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Copper(I)-catalyzed 1,3-dipolar cycloaddition between organic azides and terminal alkynes, commonly known as CuAAC or click chemistry, has been identified as one of the most successful, versatile, reliable, and modular strategies for the rapid and regioselective construction of 1,4-disubstituted 1,2,3-triazoles as diversely functionalized molecules. Carbohydrates, an integral part of living cells, have several fascinating features, including their structural diversity, biocompatibility, bioavailability, hydrophilicity, and superior ADME properties with minimal toxicity, which support increased demand to explore them as versatile scaffolds for easy access to diverse glycohybrids and well-defined glycoconjugates for complete chemical, biochemical, and pharmacological investigations. This review highlights the successful development of CuAAC or click chemistry in emerging areas of glycoscience, including the synthesis of triazole appended carbohydrate-containing molecular architectures (mainly glycohybrids, glycoconjugates, glycopolymers, glycopeptides, glycoproteins, glycolipids, glycoclusters, and glycodendrimers through regioselective triazole forming modular and bio-orthogonal coupling protocols). It discusses the widespread applications of these glycoproducts as enzyme inhibitors in drug discovery and development, sensing, gelation, chelation, glycosylation, and catalysis. This review also covers the impact of click chemistry and provides future perspectives on its role in various emerging disciplines of science and technology.

Globally recognized genetic modification with time has supported the emergence of versatile and novel featured organisms in nature, some of which can be analogized with Pandora’s box elements; like Mycobacterium sp. which has revived itself again after again in a repetitive order over decades and, gradually, contriving a red alert on the world health graph. It needs to be rectified with the motivation of new drug approval considering the pipe line moieties or, apt a choice from the existing drug genera. Although, with genetic modification and advancement Mycobacterium tuberculosis has ruined the first-line therapy in ash, it also opens up different loops and wholes to drug susceptibility. New moieties: Tiliacorinine, 2′-nortiliacorinine, tiliacorine or Cyclohexylgriselimycin raised from different sources of nature, have given another opportunity for the survival, besides, new approved drugs, like bedaquiline, delamanid, pyrifazimine, telacebec, or the under focused pharmacophores; such as diarylquinoline, quinolones, ethylurea benzimidazole, etc. are the appreciable efforts achieved. Thereupon, InhA, KatG, Clp proteases, Menaquinone, DNA gyrase, VDR Fok1, etc. are the new target sets for the drug discovery which has immense potency to generate a number of targeted molecules with effective anti-TB activity. It is a critical discussion of the TB futuristic approach including, clinical trials, repurposed drugs, pipeline motifs, natural products, upcoming drug targets from the cell wall, protein, and DNA.

Software is continually increasing in size and complexity, and therefore, vulnerability discovery would benefit from techniques that identify potentially vulnerable regions within large code bases, as this allows for easing vulnerability detection by reducing the search space. Previous work has explored the use of conventional code-quality and complexity metrics in highlighting suspicious sections of (source) code. Recently, researchers also proposed to reduce the vulnerability search space by studying code properties with neural networks. However, previous work generally failed in leveraging the rich metadata that is available for long-running, large code repositories. In this paper, we present an approach, named Bran, to reduce the vulnerability search space by combining conventional code metrics with fine-grained repository metadata. Bran locates code sections that are more likely to contain vulnerabilities in large code bases, potentially improving the efficiency of both manual and automatic code audits. In our experiments on four large code bases, Bran successfully highlights potentially vulnerable functions, outperforming several baselines, including state-of-art vulnerability prediction tools. We also assess Bran's effectiveness in assisting automated testing tools. We use Bran to guide syzkaller, a known kernel fuzzer, in fuzzing a recent version of the Linux kernel. The guided fuzzer identifies 26 bugs (10 are zero-day flaws), including arbitrary writes and reads.

