Cryptosporidiosis, a public health challenge: A combined 3D shape-based virtual screening, docking study, and molecular dynamics simulation approach to identify inhibitors with novel scaffolds for the treatment of cryptosporidiosis

296-310Cryptosporidiosis is a neglected tropical disease caused by the protozoan parasite Cryptosporidium parvum. Limited therapeutic options, limitation in in vitro parasite culture, and lack of a reliable animal model of parasite for replication of in vivo life cycle and drug testing demand alternative methods for drug development. The in silico methods of drug discovery prove a crucial process in such conditions.Recent research reported a limited number of small molecules for drug development. Purine nucleotide biosynthesis in Cryptosporidium species is dependent on the IMPDH (CpIMPDH) enzyme, so distortion of parasite IMPDH has been pursued as a compelling strategy for curbing Cryptosporidium infection due to its different kinetics from the host enzyme. Our study's primary aim was to discover novel ligand molecules with noticeable activity against Cryptosporidium parvum IMPDH. For this purpose, we selected 18 previously discovered ligands to understand the interaction feature between ligand and receptor, and their shape and electronic features are employed as a template for shape-based virtual screening of the ZINC database (drug-like subset) search approach via Schrodinger-2019 (Maestro 11.9). The obtained hits were subsequently subjected to structure-based screening, quantum polarized ligand docking (QPLD), and molecular dynamics simulations to fetch potential small molecules with the highest binding affinity for CpIMPDH protein. Further ligand binding energy and pharmacokinetic analysis were also taken into consideration as filtering criteria for selecting the most promising drug-like compounds. On this experimentation analysis, three top-ranked (ZINC24855054, ZINC58171263, and ZINC08000072) molecules were found to have appropriate pharmacokinetic properties along with surpassing in silico inhibitory potential towards the CpIMPDH compared to known inhibitors. The molecular docking and molecular dynamics simulation analysis results satisfactorily confirmed the inhibitory action. Therefore, these new scaffolds deduced by the presented computational methodology could recommend lead molecules for designing promising anti-cryptosporidial drugs targeting CpIMPDH protein

Effect of the Histone Methyltransferase Specific Probe BRD4770 on Metabolic Profiling of the Endophytic Fungus Diaporthe longicolla

The endophytic fungus Diaporthe longicolla was isolated from the stem of Saraca asoca (Roxb.) Willd., commonly known as Ashok plant in India and Sri Lanka. Since no reports are available regarding epigenetic modulations by BRD4770 in microbial entities, D. longicolla was treated with different concentrations of BRD4770 for this purpose and evaluated for its antioxidant and antibacterial potential against five human pathogenic bacteria, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Shigella boydii, Klebsiella pneumoniae, and Escherichia coli. The crude extract obtained from cultures treated with 100 nM concentration of BRD4770 showed increased antioxidant activity and inhibition zone against S. aureus and MRSA, compared to the non-treated control. The composition of the non-treated and treated crude extract was analyzed, and induced compounds were identified with the help of Gas chromatography–mass spectrometry (GC-MS) and LC-ESI-MS/MS. LC-ESI-MS/MS analysis showed that berberine (antibacterial)-, caffeine-, and theobromine (antioxidant)-like compounds were induced in the BRD4770-treated crude extract. The presence of particular absorbance at a wavelength of 346.5 nm for berberine, 259.4 nm for caffeine, and 278.4 nm for theobromine in the reverse-phase high-performance liquid chromatography (HPLC) analysis of both BRD4770-treated crude metabolites and standard solution of the above compounds strongly supported the increased antibacterial and antioxidant activities that may be due to inducing the alterations in bioactivities of the BRD4770-treated culture

The Chronology of the Ganeshwar Jodhpura Culture: A Reassessment Based on Graffiti and Cross-Cultural Comparisons

The Ganeshwar-Jodhpura Chalcolithic culture was first discovered in the 1970’s post the excavation at Jodhpura and Ganeshwar respectively. However over the years, one of the major drawbacks in the study of the culture is the dating and periodisation. This paper on the basis of ceramic analysis and comparative studies of graffiti is an attempt to divide the site of Ganeshwar into two periods viz. the Early and Mature Period and proposes a new chronology. The characteristics features specifically in terms of ceramics of both the periods have been defined

Knowledge, source and practice of spacing methods of contraception among eligible women of Varanasi slums

Background: Still many Indian states observe low spaced births and high fertility above replacement level; mostly contributed by disadvantaged society. Factors influencing are entrenched in ignorance, male child desire and traditional culture to some extent.     Aim and Objectives: To determine knowledge and practice of spacing methods of contraception and the associated socio-demographic variables.   Settings and Design: Cross-sectional study Methods and Material: A community based cross-sectional study; conducted among 590 eligible couples of slum community of Varanasi selected following two stage stratified random sampling. First stage stratification was based on slum size and second stage was caste class group size. . Statistical analysis used: Knowledge and practice were described in percent and the associated factors were identified by logistic regression. Statistical significance was judged at α = 0.05. Results: Overall knowledge of any spacing methods was in only 61.2% women and practice ever in married life was 44.4%, even those who knew the methods ever practice was only 66.2%. Knowledge gained was mostly through husband for condom, health professional for Cu-T and oral pills. In recent years (last 7 years), overall practice of spacing methods was only 30%. Contraception practice was association survival of child (lesser, if child surviving), number of births (higher, if more living born), religion (lesser, if Muslim), type of house (lesser, if living in hut/kachcha houses) and wife educational attainment (lesser, if low education level)                                                                                        Conclusion: Eligible couples of slum community need knowledge of contraception as well as motivation to practice spacing methods to reduce higher level of fertility.   Keywords: Contraception, spacing methods, fertility &nbsp

