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The foible of allopathic medicines has resulted in adopting herbal plants that have been proven cost-effective with fewer adverse effects. Thus, the evaluation of the potential of herbal plants for the formulation of innovative dosage forms has resulted in the cure of various disease conditions. Thus, in context, the main aim of this work was to formulate the topical emulgel using herbal extracts of Ocimum sanctum, Rubia cordifolia, Glycyrrhiza glabra and Punica granatum. Emulgel was prepared by use of 23 factorial designs and the influence of the type of the gelling agent on viscosity and drug release from the prepared emulgel was investigated. The results found that the EG7 formulation was the optimized batch with pH of 6.3±0.02, viscosity of 5998.7±1.2 mPas, drug release of 89.75± 3.5% and in terms of stability. The results indicated the emulgel formulations were successful concerning all of the parameters.

ASIEN: The German Journal on Contemporary Asia, Nr. 136 (2015): ASIEN (Juli)

Stickler syndrome is associated with the development of rhegmatogenous retinal detachment (RRD), and often presents with ocular, auditory, skeletal, and orofacial abnormalities. Molecular analysis has proven effective in diagnosis, confirmation and classification of the disease. We aimed to describe the utility of next-generation sequencing (NGS) in genetic analysis of four Indian families with suspected Stickler syndrome.The index cases presented with retinal detachment with family history. Genetic analysis in the index case was performed by next-generation sequencing of inherited retinal degeneration genes, and validated by Sanger sequencing followed by co-segregation analysis in the other family members.Twenty patients were included for the genetic analysis (15 males and 5 females from four families). Clinical details were available for 15 patients (30 eyes). Fourteen eyes (11 patients) developed RRD. In the 16 eyes without RRD, 8 underwent barrage laser to lattice degeneration and 8 were under observation. Disease segregating heterozygous mutations with pathogenic/likely pathogenic effect was identified in COL2A1 (c.4318-1GA, c.141GA, c.1221+1GA for 3 families) and COL11A1 (c.1737+1 GA for 1 family) gene. In addition to the mutation in the COL2A1 gene, a pathogenic heterozygous variant associated with risk for arrhythmogenic right ventricular cardiomyopathy (ARVC) was identified in one member.NGS testing confirmed the presence of the causative gene for Stickler syndrome in the index case followed by evaluation of family members and confirmation of genetic and ocular findings. We believe that this may be the first such report of families with RRD from India.

The objective of the paper is to determine the impacts of Artificial intelligence, and a machine learning on Business operations and to identify the impact by using a systematic approach of the artificial intelligence and a machine learning in an industry. With the introduction of an industry 4.0 the technology of the artificial intelligence and a machine learning is leading to an industrial revolution. A literature reviews on Machine learning and artificial intelligence is studied to identify the impacts of both technologies on business before and after this industrial 4.0 an introduction from 1999. From last few years, we have observed many products and services their industrial availability, and social economic impacts, this emerges questions on Artificial intelligence are hype or a reality. This paper addresses the impact of both these technologies on an entrepreneurial activity and thus on a global market. Keywords: Artificial intelligence, Machine learning, Industry 4.0, Technology, Entrepreneurial activity, Global market..

New drugs to treat tuberculosis (TB) are urgently needed to combat the increase in resistance observed among the current first-line and second-line treatments. Here, we propose ketol-acid reductoisomerase (KARI) as a target for anti-TB drug discovery. Twenty-two analogues of IpOHA, an inhibitor of plant KARI, were evaluated as antimycobacterial agents. The strongest inhibitor of Mycobacterium tuberculosis (Mt) KARI has a Ki value of 19.7 nM, fivefold more potent than IpOHA (Ki = 97.7 nM). This and four other potent analogues are slow- and tight-binding inhibitors of MtKARI. Three compounds were cocrystallized with Staphylococcus aureus KARI and yielded crystals that diffracted to 1.6-2.0 A resolution. Prodrugs of these compounds possess antimycobacterial activity against H37Rv, a virulent strain of human TB, with the most active compound having an MIC90 of 2.32 ± 0.04 μM. This compound demonstrates a very favorable selectivity window and represents a highly promising lead as an anti-TB agent.

The kappa opioid receptor (KOPr) has exceptional potential as an analgesic target, seemingly devoid of the many peripheral side-effects of Mu receptors. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally mediated side effects have the limited their clinical translation. Here, we modify an active endogenous Dynorphin peptide with the aim of improving drug-likeness and developing safer KOPr agonists for clinical use. Using rational, iterative design and modern peptide chemistry, we developed a series of potent, selective and metabolically stable peptides from Dynorphin 1-7. Peptides were assessed for cAMP-modulation against Kappa, Mu and Delta opioid receptors, metabolic stability, KOPr specificity and binding, and interrogated for in vitro desensitisation and pERK signalling capability. Finally, lead peptides were evaluated for efficacy in Freund’s complete adjuvant rat model of inflammatory nociception. A library of 70 peptides was synthesised and assessed for pharmacological and metabolic stability factors. At least 10 peptide candidates showed low nanomolar activity (˂50 nM) in a cAMP assay, specificity for KORr, and plasma half-life >60 min, with 6 candidates also stable in trypsin. None of the selected peptides showed pERK activity, with a bias towards cAMP signalling. In vivo, KA305 and KA311 showed anti-nociception opioid receptor-specific activity comparable to morphine and U50 844. These highly potent and metabolically stable peptides are promising opioid analgesic leads for clinical translation. Since they are biased peptide KOPr agonists, it is plausible they lack many of the most significant side effects, such as tolerance, addiction, sedation and euphoria/dysphoria, common to opioid analgesics.

