XML in Motion from Genome to Drug

Information technology (IT) has emerged as a central to the solution of contemporary genomics and drug discovery problems. Researchers involved in genomics, proteomics, transcriptional profiling, high throughput structure determination, and in other sub-disciplines of bioinformatics have direct impact on this IT revolution. As the full genome sequences of many species, data from structural genomics, micro-arrays, and proteomics became available, integration of these data to a common platform require sophisticated bioinformatics tools. Organizing these data into knowledgeable databases and developing appropriate software tools for analyzing the same are going to be major challenges. XML (eXtensible Markup Language) forms the backbone of biological data representation and exchange over the internet, enabling researchers to aggregate data from various heterogeneous data resources. The present article covers a comprehensive idea of the integration of XML on particular type of biological databases mainly dealing with sequence-structure-function relationship and its application towards drug discovery. This e-medical science approach should be applied to other scientific domains and the latest trend in semantic web applications is also highlighted

Haematological and Biochemical Changes in Response to Stress Induced by the Administration of Amikacin Injection by Autoinjector in Animals

The drugs administered by autoinjectors, may act fast reducing the morbidity and mortality in critical and emergency situations. Amikacin drug cartridge was developed for the autoinjector as an antibacterial drug for critical situations and its tolerability was studied. Rats were given either 3 doses or 7 doses on consecutive days by the autoinjector (intraperitoneal, 63 mg/mL). Blood was withdrawn on the 4th day (3 doses) or the 8th day (7 doses), and haematological and biochemical parameters were studied. All the parameters studied were within the limits and did not show any significant difference when compared with the control. Rabbits were given 3 doses of two concentrations (intramuscular, 63 or 250 mg/mL) and on the 4th day blood was withdrawn for the haematological and biochemical estimations. 63 mg/mL cartridge did not show any significant change while 250 mg/mL cartridge showed significant change in the haematological and biochemical parameters. This study showed that intraperitoneal injection of amikacin by the autoinjector designed for intramuscular injection was well tolerated by the rats. In the rabbits, low dose (63 mg/mL) was tolerated while the higher dose, which is an adult human dose (250 mg/mL) showed significant changes.Defence Science Journal, 2014, 64(2), pp. 99-105. DOI: http://dx.doi.org/10.14429/dsj.64.503

Prior COVID-19 infection may increase risk for developing endothelial dysfunction following hematopoietic cell transplantation

Endothelial dysfunction underlies many of the major complications following hematopoietic cell transplantation (HCT), including transplant-associated thrombotic microangiopathy (TA-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), and engraftment syndrome (ES). Emerging evidence similarly implicates endothelitis and microangiopathy in severe COVID-19-related multi-system organ dysfunction. Given the overlap in these two illness states, we hypothesize that prior COVID-19 infection may increase risk for HCT-related endotheliopathies. This retrospective, multicenter study included patients aged 0-25 years who underwent autologous or allogeneic HCT for any indication between January 1, 2020 and September 21, 2021, with close attention to those infected with COVID-19 in either the six months prior to transplant or twelve months following transplant. Incidences of TA-TMA, VOD/SOS, and ES were compared among patients with COVID-19 infection pre-HCT and post-HCT, as well as with historical controls who were never infected with SARS-CoV-2. Those who underwent HCT following COVID-19 infection displayed significantly increased rates of TA-TMA compared to those who were never infected. Additionally, our data suggests a similar trend for increased VOD/SOS and ES rates, although this did not reach statistical significance. Therefore, a history of COVID-19 infection prior to undergoing HCT may be a nonmodifiable risk factor for endothelial-related complications following HCT. Further studies are warranted to better clarify this relationship among larger cohorts and in the era of the Omicron SARS-CoV-2 variants

Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: The case of chelerythrine

a b s t r a c t The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Ab) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Ab aggregation as well as the ability to disaggregate already preformed Ab aggregates in an experimental set-up using HFIP as promotor of Ab aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Ab aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Ab aggregation as well as to disaggregate preformed Ab aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs

The angiogenic factor midkine is regulated by dexamethasone and retinoic acid during alveolarization and in alveolar epithelial cells

