. The inhibition of MuRF1 could be a novel mechanism to prevent or reverse muscle wasting associated with various pathologies. We screened a small molecule library for inhibitors to MuRF1 activity and identified P013222, an inhibitor of MuRF1 autoubiquitylation. Further, P013222 was shown to inhibit MuRF1-dependent substrate ubiquitylation, and was active in inhibiting MuRF1 in a cellular atrophy model. Thus MuRF1 can be targeted in a specific manner and produce positive results in cellular atrophy models.

SummaryConverting lead compounds into drug candidates is a crucial step in drug development, requiring early assessment of potency, selectivity, and off-target effects. We have utilized activity-based chemical proteomics to determine the potency and selectivity of deubiquitylating enzyme (DUB) inhibitors in cell culture models. Importantly, we characterized the small molecule PR-619 as a broad-range DUB inhibitor, and P22077 as a USP7 inhibitor with potential for further development as a chemotherapeutic agent in cancer therapy. A striking accumulation of polyubiquitylated proteins was observed after both selective and general inhibition of cellular DUB activity without direct impairment of proteasomal proteolysis. The repertoire of ubiquitylated substrates was analyzed by tandem mass spectrometry, identifying distinct subsets for general or specific inhibition of DUBs. This enabled identification of previously unknown functional links between USP7 and enzymes involved in DNA repair.

Synthesis of Zn or CO32− substituted nano‐hydroxyapatite (HA) and its physico‐chemical properties have been well documented. However, the effects of the simultaneous substitution of Zn and CO32− in nano‐HA have not been reported. In the present study, Zn and CO32− substitutions in nano HA independently and concurrently have been done by wet precipitation method and characterized by XRD and FT‐IR for its phase purity and chemical homogeneity. Further modulations of the bioactivity and thermal stability of HA due to the substitutions have been studied.

The effect of experimentally induced atherosclerosis on the synthesis and secretion of lipoproteins in the density range of very low density lipoproteins (VLDL) and low density lipoproteins (LDL) have been studied using primary cultures of rat hepatocytes. Rats fed atherogenic diet showed higher levels of lipids associated with serum VLDL and LDL fraction, aorta and liver when compared with animals fed normal diet. Incorporation of [3H]leucine into apo B associated with the cell layer and secreted by hepatocytes from rats fed atherogenic diet was significantly more when compared with normal hepatocytes. [14C]Acetate incorporation studies showed that the synthesis of cholesterol was lower in hepatocytes from atherogenic diet fed rats, but more of the newly synthesised cholesterol was found in the secreted VLDL; secretion of lipids, particularly triglycerides, unesterified cholesterol and cholesterol in the lipoproteins in the density range of VLDL and LDL was significantly more in these hepatocytes. The relative distribution of [3H]-radioactivity in the LDL density range was 57% in hepatocytes from atherogenic diet fed animals as compared with 28% in controls, suggesting a relatively higher production of lipoproteins in the LDL density range than VLDL by these cells. These results indicate that the hypercholesterolemia in atherogenic diet fed animals may among other factors be caused by increased synthesis of apo B by liver cells and resultant increase in the secretion of apo B containing lipoproteins.

An efficient method for the reduction of aromatic nitro and azido compounds on solid support using indium/NH 4 Cl is described. This solid-phase reduction technique has been applied to the synthesis of pyrrolo[2,1- c ][1,4]benzodiazepine-5,11-diones.

The solid-phase synthesis of biologically important pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones using Wang resin through amide formation and reductive cyclization procedures is described. Further, N10-substituents have been introduced in the final products and these have been cleaved from the solid support in good yields.

Pharmacologically motivated natural product investigations have yielded a large variety of structurally unique lead compounds with interesting biomedical properties, but the natural roles of these molecules often remain unknown. In the present investigation, a series of benzyl substituted-flavone derivatives have been synthesized from the lead compounds and were screened against 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and α-glucosidase inhibitory properties. The resulting activity profiles of these flavone derivatives were compared for degree of similarity to the profile of 1-3. Most of the synthesized derivatives displayed potent activities when compared to the parent compounds. Maximum potencies for DPPH free radical scavenging activity were observed only in compounds containing the 4-hydroxyl substitution and 3-methoxyl group on the phenyl ring. While the 2- and 4-hydroxyl group substitutions on the phenyl ring seem to be crucial for the intestinal α-glucosidase inhibitory activity.

The ubiquitin-proteasome system is central to the regulation of numerous cellular events, and dysregulation may lead to disease pathogenesis. E3 ubiquitin ligases typically function in concert with E1 and E2 enzymes to recruit specific substrates, thereby coordinating their ubiquitylation and subsequent proteasomal degradation or cellular activity. E3 ligases have been implicated in a wide range of pathologies, and monitoring their activity in a rapid and cost-effective manner would be advantageous in drug discovery. The relative lack of high-throughput screening (HTS)–compliant E3 ligase assays has significantly hindered the discovery of E3 inhibitors. Herein, the authors describe a novel HTS-compliant E3 ligase assay platform that takes advantage of a ubiquitin binding domain’s inherent affinity for polyubiquitin chains, permitting the analysis of ubiquitin chain formation in an E3 ligase-dependent manner. This assay has been used successfully with members of both the RING and HECT families, demonstrating the platform’s broad utility for analyzing a wide range of E3 ligases. The utility of the assay platform is demonstrated by the identification of inhibitors of the E3 ligase CARP2. As the number of E3 ligases associated with various disease states increases, the ability to quantitate the activity of these enzymes in an expeditious manner becomes imperative in drug discovery. (Journal of Biomolecular Screening XXXX:xx-xx)

Chemical investigation of the stem bark of Oroxylum indicum resulted in the isolation and characterization of two new flavonoid glycosides (1, 2), along with seven known compounds (3-9). Their structures were established on the basis of extensive spectroscopic (IR, MS, 2D NMR) data analysis and by the comparison with spectroscopic data reported in the literature. In addition, all the compounds were tested for their ulcer protective effects against various gastric ulceritis inducing models in rats.