Bacterial Indole as a Multifunctional Regulator of Klebsiella oxytoca Complex Enterotoxicity.

Gastrointestinal microbes respond to biochemical metabolites that coordinate their behaviors. Here, we demonstrate that bacterial indole functions as a multifactorial mitigator of Klebsiella grimontii and Klebsiella oxytoca pathogenicity. These closely related microbes produce the enterotoxins tilimycin and tilivalline; cytotoxin-producing strains are the causative agent of antibiotic-associated hemorrhagic colitis and have been associated with necrotizing enterocolitis of premature infants. We demonstrate that carbohydrates induce cytotoxin synthesis while concurrently repressing indole biosynthesis. Conversely, indole represses cytotoxin production. In both cases, the alterations stemmed from differ- ential transcription of npsA and npsB, key genes involved in tilimycin biosynthesis. Indole also enhances conversion of tilimycin to tilivalline, an indole analog with reduced cytotox- icity. In this context, we established that tilivalline, but not tilimycin, is a strong agonist of pregnane X receptor (PXR), a master regulator of xenobiotic detoxification and intestinal inflammation. Tilivalline binding upregulated PXR-responsive detoxifying genes and inhib- ited tubulin-directed toxicity. Bacterial indole, therefore, acts in a multifunctional manner to mitigate cytotoxicity by Klebsiella spp.: suppression of toxin production, enhanced con- version of tilimycin to tilivalline, and activation of PXR

Change in the Prevalence and Determinants of Consanguineous Marriages in India between National Family and Health Surveys of 1992–1993 and 2015–2016

This study aimed to determine the changing prevalence of consanguineous marriage in India between two national-level surveys. The primary hypothesis was whether region of residence and religious affiliation continue to play a significant role in determining consanguineous marriage even after controlling other potentially significant confounding variables. Data from the 81,781 and 85,851 ever-married women during the National Family and Health Surveys (NFHS) survey periods 1992–1993 (NFHS-1) and 2015–2016 (NFHS-4), respectively, were used in the analysis. Multinomial and binary logistic regression analyses examined determinants of consanguineous marriage types and of paternal and maternal first-cousin marriages, respectively. In both analyses a systematic model-building procedure was adopted. Altogether, four models were estimated. In the final model (model 4) of both the analyses, all respondent background characteristics (region of residence, religious affiliation, sociodemographic, household wealth) and years of survey were included. Although the overall prevalence of consanguineous marriage in India declined significantly (16%), it was not uniform across respondent background characteristics. The northern region of India (154%) showed a significant increase in consanguineous marriage, whereas eastern (31%), central (2.3%), northeastern (40%), and southern (8%) regions showed a significant decline. Significant declines in consanguineous marriage were found for Hindus (16%) and Muslims (29%); for Muslims of eastern (48%), central (29%), western (31%), and southern (27%) regions; and for Hindus in the western region (37%). Relative risk ratios estimated using multinomial logistic regression models suggest those living in the southern region show 9.55 (p \u3c 0.001), 5.96 (p \u3c 0.001), and 38.16 (p \u3c 0.001) times more likelihood in the prevalence of first-cousin, second-cousin, and uncle-niece marriages, respectively, compared to the northern region after controlling all other confounding variables. Muslims also showed 3.76 (p \u3c 0.001) and 2.91 (p \u3c 0.001) times more likelihood in first-cousin and second-cousin marriages, respectively, compared to Hindus. Adjusted odds ratios (AORs) estimated using binary logistic regression models suggest those living in southern and northeastern regions were 1.25 (p \u3c 0.001) and 1.36 (p \u3c 0.05) times more likely, respectively, to marry a maternal first cousin compared to the northern region. The AOR estimates also show that Muslims were 1.11 (p \u3c 0.01) times more likely to marry a maternal first cousin compared to Hindus. The authors conclude that, despite significant development in the socioeconomic condition of India during the postglobalization era (beginning in 1992–1993), region of residence and religious affiliation continue to play significant role in determining consanguineous marriage

Heuristics driven chart-parsing

To integrate Computer Aided systems (CA"*-systems) in the area of Mechanical Engineering (ME) with other applications in the world of Computer Integrated Manufacturing (CIM), one principal approach under development is based on feature representation. It enables any CA"*-system to recognize the higher-level entities - the so-called features in ME - out of a lower-data exchange format. In this paper we present a heuristic component of the heuristic driven parser GraPaKL. The parser analyzes graphs (representing workpieces) with a so-called 1-NRCF graph grammar (representing descriptions of features in ME) yielding a high level description of the workpiece in terms of features. Using a back propagation net the heuristic component is able to learn how good parses will be derived. (orig.)SIGLEAvailable from TIB Hannover: RO 802(1995,2) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Mechanism of regulation of phosphorylation-dephosphorylation of Ca²⁺, Mg²⁺- and Ca²⁺-ATPases by modulator proteins isolated from rat brain cytosol

162-166Two proteins of molecular mass 13 kDa, a specific inhibitor of Na⁺, K⁺-ATPase and another of 12 kDa, which can distinguish between Ca²⁺, Mg²⁺- and Ca²⁺-ATPase activities have been obtained from the pooled fractions isolated from rat brain, using Sephadex G-100 chromatography. In order to determine the key step(s), which is affected by the modulators, we have designed an in vitro experiment of phosphorylation and dephosphorylation of these ATPases in the absence and presence of the modulators. The results suggest that the phosphorylation step of Mg²⁺-independent Ca²⁺-ATPase is inhibited, while in Mg²⁺-dependent Ca²⁺-ATPase, the dephosphorylation step is stimulated by the modulators. The findings support our earlier observation that the modulators are able to distinguish between Mg²⁺-independent and dependent Ca²⁺-ATPases activities

Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Anti-Tuberculosis Drug Bedaquiline

Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this molecule relies on a nucleophilic addition reaction of two complex starting materials, but suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. M4ALL has developed a new approach to this process that not only allows high conversion of starting materials, but also results in good diastereo- and enantioselectivity towards the desired BDQ stereoisomer. A variety of chiral lithium amides derived from amino acids were studied, and it was found that lithium (R)-2-(methoxymethyl)pyrrolidide, obtained from D-proline, results in high assay yield of the syn-diastereomer pair (82 %) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56 % ee) providing bedaquiline in up to 64 % assay yield before purification steps towards the final API. This represents a considerable improvement in the BDQ yield compared to previously reported conditions and could be critical to further lowering the cost of this life-saving drug

Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Antituberculosis Drug Bedaquiline

Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this molecule relies on a nucleophilic addition reaction of a quinoline fragment to a ketone, but it suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. The Medicines for All Institute (M4ALL) has developed a new reaction methodology to this process that not only allows high conversion of starting materials but also results in good diastereo- and enantioselectivity toward the desired BDQ stereoisomer. A variety of chiral lithium amides derived from amino acids were studied, and it was found that lithium (R)-2-(methoxymethyl)pyrrolidide, obtained from d-proline, results in high assay yield of the desired syn-diastereomer pair (82%) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56% ee), providing BDQ in up to a 64% assay yield before purification steps toward the final API. This represents a considerable improvement in the BDQ yield compared to previously reported conditions and could be critical to further lowering the cost of this life-saving drug