Search of antitubercular activities in tetrahydroacridines: synthesis and biological evaluation

A series of 9-substituted tetrahydroacridines were synthesized by nucleophilic substitution of chloro group with different nucleophiles in 9-chlorotetrahydroacridine (2). The latter could be obtained by POCl(3) mediated cyclization of the intermediate enamine, which in turn, was prepared by acid catalyzed condensation of anthranilic acid and cyclohexanone. Most of the compounds on antitubercular evaluation against M. tuberculosis H37 Rv and H37 Ra strains exhibited potent activities with MIC 6.125-0.78 microg/mL comparable to the standard drugs.     

Association Models for Clustered Data with Binary and Continuous Responses

Summary .  We consider analysis of clustered data with mixed bivariate responses, i.e., where each member of the cluster has a binary and a continuous outcome. We propose a new bivariate random effects model that induces associations among the binary outcomes within a cluster, among the continuous outcomes within a cluster, between a binary outcome and a continuous outcome from different subjects within a cluster, as well as the direct association between the binary and continuous outcomes within the same subject. For the ease of interpretations of the regression effects, the marginal model of the binary response probability integrated over the random effects preserves the logistic form and the marginal expectation of the continuous response preserves the linear form. We implement maximum likelihood estimation of our model parameters using standard software such as PROC NLMIXED of SAS . Our simulation study demonstrates the robustness of our method with respect to the misspecification of the regression model as well as the random effects model. We illustrate our methodology by analyzing a developmental toxicity study of ethylene glycol in mice.     

Mechanism of inhibition of deoxyribonucleic acid synthesis in Escherichia coli by hydroxyurea

The effects of hydroxyurea on Escherichia coli B/5 physiology (increases in cell mass, number of viable cells, and deoxyribonucleic acid [DNA], RNA, and protein concentrations) were studied in an attempt to find a concentration that completely inhibits DNA synthesis and increase in number of viable cells but has little or no effect on other metabolic processes. These conditions were the most closely approached at an hydroxyurea concentration of 0.026 to 0.033 m. A concentration of 0.026 or 0.033 m was used in subsequent experiments to study the site(s) of inhibition of DNA synthesis in E. coli B/5 by hydroxyurea. Hydroxyurea at a concentration of 10(-2)m was found to inhibit ribonucleoside diphosphate reductase activity completely in crude extracts of E. coli. The synthesis of deoxyribonucleotides was greatly reduced when E. coli cells were grown in the presence of 0.033 m hydroxyurea. Studies on the acid-soluble DNA precursor pools showed that hydroxyurea causes a decrease in the concentration of deoxyribonucleoside diphosphates and deoxyribonucleoside triphosphates and an increase in the total concentration of ribonucleotides. Sucrose density gradient sedimentation of DNA from cells treated with 0.026 m hydroxyurea for 30 min indicated that at this concentration hydroxyurea induces no detectable single- or double-strand breaks. In addition, both replicative and repair syntheses of DNA were found to occur normally in toluene-treated cells in the presence of relatively high concentrations of hydroxyurea. Pulse-chase studies showed that deoxyribonucleotides synthesized prior to the addition of hydroxyurea to cells are utilized normally for DNA synthesis in the presence of hydroxyurea. On the basis of these observations, we have concluded that the primary, if not the only, site of inhibition of DNA synthesis in E. coli B/5 by low concentrations of hydroxyurea is the inhibition of the enzyme ribonucleoside diphosphate reductase.     

Factors determining the midday depression of photosynthesis in trees under monsoon climate

 Field studies of gas exchange of Populus deltoides, Prosopis juliflora and Acacia auriculiformis showed large diurnal changes in net photosynthesis (A) and stomatal conductance (g_s) during autumn. P. deltoides and P. juliflora undergo pronounced midday depression in A and g_s while A. auriculiformis showed a one-peak response. Several factors indicative of photosynthetic performance were found to be reversibly affected during afternoon decline. These include (i) decrease in initial slope of the CO₂ response curve (carboxylation efficiency), (ii) substantial increase in CO₂ compensation point and (iii) decrease in overall quantum yield of photosystem II. The phenomenon can be duplicated in potted plants by simulating a typical daily pattern of PPFD and VPD. It is found that high VPD induces significant decline in A and g_s at moderate temperature and saturating PPFD (800 μmol m^–2 s^–1) whereas these parameters are only marginally affected at high PPFD and low VPD. Fluorescence data show that the tree species under study have a high capacity for safe dissipation of excessive excitation energy. The activation of photorespiration, as evident from an increase in CO₂ compensation point, maintains constant internal CO₂ concentration (C_i) which may aid in minimizing photoinhibition during stomatal closure at midday. In case of P. deltoides and P. juliflora the stomata seem to be quite sensitive to the changes in humidity whereas this does not appear to be essential in case of A. auriculiformis because of its phyllode structure that endows it with mechanisms for conserving water without undergoing large-scale stomatal changes. Received: 16 October 1997 / Accepted: 5 March 1998     

