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Pipelines are considered safest mode of transport because of their limited number of facilities. It is therefore very important to monitor and optimize their operation and reduce their facilities to acceptable limits. Hence, it is an immediate requirement to assess and predict condition of existing oil and gas pipelines and to prioritize the planning of their inspection on a timely basis. Therefore, this study presents the development of models based on specific factors, that can predict the condition of onshore oil and gas pipelines. The model was developed using BPN (Back Propagation Network) techniques based on historical inspection data collected from the oil and gas fields. The model is expected to help pipeline operators to assess the condition of existing oil and gas pipelines and hence prioritize their inspection and rehabilitation operations.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and behavioral alterations. The N-methyl-D-aspartate (NMDA) receptor has emerged as a promising target for AD pharmacotherapy due to its role in the disease's pathogenesis. This study leverages advanced computational methods to screen 80 active constituents of Withania somnifera (Ashwagandha), a traditional herb known for its neuroprotective effects, against the NMDA receptor, using FDA-approved Ifenprodil as a reference. Our blind virtual screening results demonstrated that all tested compounds could bind to various domains of the NMDA receptor, with binding energies ranging from - 4.1 to -11.9 kcal/mol, compared to Ifenprodil's -7.8 kcal/mol. Binding preference analysis revealed 7 compounds bound to the A-chain, 37 to the B-chain, 7 to the C-chain, and 29 to the D-chain of the receptor. Notable binding was observed predominantly at the Amino Terminal Domain (ATD) core site, some at the ATD-Ligand Binding Domain (LBD) interface, and a few at the Transmembrane Domain (TMD). Particularly, 17alpha-hydroxywithanolide D, with a binding energy of -11.9 kcal/mol, emerged as a prime candidate for further investigation. Molecular dynamics simulations of this compound revealed key interactions, including direct hydrogen bonding with residues ASP165, ARG431, THR433, LYS466, and TYR476 on the D-chain, as well as additional hydrophobic and water-bridging interactions. These simulations highlighted the compound's influence on dynamic conformational states of the GluN1b-GluN2B receptor complex, modulating interactions between GluN1b Lys178 and GluN2B Asn184. Furthermore, the compound affected the distance between LBD heterodimers and the tension within the LBD-M30 linker, demonstrating its potential to modulate NMDA receptor activity. This comprehensive study not only underscores the therapeutic promise of Withania somnifera derivatives for AD but also provides a detailed molecular basis for their efficacy, offering valuable insights for targeted drug development and innovative therapeutic strategies against Alzheimer's disease., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

A0A6P1CI42_RHITR, a protein originating from Rhizobium tropici strain CIAT 899, has emerged as a key player in leguminous plant symbiosis and nitrogen fixation processes. Understanding the intricate details of its structure and function holds immense significance for unraveling the molecular mechanisms underlying its biological activities. In this study, we employed molecular modeling and molecular dynamics (MD) simulations to investigate the A0A6P1CI42_RHITR protein, with a specific emphasis on the influence of Fe-atoms, linker structural integrity, and conformational changes within the GAF domain. Our findings unveiled noteworthy conformational changes in the A0A6P1CI42_RHITR protein, particularly within the GAF domain, when Fe-atoms were present compared to its apo form. Significant conformational rearrangements after an initial 20 ns, accompanied by the opening of the ligand substrate accommodating loop in the GAF domain influenced by Fe-atoms was observed. At the residue level, the investigation revealed substantial activity variations in individual residues, particularly in those contributing to the GAF domain from positions 51 to 223. Intriguingly, the presence of Fe-atoms led to controlled movement of conserved cysteine residues at positions 467 and 472, indicating a correlation between interlinker domain motion and the activity of the GAF domain loop responsible for substrate accommodation. Moreover, in the presence of Fe-atoms, the distance between Cys467 and Cys472 residues was maintained, ensuring the overall structural integrity of the interdomain loop necessary for protein activation. Conversely, in the apo form, a sudden flip motion of cysteine residues' thiol groups was observed, leading to a loss of structural integration. Overall, our study utilizing molecular modeling and MD simulations offers valuable insights into the structural dynamics and functional implications of the A0A6P1CI42_RHITR protein.Communicated by Ramaswamy H. Sarma.