Cryptosporidiosis, a public health challenge: A combined 3D shape-based virtual screening, docking study, and molecular dynamics simulation approach to identify inhibitors with novel scaffolds for the treatment of cryptosporidiosis

Cryptosporidiosis is a neglected tropical disease caused by the protozoan parasite Cryptosporidium parvum. Limited therapeutic options, limitation in in vitro parasite culture, and lack of a reliable animal model of parasite for replication of in vivo life cycle and drug testing demand alternative methods for drug development. The in silico methods of drug discovery prove a crucial process in such conditions.Recent research reported a limited number of small molecules for drug development. Purine nucleotide biosynthesis in Cryptosporidium species is dependent on the IMPDH (CpIMPDH) enzyme, so distortion of parasite IMPDH has been pursued as a compelling strategy for curbing Cryptosporidium infection due to its different kinetics from the host enzyme. Our study's primary aim was to discover novel ligand molecules with noticeable activity against Cryptosporidium parvum IMPDH. For this purpose, we selected 18 previously discovered ligands to understand the interaction feature between ligand and receptor, and their shape and electronic features are employed as a template for shape-based virtual screening of the ZINC database (drug-like subset) search approach via Schrodinger-2019 (Maestro 11.9). The obtained hits were subsequently subjected to structure-based screening, quantum polarized ligand docking (QPLD), and molecular dynamics simulations to fetch potential small molecules with the highest binding affinity for CpIMPDH protein. Further ligand binding energy and pharmacokinetic analysis were also taken into consideration as filtering criteria for selecting the most promising drug-like compounds. On this experimentation analysis, three top-ranked (ZINC24855054, ZINC58171263, and ZINC08000072) molecules were found to have appropriate pharmacokinetic properties along with surpassing in silico inhibitory potential towards the CpIMPDH compared to known inhibitors. The molecular docking and molecular dynamics simulation analysis results satisfactorily confirmed the inhibitory action. Therefore, these new scaffolds deduced by the presented computational methodology could recommend lead molecules for designing promising anti-cryptosporidial drugs targeting CpIMPDH protein

Management of a case of ankylosing spondylitis for total hip replacement surgery with the use of ultrasound-assisted central neuraxial blockade

Management of a case of ankylosing spondylitis can be very challenging when the airway and the central neuraxial blockade, both are difficult. Ultrasound-assisted central neuraxial blockade may lead to predictable success in the field of regional anaesthesia. We present a young patient with severe ankylosing spondylitis where conventional techniques failed and ultrasound helped in successful combined spinal-epidural technique for total hip replacement surgery

Effect of radiofrequency radiation on reproductive health

The development of cellular phone system has greatly increased the extent and magnitude of radiofrequency radiation (RFR) exposure. The RFR emitted from mobile phone and mobile phone base stations exerts thermal and non-thermal effects. The short-term and long-term exposure to RFR may have adverse effect on humans as well as animals. Most laboratory studies have indicated a direct link between exposure to RFR and adverse biological effects. Several in vitro studies have reported that RFR induces various types of cancer and DNA or chromosomal damage. On the other hand, some animal studies have not reported adverse effects of this radiation. The present review summarizes information available on the possible effects of RFR on the reproductive health

Continuous transition from weakly localized regime to strong localization regime in Nd0.7La0.3NiO3 films

We report an investigation of metal-insulator transition (MIT) using conductivity and magnetoconductance (MC) measurements down to 0.3 K in Nd0.7La0.3NiO3 films grown on crystalline substrates of LaAlO3 (LAO), SrTiO3 (STO), and NdGaO3 (NGO) by pulsed laser deposition. The film grown on LAO experiences a compressive strain and shows metallic behavior with the onset of a weak resistivity upturn below 2 K which is linked to the onset of weak localization contribution. Films grown on STO and NGO show a cross-over from a positive temperature coefficient (PTC) resistance regime to negative temperature coefficient (NTC) resistance regime at definite temperatures. We establish that a cross-over from PTC to NTC on cooling does not necessarily constitute a MIT because the extrapolated conductivity at zero temperature (lim(T -> 0) sigma - sigma(0)) though small (< 10 S cm(-1)) is finite, signaling the existence of a bad metallic state and absence of an activated transport. The value of sigma(0) for films grown on NGO is reduced by a factor of 40 compared to that for films grown on STO. We show that a combination of certain physical factors makes substituted nickelate (that are known to exhibit first-order Mott type transition), undergo a continuous transition as seen in systems undergoing disorder/composition driven Anderson transition. The MC measurement also supports the above observation and shows that at low temperatures, there exists a positive MC that arises from the quantum interference which co-exists with a spin-related negative MC that becomes progressively stronger as the electrons approach a strongly localized state in the film grown on NGO

Electrochemical impedance spectroscopy study of oxygen evolution reaction on nanosized CoWO₄ and NiWO₄

1100-1105CoWO4 and NiWO4 have been prepared by a co-precipitation method and investigated as electrocatalysts for the oxygen evolution reaction in 1 M KOH by electrochemical impedance spectroscopy. The electrode kinetic parameters such as the electrochemical active surface area, exchange current density, Tafel slope, and the reaction order are determined. Results have shown that the values of the Tafel slope and reaction order obtained from the EIS study excellently match with those determined by dc techniques