Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH

Background Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. Methodology/Principal Findings Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the β-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylateinhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. Conclusions/Significance These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents

Dealing with non-metric dissimilarities in fuzzy central clustering algorithms

Clustering is the problem of grouping objects on the basis of a similarity measure among them. Relational clustering methods can be employed when a feature-based representation of the objects is not available, and their description is given in terms of pairwise (dis)similarities. This paper focuses on the relational duals of fuzzy central clustering algorithms, and their application in situations when patterns are represented by means of non-metric pairwise dissimilarities. Symmetrization and shift operations have been proposed to transform the dissimilarities among patterns from non-metric to metric. In this paper, we analyze how four popular fuzzy central clustering algorithms are affected by such transformations. The main contributions include the lack of invariance to shift operations, as well as the invariance to symmetrization. Moreover, we highlight the connections between relational duals of central clustering algorithms and central clustering algorithms in kernel-induced spaces. One among the presented algorithms has never been proposed for non-metric relational clustering, and turns out to be very robust to shift operations. (C) 2008 Elsevier Inc. All rights reserved

CD4+CD25+ T-Cells Control Autoimmunity in the Absence of B-Cells

OBJECTIVE: Tumor necrosis factor ligand family members B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) can exert powerful effects on B-cell activation and development, type 1 T-helper cell (Th1) immune responses, and autoimmunity. We examined the effect of blocking BAFF and APRIL on the development of autoimmune diabetes. RESEARCH DESIGN AND METHODS: Female NOD mice were administered B-cell maturation antigen (BCMA)-Fc from 9 to 15 weeks of age. Diabetes incidence, islet pathology, and T- and B-cell populations were examined. RESULTS: BCMA-Fc treatment reduced the severity of insulitis and prevented diabetes development in NOD mice. BCMA-Fc-treated mice showed reduced follicular, marginal-zone, and T2MZ B-cells. B-cell reduction was accompanied by decreased frequencies of pathogenic CD4(+)CD40(+) T-cells and reduced Th1 cytokines IL-7, IL-15, and IL-17. Thus, T-cell activation was blunted with reduced B-cells. However, BCMA-Fc-treated mice still harbored detectable diabetogenic T-cells, suggesting that regulatory mechanisms contributed to diabetes prevention. Indeed, BCMA-Fc-treated mice accumulated increased CD4(+)CD25(+) regulatory T-cells (Tregs) with age. CD4(+)CD25(+) cells were essential for maintaining euglycemia because their depletion abrogated BCMA-Fc-mediated protection. BCMA-Fc did not directly affect Treg homeostasis given that CD4(+)CD25(+)Foxp3(+) T-cells did not express TACI or BR3 receptors and that CD4(+)CD25(+)Foxp3(+) T-cell frequencies were equivalent in wild-type, BAFF(-/-), TACI(-/-), BCMA(-/-), and BR3(-/-) mice. Rather, B-cell depletion resulted in CD4(+)CD25(+) T-cell-mediated protection from diabetes because anti-CD25 monoclonal antibody treatment precipitated diabetes in both diabetes-resistant NOD.microMT(-/-) and BCMA-Fc-treated mice. CONCLUSIONS: BAFF/APRIL blockade prevents diabetes. BCMA-Fc reduces B-cells, subsequently blunting autoimmune activity and allowing endogenous regulatory mechanisms to preserve a prehyperglycemic state

Raman spectroscopy monitoring of the cellular activities of a tissue-engineered ex vivo produced oral mucosal equivalent

To ensure quality control and assurance in tissue engineering, noninvasive, real-time and aseptic evaluation of cell-based devices is required before product release. In this study, Raman spectroscopy was applied to monitor the cellular activities of an oral mucosa equivalent (EVPOME) produced ex vivo from cultured autogenous oral keratinocytes and acellular dermis—AlloDerm. Raman spectra showed a positive correlation of the peak area ratio of amide I (1655 cm −1 )/phenylalanine (1004 cm −1 ) with a negative linear regression ( R 2 > 0.95) according to the number of cultured days, especially on the 14thand 21st day. This work demonstrates the successful application of Raman spectroscopy for quantitatively monitoring and evaluating the maturity of EVPOME. Copyright © 2010 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83170/1/2688_ftp.pd

Self-reported use of tobacco products in nine rural INDEPTH Health and Demographic Surveillance Systems in Asia