The highly spreading virus, COVID-19, created a huge need for an accurate and speedy diagnosis method. The famous RT-PCR test is costly and not available for many suspected cases. This article proposes a neurotrophic model to diagnose COVID-19 patients based on their chest X-ray images. The proposed model has five main phases. First, the speeded up robust features (SURF) method is applied to each X-ray image to extract robust invariant features. Second, three sampling algorithms are applied to treat imbalanced dataset. Third, the neutrosophic rule-based classification system is proposed to generate a set of rules based on the three neutrosophic values < T; I; F>, the degrees of truth, indeterminacy falsity. Fourth, a genetic algorithm is applied to select the optimal neutrosophic rules to improve the classification performance. Fifth, in this phase, the classification-based neutrosophic logic is proposed. The testing rule matrix is constructed with no class label, and the goal of this phase is to determine the class label for each testing rule using intersection percentage between testing and training rules. The proposed model is referred to as GNRCS. It is compared with six state-of-the-art classifiers such as multilayer perceptron (MLP), support vector machines (SVM), linear discriminant analysis (LDA), decision tree (DT), naive Bayes (NB), and random forest classifiers (RFC) with quality measures of accuracy, precision, sensitivity, specificity, and F1-score. The results show that the proposed model is powerful for COVID-19 recognition with high specificity and high sensitivity and less computational complexity. Therefore, the proposed GNRCS model could be used for real-time automatic early recognition of COVID-19., Competing Interests: Conflict of InterestThe authors of this paper declare that there is no conflict of interest regarding its publication., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021.)

Background: Expressed by endothelial cells, CDH5 is a cadherin involved in vascular morphogenesis and in the maintenance of vascular integrity and lymphatic function. The main purpose of our study was to identify distinct variants of the CDH5 gene that could be associated with lymphatic malformations and predisposition for lymphedema. Methods and Results: We performed Next Generation Sequencing of the CDH5 gene in 235 Italian patients diagnosed with lymphedema but who tested negative for variants in known lymphedema genes. We detected six different variants in CDH5 five missense and one nonsense. We also tested available family members of the probands. For family members who carried the same variant as the proband, we performed lymphoscintigraphy to detect any lymphatic system abnormalities. Variants were modeled in silico. The results showed that CDH5 variants may contribute to the onset of lymphedema, although further in vitro studies are needed to confirm this hypothesis. Conclusions: Based on our findings, we propose CDH5 as a new gene that could be screened in patients with lymphedema to gather additional evidence.

Macrophages are considered to be key players in innate immunity and inflammatory responses. Domestic cattle with standard body size quickly reach their heat tolerance limit and are prone to heat stress. The combined effects of high temperature and endotoxemia on bovine monocyte-derived macrophages remain almost undisclosed. This study aims to unravel the molecular and functional responses of bovine monocyte-derived macrophages to thermal cum lipopolysaccharide induced stress challenge in vitro. The cells were incubated at 37 °C or 40 °C with lipopolysaccharide (1.0 μg/mL) for 24 h and 48 h. At the end of each treatment, cell viability, apoptotic rate, mitochondrial membrane potential, oxidative activity, phagocytosis, and autophagy functions were assessed and mRNA abundance of genes related to heat shock (HSP 70), inflammation (IL1β, IL6, IL 12, TNF, INF γ), cell signalling (TLR4), cell viability (Bax, Bcl2), nitric oxide synthesis (NOS2) and natural resistant associated macrophage protein were quantified by quantitative polymerase chain reaction (qPCR). The results revealed the increased apoptosis, reduced mitochondrial membrane potential, and cell viability, decreased oxidative and phagocytosis ability in cells co-stimulated with LPS and thermal stimuli. Upregulation of HSP 70 gene and downregulation of natural resistant associated macrophage protein, cell signalling, and inflammation related genes mRNA expressions were also identified due to these stressors. In conclusion, the observed thermal cum LPS stress induced dysregulation in macrophage functionality may be one facet of the increased disease susceptibility in dairy cattle during thermal stress., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Carbonic anhydrases catalyze the reversible hydration of carbon dioxide to form bicarbonate, a reaction required for many functions such as carbon assimilation, pH acid-base homeostasis, respiration and photosynthesis via a zinc-hydroxide mechanism for carbon dioxide hydration. In earlier studies, it was revealed that Carbonic anhydrases are inactive at pH 7.5 and active at pH 8.4. This steep pH dependence for its activity led us to design this work to understand its mode of action at atomic level detail. In our microsecond simulation based analysis, it was revealed that the interaction between Glu106 and Thr199 plays a critically important role in its activity. Thr199 co-ordinated loop movement was observed to be acting as a lid, with 'open' and 'close' mechanism for substrate entry to the core of the catalytic site, where Zn-ion resides and executes its carbon dioxide hydration mechanism. On the other hand, decline in the total secondary structural elements percentage in the protein was observed in correspondence to the pH condition change. The α-helices between Thr125-Gly145 and Val150-Lys170 residues were especially noticed to be losing their structural integrity responsible for formation of dimer and tetramers. In conclusion, our analysis showed that the interaction between Glu106 and Thr199 is crucial for maintaining the structural integrity of the Thr199 coordinated loop, responsible for allowing substrate towards the catalytic site.Communicated by Ramaswamy H. Sarma.