An efficient chemical approach to bispecific antibodies and antibodies of high valency

Irreversible chemical programming of monoclonal aldolase antibody (mAb) 38C2 has been accomplished with β-lactam equipped mono- and bifunctional targeting modules, including a cyclic-RGD peptide linked to either the peptide (d-Lys⁶)-LHRH or another cyclic RGD unit and a small-molecule integrin inhibitor SCS-873 conjugated to (d-Lys⁶)LHRH. We also prepared monofunctional targeting modules containing either cyclic RGD or (d-Lys⁶)-LHRH peptides. Binding of the chemically programmed antibodies to integrin receptors α(v)β(3) and α(v)β(5) and to the luteinizing hormone releasing hormone receptor were evaluated. The bifunctional and bivalent c-RGD/LHRH and SCS-783/LHRH, the monofunctional and tetravalent c-RGD/c-RGD, and the monofunctional bivalent c-RGD chemically programmed antibodies bound specifically to the isolated integrin receptor proteins as well as to integrins expressed on human melanoma M-21 cells. c-RGD/LHRH, SCS-783/LHRH, and LHRH chemically programmed antibodies bound specifically to the LHRH receptors expressed on human ovarian cancer cells. This approach provides an efficient, versatile, and economically viable route to high-valency therapeutic antibodies that target defined combinations of specific receptors. Additionally, this approach should be applicable to chemically programmed vaccines.     

Winter ecology of the Arunachal macaque Macaca munzala in Pangchen Valley,western Arunachal Pradesh,northeastern India

The newly described Arunachal macaque Macaca munzala occurs largely in sub‐tropical to temperate environments at elevations of c. 1,800–3,000 m in Arunachal Pradesh, northeastern India. We studied its over‐wintering strategy by comparing the diet, ranging, and behavior of a troop of 24 individuals during winter and spring (December 2005 to May 2006) through instantaneous scan sampling (3,002 records, 448 scans, 112 hr of observation). We also monitored the phenology of food plants. The macaques spent more time (41–66%) feeding in the winter than in spring (33–51%), whereas time spent moving and resting was greater in spring. The diet composed largely of plants, with animal matter being eaten rarely. The number of plant species in the diet increased from 18 to 25 whereas food types rose from 18 to 36 from winter to spring, respectively. Although only two species formed 75% of the winter diet, seven species comprised this proportion in spring. Availability of fruits and young leaves increased in spring; the troop moved more and utilized a larger part of its range during this time. Seasonal changes in behavior could be explained by the scarcity of food and the costs of thermoregulation in winter. Our study suggests that the Arunachal macaque inhabits a highly seasonal environment and has an over‐wintering strategy that includes subsisting on a high‐fiber diet by increasing the time spent feeding, and minimizing energy expenditure by reducing the time spent moving. Am. J. Primatol. 71:939–947, 2009. © 2009 Wiley‐Liss, Inc.     

Biotechnological and industrial significance of cyanobacterial secondary metabolites

Cyanobacteria are considered to be a rich source of novel metabolites of a great importance from a biotechnological and industrial point of view. Some cyanobacterial secondary metabolites (CSMs), exhibit toxic effects on living organisms. A diverse range of these cyanotoxins may have ecological roles as allelochemicals, and could be employed for the commercial development of compounds with applications such as algaecides, herbicides and insecticides. Recently, cyanobacteria have become an attractive source of innovative classes of pharmacologically active compounds showing interesting and exciting biological activities ranging from antibiotics, immunosuppressant, and anticancer, antiviral, antiinflammatory to proteinase-inhibiting agents. A different but not less interesting property of these microorganisms is their capacity of overcoming the toxicity of ultraviolet radiation (UVR) by means of UV-absorbing/screening compounds, such as mycosporine-like amino acids (MAAs) and scytonemin. These last two compounds are true ‘multipurpose’ secondary metabolites and considered to be natural photoprotectants. In this sense, they may be biotechnologically exploited by the cosmetic industry. Overall CSMs are striking targets in biotechnology and biomedical research, because of their potential applications in agriculture, industry, and especially in pharmaceuticals.     

Bayesian case influence diagnostics for survival models

We propose Bayesian case influence diagnostics for complex survival models. We develop case deletion influence diagnostics for both the joint and marginal posterior distributions based on the Kullback-Leibler divergence (K-L divergence). We present a simplified expression for computing the K-L divergence between the posterior with the full data and the posterior based on single case deletion, as well as investigate its relationships to the conditional predictive ordinate. All the computations for the proposed diagnostic measures can be easily done using Markov chain Monte Carlo samples from the full data posterior distribution. We consider the Cox model with a gamma process prior on the cumulative baseline hazard. We also present a theoretical relationship between our case-deletion diagnostics and diagnostics based on Cox's partial likelihood. A simulated data example and two real data examples are given to demonstrate the methodology.