The branched-chain amino acids (BCAAs) leucine, isoleucine and valine are synthesized via a common biosynthetic pathway. Ketol-acid reductoisomerase (KARI) is the second enzyme in this pathway. In addition to its role in BCAA biosynthesis, KARI catalyzes two rate-limiting steps that are key components of a cell-free biofuel biosynthesis route. For industrial applications, reaction temperature and enzyme stability are key factors that affect process robustness and product yield. Here, we have solved the cryo-EM structure (2.94 Å resolution) of a homododecameric Class I KARI (from Campylobacter jejuni) and demonstrated how a triad of amino acid side chains plays a crucial role in promoting the oligomerization of this enzyme. Importantly, both its thermal and solvent stability are greatly enhanced in the dodecameric state when compared to its dimeric counterpart (apparent melting temperatures (Tm) of 83.1 °C and 51.5 °C, respectively). We also employed protein design (PROSS) for a tetrameric Class II KARI (from Escherichia coli) to generate a variant with improved thermal and solvent stabilities. In total, 34 mutations were introduced, which did not affect the oligomeric state of this enzyme but resulted in a fully functional catalyst with a significantly elevated Tm (58.5 °C vs. 47.9 °C for the native version).

New drugs to treat tuberculosis (TB) are urgently needed to combat the increase in resistance observed among the current first-line and second-line treatments. Here, we propose ketol-acid reductoisomerase (KARI) as a target for anti-TB drug discovery. Twenty-two analogues of IpOHA, an inhibitor of plant KARI, were evaluated as antimycobacterial agents. The strongest inhibitor of

The biosynthetic pathway for the branched-chain amino acids is present in plants, fungi and bacteria, but not in animals, making it an attractive target for herbicidal and antimicrobial drug discovery. Ketol-acid reductoisomerase (KARI; EC 1.1.1.86) is the second enzyme in this pathway, converting in a Mg(2+) - and NADPH-dependent reaction either 2-acetolactate or 2-aceto-2-hydroxybutyrate to their corresponding 2,3-dihydroxy-3-alkylbutyrate products. Here, we have determined the crystal structure of Mycobacterium tuberculosis (Mt) KARI, a class I KARI, with two magnesium ions bound in the active site. X-ray data were obtained to 1.0 Å resolution and the final model has an Rfree of 0.163. The structure shows that the active site is solvent-accessible with the two metal ions separated by 4.7 Å. A comparison of this structure with that of Mg(2+) -free Pseudomonas aeruginosa KARI suggests that upon magnesium binding no movement of the N domain relative to the C domain occurs. However, upon formation of the Michaelis complex, as illustrated in the structure of Slackia exigua KARI in complex with NADH.Mg(2+) . N-hydroxy-N-isopropyloxamate (IpOHA, a transition state analog), domain movements and reduction of the metal-metal distance to 3.5 Å are observed. This inherent flexibility therefore appears to be critical for initiation of the KARI-catalyzed reaction. This study provides new insights into the complex structural rearrangements required for activity of KARIs, particularly those belonging to class I, and provides the framework for the rational design of Mt KARI inhibitors that can be tested as novel antituberculosis agents.Coordinates and structure factors for the Mt KARI.Mg(2+) complex are available in the Protein Data Bank under accession number 4YPO.

This chapter focuses on the educational and cultural experiences of African international students from Nigeria and Sudan studying in Malaysian tertiary education institutions, since Nigeria and Sudan were among the top ten sending countries of international students in Malaysia. The Malaysian public continues to display racial discrimination when it comes to the visibly different African international students. The English medium of instruction in the Malaysian private higher education institutions attracts a growing number of international students as this provides them with a degree qualification to work in the global marketplace. The chapter examines the ways in which research participants negotiated racialization and othering as African international students in the Malaysian context. It discusses the ways in which African international students are racially and religiously positioned by the Malaysian media and broader society. African students have been drawn to Malaysian public and especially private universities by extensive marketing campaigns to bring foreign capital into the Malaysian educational market..

Ketol-acid reductoisomerase (KARI) is an NAD(P)H and Mg2+-dependent enzyme of the branched-chain amino acid (BCAA) biosynthesis pathway. Here we describe the first crystal structures of Staphylococcus aureus (Sa) KARI, these in complex with two transition state analogs, cyclopropane-1,1-dicarboxylate (CPD) and N-isopropyloxalyl hydroxamate (IpOHA). These compounds bind competitively and in multi-dentate manner to KARI with Ki values of 2.73 μM and 7.9 nM, respectively; however, IpOHA binds slowly to the enzyme. Interestingly, intact IpOHA is present in only ~25% of binding sites, while its deoxygenated form is present in the remaining sites. This deoxy form of IpOHA binds rapidly to Sa KARI, but with much weaker affinity (Ki = 21 μM). Thus, our data pinpoint the origin of the slow binding mechanism of IpOHA. Furthermore, we propose that CPD mimics the early stage of the catalytic reaction (preceding the reduction step), while IpOHA mimics the late stage (after the reduction took place). These structural insights will guide strategies to design potent and rapidly binding derivatives of these compound for the development of novel biocides.