Background: The biotherapeutic asparaginase is a cornerstone of therapy in acute lymphoblastic leukaemia (ALL). With limited access to the original native Escherichia coli-derived asparaginase (EcASNase), a variety of EcASNase biogenerics are used in low-middle-income countries (LMICs). The variable quality of these biogenerics potentially influences clinical outcomes. Procedure: Seven biogeneric EcASNases (P1–P7) marketed widely in India were evaluated, with P2 as an exemplar for in vivo monitoring. Therapeutic activity of P2 (10,000 IU/m 2/dose, intramuscular, every 72 hours) was monitored during induction therapy, and drug-related toxicities recorded. Molecular identity, purity and in vitro drug activity of seven biogenerics were characterised using multimodal analyses, and findings compared with reference EcASNase (R). Results: In patients (N = 62) receiving P2, subtherapeutic asparaginase activity (

More than two decades have passed with the glorified research works in the field of ionic liquids (ILs), and the explorartion is still counting by varying research groups across the world. ILs find versatile applications in organic synthesis as solvents, reaction media, and catalysts. The eye-catching advantages of ILs include easy handling, green approach, adjustable-desired physico-chemical properties, and versatile applications in preestablished reactions with much more cost-effective manner. Applications of ILs in developing suitable protocols for the syntheses of different heterocyclic skeletons have been explored with much positivity in the recent past. Among heterocycles, particularly five- and six-membered heterocycles are in the lime-light of medicinal chemistry for pharmacological activities and investigations. This chapter focuses on the properties and wide-spread applications of versatile ILs in the syntheses of heterocyclic scaffolds of promising pharmacological potential.

Among all the malaria parasites, P. falciparum is the most predominant species which has developed drug resistance against most of the commercial anti-malarial drugs. Thus, finding a new molecule for the inhibition of enzymes of P. falciparum is the pharmacological challenge in present era. Herein, ten novel molecules have been designed with an amalgamation of cinchonidine, carbohydrate moiety and triazole ring by utilizing copper-catalyzed click reaction of cinchonidine-derived azide and clickable glycosyl alkynes. The molecular docking of developed molecules showed promising results for plasmepsin inhibition in the form of effective binding with target proteins.

In nature, all cells are covered with a complex array of carbohydrates particularly sialic acids which is chemically a negatively charged nine-carbon α-keto aldonic acids. Because of their significant role on cell surfaces, the sialic acid-containing glycans certainly can mediate and modulate many important cellular interactions. Further, proteins having receptors to bind sialic acids are recognized to be involved in a wide variety of biological processes. Thus evaluation of carbohydrate-protein interaction and further their roles in vertebrates may results in enhanced understanding of normal physiology, pathological variance and human evolution. This chapter summarizes the structures and biological significance of sialic acid, their chemical diversity, biosynthesis followed by chemical modification and enzymatic synthesis of sialic acids, their impact in chemical biology, and also the neurobiology of sialic acid. Conclusively, this chapter highlights the recent advances and challenges at the interface of chemistry and biology of sialic acids in order to find out their scope in drug discovery and development.

Background Most patients with transient ischaemic attack (TIA) present to their GP. Early identification and treatment reduces the risk of subsequent stroke and consequent disability and mortality. Objective To explore GPs' views on the diagnosis and immediate management of suspected TIA, and the potential utility of a diagnostic tool. Methods This is a qualitative interview study based in Leicestershire, UK. A purposive sample of 10 GPs participated in 30-minute semi-structured telephone interviews. Data were analysed thematically. Results GPs reported that TIA was more likely to be suspected when patients were more obvious candidates for TIA based on their history, characteristics and symptom presentation. Referrals were in part a strategy to manage risk under conditions of uncertainty and to seek reassurance. GPs valued using a TIA risk stratification tool but felt this did not inform their diagnostic decision making. A diagnostic tool for TIA in primary care was seen to have potential to improve the decision-making process about diagnosis and management and enhance confidence of GPs, particularly in ruling out TIAs. GPs saw benefits of using hard thresholds, but remained concerned about missing TIAs and saw a tool as an adjunct to clinical judgement. Conclusions GPs weigh up the likelihood of TIA in the context of assessments of candidacy and diverse, often vague, symptoms. A diagnostic tool could support GPs in this process and help reduce reliance on referrals to TIA clinics for reassurance, provided the tool was designed to support decision making in cases of less 'typical' presentations.

