Catalytic Water Co-Existing with a Product Peptide in the Active Site of HIV-1 Protease Revealed by X-Ray Structure Analysis

BACKGROUND: It is known that HIV-1 protease is an important target for design of antiviral compounds in the treatment of Acquired Immuno Deficiency Syndrome (AIDS). In this context, understanding the catalytic mechanism of the enzyme is of crucial importance as transition state structure directs inhibitor design. Most mechanistic proposals invoke nucleophilic attack on the scissile peptide bond by a water molecule. But such a water molecule coexisting with any ligand in the active site has not been found so far in the crystal structures. PRINCIPAL FINDINGS: We report here the first observation of the coexistence in the active site, of a water molecule WAT1, along with the carboxyl terminal product (Q product) peptide. The product peptide has been generated in situ through cleavage of the full-length substrate. The N-terminal product (P product) has diffused out and is replaced by a set of water molecules while the Q product is still held in the active site through hydrogen bonds. The position of WAT1, which hydrogen bonds to both the catalytic aspartates, is different from when there is no substrate bound in the active site. We propose WAT1 to be the position from where catalytic water attacks the scissile peptide bond. Comparison of structures of HIV-1 protease complexed with the same oligopeptide substrate, but at pH 2.0 and at pH 7.0 shows interesting changes in the conformation and hydrogen bonding interactions from the catalytic aspartates. CONCLUSIONS/SIGNIFICANCE: The structure is suggestive of the repositioning, during substrate binding, of the catalytic water for activation and subsequent nucleophilic attack. The structure could be a snap shot of the enzyme active site primed for the next round of catalysis. This structure further suggests that to achieve the goal of designing inhibitors mimicking the transition-state, the hydrogen-bonding pattern between WAT1 and the enzyme should be replicated

Gene encoder: a feature selection technique through unsupervised deep learning-based clustering for large gene expression data

© 2020, Springer-Verlag London Ltd., part of Springer Nature. Cancer is a severe condition of uncontrolled cell division that results in a tumor formation that spreads to other tissues of the body. Therefore, the development of new medication and treatment methods for this is in demand. Classification of microarray data plays a vital role in handling such situations. The relevant gene selection is an important step for the classification of microarray data. This work presents gene encoder, an unsupervised two-stage feature selection technique for the cancer samples’ classification. The first stage aggregates three filter methods, namely principal component analysis, correlation, and spectral-based feature selection techniques. Next, the genetic algorithm is used, which evaluates the chromosome utilizing the autoencoder-based clustering. The resultant feature subset is used for the classification task. Three classifiers, namely support vector machine, k-nearest neighbors, and random forest, are used in this work to avoid the dependency on any one classifier. Six benchmark gene expression datasets are used for the performance evaluation, and a comparison is made with four state-of-the-art related algorithms. Three sets of experiments are carried out to evaluate the proposed method. These experiments are for the evaluation of the selected features based on sample-based clustering, adjusting optimal parameters, and for selecting better performing classifier. The comparison is based on accuracy, recall, false positive rate, precision, F-measure, and entropy. The obtained results suggest better performance of the current proposal

The heroic cult of the sovereign goddess in mediaeval India

This thesis examines why the cult of the sovereign goddess was considered important for the expression of royal power in mediaeval India. In literature and ritual, the goddess was conceptualized as the sovereign of heaven and earth. Her cult was heroic because it was primarily a cult of warriors: a good hero was one who worshipped the goddess for great powers, foremost among them being sovereignty. Certain ritual practices of the cult such as self-mutilation formed the criteria for a warrior- worshipper’s heroism. By assessing the available epigraphical, literary, scriptural and anthropological material, I will attempt to show that the association between Indic kingship and the cult’s belief-systems, also referred to as heroic Śāktism, was indeed an ancient one. Tracing its roots to non-Aryan religion, the cult of the sovereign goddess became a vital part of the Sanskritic kingdom, particularly from the latter half of the 6th c., when tribal kingdoms began to elevate themselves on the political map. One of the hallmarks of the cult, responsible for its pan-Indic popularity, was its syncretic nature: besides outcastes, its followers were from a number of sects. The goddess at its centre had no fixed identity but was formed of various personalities. The more public and well-attested of these was the martial goddess Durgā/Caṇḍī/Caṇḍikā, although other goddesses were also worshipped as her other aspects. In all these aspects the sovereign goddess was believed to grant the power of the king and the community. This idea was evoked in the mediaeval Indic world in an array of symbols: sacred statues, ritually empowered swords and insignia put on display for all to see, legends circulated throughout the kingdom, festivals where the sacred might of the realm was ritually reinforced. By assessing these symbols, I will attempt to show the vibrant forms whereby the connection of the cult with power was manifested in the mediaeval period.This thesis is not currently available in ORA

Root-knot Nematode (Meloidogyne Incognita) and Its Management: a Review

Root-knot nematode (RKN) Meloidogyne incognita stands out among the most harmful polyphagous endoparasite causing serious harm to plants, and distributed all over the globe. RKN causes reduced growth, quality and yield along with reduced resistance of the host against biotic and abiotic stresses. Infective second stage juvenile enters host roots with the help of the stylet and becomes sedentary getting into the vascular cylinder. Dramatic changes occur in host cells, making a specialized feeding site, induced by the secretion of effector protein by RKN. M. incognita can be controlled by nematicides, biocontrol agents, botanicals essential oils and growing resistant cultivars. Nematicides are no longer allowed to use in many parts of the world because of environmental hazards and toxicity to humans and other organisms. Researchers are concentrating on searching suitable alternatives to nematicides for effective management of M. incognita. This review mainly tries to explain the biology of M. incognita and different management options recommended in recent years. However, an effective and economical management of M. incognita remains an immense challenge