BACKGROUND: Tobacco use is the most preventable cause of premature death and disability. Even though tobacco use is common in many Asian countries, reliable and comparable data on the burden imposed by tobacco use in this region are sparse, and surveillance systems to track trends are in their infancy. OBJECTIVE: To assess and compare the prevalence of tobacco use and its associated factors in nine selected rural sites in five Asian countries. METHODS: Tobacco use among 9,208 men and 9,221 women aged 25-64 years in nine Health and Demographic Surveillance System (HDSS) sites in five Asian countries of the INDEPTH Network were examined in 2005 as part of a broader survey of the major chronic non-communicable disease risk factors. All sites used a standardised protocol based on the WHO STEPS approach to risk factor surveillance; expanded questions of local relevance, including chewing tobacco, were also included. Multivariable logistic regression was used to assess demographic factors associated with tobacco use. RESULTS: Tobacco use, whether smoked or chewed, was common across all sites with some notable variations. More than 50% of men smoked daily; this applied to almost all age groups. Few women smoked daily in any of the sites. However, women were more likely to chew tobacco than men in all sites except Vadu in India. Tobacco use in men began in late adolescence in most of the sites and the number of cigarettes smoked daily ranged from three to 15. Use of both forms of tobacco, smoked and chewed, was associated with age, gender and education. Men were more likely to smoke compared to women, smoking increased with age in the four sites in Bangladesh but not in other sites and with low level of education in all the sites. CONCLUSION: The prevalence of tobacco use, regardless of the type of tobacco, was high among men in all of these rural populations with tobacco use started during adolescence in all HDSS sites. Innovative communication strategies for behaviour change targeting adolescents in schools and adult men and women at work or at home, may create a mass awareness about adverse health consequences of tobacco smoking or chewing tobacco. Such efforts, to be effective, however, need to be supported by strong legislation and leadership. Only four of the five countries involved in this multi-site study have ratified the Framework Convention on Tobacco Control, and even where it has been ratified, implementation is uneven.Supplement: 1</p

Prevalence and determinants of tobacco use among young people in the Gambia

Introduction: Tobacco consumption, and consequent morbidity and mortality, are expected to grow most markedly over coming decades in low and middle income countries (LMICs). Preventing tobacco experimentation and uptake among young people in LMICs is therefore vital. However, data on smoking in these countries, particularly in sub-Saharan Africa, remain sparse. Method: We used two-stage cluster random sampling to select students in upper and senior secondary schools throughout The Gambia, and a self-administered questionnaire to collect data on their tobacco use, risk factors, and demographic details. Results: Of 10,392 eligible students, 10,289 (99%; 55% girls and 44% boys, age 12-20 years) participated. The prevalence of ever smoking cigarettes, cigars or pipes was 16.7% (25.7% boys and 9.4% girls) and current (past 30 days) smoking 4.5% (7.9% boys and 1.5% girls). Smoking was more common among students attending private schools (OR1.69, 95% CI 1.29-2.22), of Christian) or other faiths compared to Muslims, living with parents (OR1.39, 95% CI 1.06-1.81), who had smoking allowed in their homes (OR1.67, 95% CI 1.30-2.13), with family members who smoked or had one or more friends who smoked. Most (55.6%) smokers want to stop, but only 22% received any stop smoking support. Ever smoking of shisha, at 8.1%, was unexpectedly high, and relatively prevalent among girls (11.4% of boys and 5.4% of girls). Conclusions: Tobacco use is common among young people in the Gambia. Shisha smoking is also common in this population, and in relative terms especially among girls. Further work is required to determine whether this is a problem local to The Gambia, or reflects a wider pattern of tobacco use in sub-Saharan Africa

Tobacco prevention policies in west-African countries and their effects on smoking prevalence

Background: The WHO Framework Convention on Tobacco Control was shown to effectively lower smoking prevalence in in high income countries, however knowledge for low and middle income settings is sparse. The objective of this study was to describe WHO MPOWER policy measures in thirteen West-African countries and to investigate their correlation with smoking prevalence. Methods: Age-standardized smoking prevalence data and policy measures were collected from various WHO reports. For analysis MPOWER measures from 2008 and 2010, were combined with prevalence data from 2009 and 2011. Multiple linear regression models were set up. Results: In West-Africa mean smoking prevalence was approximately 20 % among males and approximately 3 % among females. Policy measures were mostly at a middle or low level. Regression analysis showed that tobacco cessation programs, health warnings on cigarettes, and higher price of cigarettes were negatively correlated with smoking prevalence. Significant effects were observed for only one policy measure (tobacco cessation programs) and only within the male population where smoking prevalence is generally higher. Conclusions: Tobacco control policies are enforced at relatively low levels in West-African countries. However, improving tobacco control policy implementation according to the WHO Framework Convention on Tobacco Control should assist in the reduction of smoking prevalence in African countries, thereby counteracting pro-smoking initiatives set forth by the tobacco industry

Personal reflections on the history of aperiodic crystals from early days to the state of the art

International audienceAperiodic crystals occur as modulated, intergrowth and quasicrystal structures. Their characterization in terms of symmetries possibly requires not only a higher-dimensional description, but also non-Euclidean transformations (like scaling). These crystallographic symmetries, observed in nature, have been investigated but only partially classified. Turning points in the structure determination of aperiodic crystals are presented in historical perspective up to the present time, together with methods and programs. The WEB allows to get more information on all that, on additional tools and on databases. An attempt to present challanges towards lines of future research concludes the review