The recent emergence of hypervirulent clinical variants of

The 2,4-diaminoquinazoline is a well-known scaffold with a great potential to generate a library. In the following research work different computational strategies were applied on 2,4-diaminoquinazoline moiety to estimate its efficiency as an antitubercular scaffold among its other versatile biological activities reported in several published studies. Each data has defined specific substitution mode on the scaffold to be active on different protein site or for disease condition. The following experiment regards of 2D-QSAR, 3D-QSAR, active site and blind docking, structural orientation, pharmacophore mapping and further designing of the data set with possible real active moiety. 2D-QSAR has shown good reliability with r2 = 0.8190, q2_LOO = 0.7711 and external pred_r2 = 0.5321, along with 3D-QSAR has good predictability, q2 (r2cv) = 0.7601, pred_r2 = 0.5567. Further ligand based pharmacophore mapping was carried out for estimating atomic contribution to chemical feature for the compound. The generated hypothesis established that hydrogen accepter, donor and aromatic ring with electronegative atom are the important features. Finally, outcomes of all results were recapitulated to design new compounds. Some compounds also were designed depending on the computational finding and concludes the suitability of the scaffold to be antiTB active.

A cost-effective and expeditious one-pot synthesis of 1-(2-bromo-1-arylethyl)-1H-benzotriazoles has been devised by reacting styrene and their derivatives with 1H-benzotriazole in presence of N-bromosuccinimide in anhydrous CH2Cl2 at room temperature. Further, the resulted compounds undergo E2-ellimination to afford the respective 1-(1-aryl-vinyl)-1H-benzotriazoles. At the end, 1-(1-phenylvinyl)-1H-benzotriazoles underwent benzotriazole ring cleavage (BtRC) under free radical condition to produce phenanthridine as the final product.

Epstein-Barr virus (EBV) oncoprotein EBNA3C is indispensable for primary B-cell transformation and maintenance of lymphoblastoid cells outgrowth. EBNA3C usurps two putative cellular pathways—cell-cycle and apoptosis, essentially through modulating ubiquitin-mediated protein-degradation or gene transcription. In cancer cells, these two pathways are interconnected with autophagy,—a survival-promoting catabolic network in which cytoplasmic material including mis/un-folded protein aggregates and damaged organelles along with intracellular pathogens are degraded and recycled in lysosomal compartments. Studies have shown that tumor viruses including EBV can manipulate autophagy as a survival strategy. Here, we demonstrate that EBNA3C elevates autophagy, which serves as a prerequisite for apoptotic inhibition and maintenance of cell growth. Using PCR based micro-array we show that EBNA3C globally accelerates autophagy gene transcription under growth limiting conditions. Reanalyzing the ENCODE ChIP-sequencing data (GSE52632 and GSE26386) followed by ChIP-PCR demonstrate that EBNA3C recruits several histone activation epigenetic marks (H3K4me1, H3K4me3, H3K9ac, and H3K27ac) for transcriptional activation of autophagy genes, notably ATG3, ATG5, and ATG7 responsible for autophagosome formation. Moreover, under growth limiting conditions EBNA3C further stimulates the autophagic response through upregulation of a number of tumor suppressor genes, notably cyclin-dependent kinase inhibitors—CDKN1B (p27Kip1) and CDKN2A (p16INK4a) and autophagy mediated cell-death modulators—DRAM1 and DAPK1. Together our data highlight a new role of an essential EBV oncoprotein in regulating autophagy cascade as a survival mechanism and offer novel-targets for potential therapeutic expansion against EBV induced B-cell lymphomas.