<p>Abstract</p> <p>Background</p> <p>A precise balance exists between the actions of endogenous glucocorticoids (GC) and retinoids to promote normal lung development, in particular during alveolarization. The mechanisms controlling this balance are largely unknown, but recent evidence suggests that midkine (MK), a retinoic acid-regulated, pro-angiogenic growth factor, may function as a critical regulator. The purpose of this study was to examine regulation of MK by GC and RA during postnatal alveolar formation in rats.</p> <p>Methods</p> <p>Newborn rats were treated with dexamethasone (DEX) and/or all-trans-retinoic acid (RA) during the first two weeks of life. Lung morphology was assessed by light microscopy and radial alveolar counts. MK mRNA and protein expression in response to different treatment were determined by Northern and Western blots. In addition, MK protein expression in cultured human alveolar type 2-like cells treated with DEX and RA was also determined.</p> <p>Results</p> <p>Lung histology confirmed that DEX treatment inhibited and RA treatment stimulated alveolar formation, whereas concurrent administration of RA with DEX prevented the DEX effects. During normal development, MK expression was maximal during the period of alveolarization from postnatal day 5 (PN5) to PN15. DEX treatment of rat pups decreased, and RA treatment increased lung MK expression, whereas concurrent DEX+RA treatment prevented the DEX-induced decrease in MK expression. Using human alveolar type 2 (AT2)-like cells differentiated in culture, we confirmed that DEX and cAMP decreased, and RA increased MK expression.</p> <p>Conclusion</p> <p>We conclude that MK is expressed by AT2 cells, and is differentially regulated by corticosteroid and retinoid treatment in a manner consistent with hormonal effects on alveolarization during postnatal lung development.</p

Crystal structure of protoporphyrinogen oxidase from Myxococcus xanthus and its complex with the inhibitor acifluorfen

Protoporphyrinogen IX oxidase, a monotopic membrane protein, which catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX in the heme/chlorophyll biosynthetic pathway, is distributed widely throughout nature. Here we present the structure of protoporphyrinogen IX oxidase from Myxococcus xanthus, an enzyme with similar catalytic properties to human protoporphyrinogen IX oxidase that also binds the common plant herbicide, acifluorfen. In the native structure, the planar porphyrinogen substrate is mimicked by a Tween 20 molecule, tracing three sides of the macrocycle. In contrast, acifluorfen does not mimic the planarity of the substrate but is accommodated by the shape of the binding pocket and held in place by electrostatic and aromatic interactions. A hydrophobic patch surrounded by positively charged residues suggests the position of the membrane anchor, differing from the one proposed for the tobacco mitochondrial protoporphyrinogen oxidase. Interestingly, there is a discrepancy between the dimerization state of the protein in solution and in the crystal. Conserved structural features are discussed in relation to a number of South African variegate porphyria-causing mutations in the human enzyme

Dual Binding Site and Selective Acetylcholinesterase Inhibitors Derived from Integrated Pharmacophore Models and Sequential Virtual Screening

In this study, we have employed in silico methodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer’s randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predicted activities and promising ADME/T properties

Molecular structure-activity relationship study of some non-steroidal antiinflammatory agents using electrostatic potential mapping

268-272A series of 6, 11 -dihydro-11-oxodibenz[b,e]oxepin-2-acetic acids (DOAA) which are known to be anti-inflammatory agents were studied. The geometries of some of the molecules obtained from X-ray crystallography were used in the calculations as such while the geometries of their derivatives were obtained by local, partial geometry optimization around the sites of substitution employing the AM1 method, keeping the remaining parts of the geometries the same as those in the parent molecules. Molecular electrostatic potential (MEP) mapping was performed for the molecules using optimized hybridization displacement charges (HDC) combined with Lowdin charges, as this charge distribution has been shown earlier to yield near ab initio quality results. A good correlation has been found between the MEP values near the oxygen atoms of the hydroxyl groups of the carboxy groups of the molecules and their anti-inflammatory activities. The result is broadly in agreement with the model proposed earlier by other authors regarding the structure-activity relationship for other similar molecules

The unequal status afforded to women in South African universities : a journey towards inclusion

Abstract: This research zones in on the unequal status afforded to women in universities. The argument is that women continue to be discriminated against in universities as a direct result of ideas and practices of universities. The main aim of the research study is to explore as to what extent the current ideas and practices of universities afford equal status to women. This research is an in-depth conceptual analysis of documents, policies and text based on female‟s unequal status in universities. Moreover, the research provides constitutive practices to allow women to be effectively included in universities.M.Ed. (Higher Education