Although decades of worship bring a light of new chemical classes and moieties for the treatment of tuberculosis and still running to enlighten more possible ways to withstand and draw a full stop to the condition the standard reports of tuberculosis enlisting cases are still on the increment side rather to declining state Since s the regimen of anti TB drugs is well established but now it is under red alters concern as the drugs are resistant to the causative bacilli M tuberculosis endangering mostly the developing countries and disease prone areas of the world With the motivation of new drug approved for the disease the moieties in the pipe line for the consideration of being a successful drug the review also concerns about possible new classes for lead optimization process along with repurposed drugs trial

Epstein-Barr virus (EBV) is highly ubiquitous in human population and establishes a lifelong asymptomatic infection within the infected host unless the immune system is compromised. Following initial infection in the oropharyngeal epithelial cells, EBV primarily infects naive B-lymphocytes and develops a number of B-cell lymphomas particularly in immune-deficient individuals. In vitro, EBV can also infect and subsequently transform quiescent B-lymphocytes into continuously proliferating lymphoblastoid cell lines (LCLs) resembling EBV-induced lymphoproliferative disorders in which a subset of latent transcripts are detected. Genetic studies revealed that EBNA-3 family comprising of three adjacent genes in the viral genome – EBNA-3A and -3C, but not -3B, are critical for B-cell transformation. Nevertheless, all three proteins appear to significantly contribute to maintain the overall proliferation and viability of transformed cells, suggesting a critical role in lymphoma development. Apart from functioning as important viral transcriptional regulators, EBNA-3 proteins associate with many cellular proteins in different signalling networks, providing a suitable platform for lifelong survival of the virus and concurrent lymphoma development in the infected host. The chapter describes the function of each these EBV nuclear antigen 3 proteins employed by the virus as a means to understand viral pathogenesis of several EBV-associated B-cell malignancies.

Ring signature enables an user to anonymously sign a message on behalf of a group of users termed as ‘ring’ formed in an ‘ad-hoc’ manner. A naive scheme produces a signature linear in the size of the ring, but this is extremely inefficient when ring size is large. Dodis et al. proposed a constant size scheme in EUROCRYPT’13, but its security is provided in random oracle model. Best known result without random oracle is a sub-linear size construction by Chandran et al. in ICALP’07 and a follow-up work by Essam Ghadafi in IMACC’13. Therefore, construction of a constant size ring signature scheme without random oracle meeting stringent security requirement still remained as an interesting open problem.

INTRODUCTION Many patients who suffer a transient ischaemic attack (TIA) present to their general practitioner (GP). Early identification and treatment reduces the risk of subsequent stroke, disability and mortality. AIM To review the accuracy of TIA diagnosis in primary care, immediate management and interventions to assist GPs with the condition. METHODS This study included the search of Medline, Embase, Web of Science and Scopus databases (1995–2015). Relevant titles and abstracts were obtained using structured criteria (diagnosis, immediate management or intervention of TIAs in primary care), with full review and data extraction for eligible publications. Two reviewers independently assessed quality and extracted information from the 24 eligible studies. The studies had heterogeneous methodology rendering meta-analysis inappropriate, so a narrative synthesis was undertaken. RESULTS Most studies found limitations in GPs’ knowledge and ability to diagnose TIAs to varying extent over time and between countries. GPs tended to over-interpret non-specific symptoms (e.g. isolated vertigo) when considering a TIA diagnosis. Reported referral behaviour varied between countries, with some favouring admission and others preferring outpatient management. Consistent under-referral and under-use of effective medication was reported. However, GPs may refer some patients to exclude rather than confirm a final diagnosis. This, alongside evidence of under-referral, suggests the need for education and decision support tools to enhance referral patterns. Intervention studies suggested that electronic decision support may increase referrals and timely management. CONCLUSION This review revealed deficiencies in knowledge and clinical practice, and identified potential avenues to addressing these. Issues for future research were also identified.