Fluoride ion channels of the Fluc family plays a critically important role in combating environmental fluoride toxicity. As per the crystal structure of these fluoride ion channels, the pore region is densely packed with a series of hydrogen bond donating residues arranged in a ladder fashion creating an ion conducting pathway. In earlier studies, it was revealed that although the ion conducting pathway polarity is highly conserved, however the functionality of the channel protein depends on several residues at particular positions. While, a threonine at end of the pore is critically important in forming initial interactions, two phenylalanines at the central region coordinate F- transportation through the channel. It was also revealed that these two phenylalanines cannot be substituted by any other aromatic, polar or non-polar residues without hindering the functionality with exception of methionine. In another study, it was revealed that these two phenylalanines F80 and F83 when mutated with methionine; F80M lead to active state, while the F83M has lead to inactivity of F- anion conductivity. However, the exact atomic level detailing on how exactly these mutations have impacted the conductivity remained elusive. In this scenario, in this present study, we have modeled these two mutations and performed a microsecond level simulation on each mutation compared with wild type towards understanding the atomic level detailing revealing several insights on what exactly happening at these residues responsible for the selective conductivity of F- ions.Communicated by Ramaswamy H. Sarma.

Natural products of herbal origin are prodigious to display diverse pharmacological activities. In the present study, five guaiane-type sesquiterpene dimers, xylopidimers A   - E ( 1-5 ), isolated from Xylopia vielana species were tested against COX-2 protein target (PDB: 1CX2), a potent target for anti-inflammatory agents. To better understand the pharmacological properties of all these compounds, in this work, a systemic in silico study was performed on xylopidimers A-E using molecular docking, ADMET analysis and MD simulations. During ADMET predictions the two compounds xylopidimer C, D displayed best results as compared to others. The compound xylopidimer C was further evaluated for its MD simulations and its molecular interactions with COX2 complex showed clear interactions with active gorge of the enzyme through hydrogen bonding as well as hydrophobic contacts. The xylopidimer C has shown the best binding potential with -10.57Kcal/mol energy with 17.92 nano molar of predicted inhibition constant better than Ibuprofen and Felbinac. These findings provide enough significant information for designing and developing novel targeted base anti-inflammatory drugs from guaiane dimers.

Background: RAR-related Orphan Receptor C (RORC) is a DNA-binding transcription factor and the key transcription factor responsible for differentiation of T helper 17 cells. The RORC gene plays a role in lymphoid organogenesis, thymopoiesis, and lymph node organogenesis. The aim of our study was to determine the possible role of RORC in the development of lymphatic system malformations by combining data from the scientific literature and next-generation sequencing of RORC in lymphedema patients negative for known causative genes. Methods and Results: We sequenced RORC in 235 lymphedema patients negative for known lymphedema-associated genes. We found two probands carrying nonsense RORC variants. Conclusions: We show that RORC is important for normal function of the lymphatic system and that a rare variant with a possible causative effect may imply predisposition for lymphedema.

Background: We developed a Next-Generation-Sequencing (NGS) protocol to screen the most frequent genetic variants related to lymphedema and a group of candidate genes. The aim of the study was to find the genetic cause of lymphedema in the analyzed patients., Methods: We sequenced a cohort of 246 Italian patients with lymphatic malformations. In the first step, we analyzed genes known to be linked to lymphedema: 235 out of 246 patients tested negative for the most frequent variants and underwent testing for variants in a group of candidate genes, including the NOTCH1 gene, selected from the database of mouse models. We also performed in silico analysis to observe molecular interactions between the wild-type and the variant amino acids and other protein residues., Results: Seven out of 235 probands, five with sporadic and two with familial lymphedema, were found to carry rare missense variants in the NOTCH1 gene., Conclusions: Our results propose that NOTCH1 could be a novel candidate for genetic predisposition to lymphedema., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

SVEP1, also known as Polydom, is a large extracellular mosaic protein with functions in protein interactions and adhesion. Since Svep1 knockout animals show severe edema and lymphatic system malformations, the aim of this study is to evaluate the presence of SVEP1 variants in patients with lymphedema. We analyzed DNA from 246 lymphedema patients for variants in known lymphedema genes, 235 of whom tested negative and underwent a second testing for new candidate genes, including SVEP1, as reported here. We found three samples with rare heterozygous missense single-nucleotide variants in the SVEP1 gene. In one family, healthy members were found to carry the same variants and reported some subclinical edema. Based on our findings and a review of the literature, we propose SVEP1 as a candidate gene that should be sequenced in patients with lymphatic malformations, with or without lymphedema, in order to investigate and add evidence on its possible involvement in the development of lymphedema., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

Neuropilins are transmembrane coreceptors expressed by endothelial cells and neurons. NRP1 and NRP2 bind a variety of ligands, by which they trigger cell signaling, and are important in the development of lymphatic valves and lymphatic capillaries, respectively. This study focuses on identifying rare variants in the NRP1 and NRP2 genes that could be linked to the development of lymphatic malformations in patients diagnosed with lymphedema. Two hundred and thirty-five Italian lymphedema patients, who tested negative for variants in known lymphedema genes, were screened for variants in NRP1 and NRP2 . Two probands carried variants in NRP1 and four in NRP2 . The variants of both genes segregated with lymphedema in familial cases. Although further functional and biochemical studies are needed to clarify their involvement with lymphedema and to associate NRP1 and NRP2 with lymphedema, we suggest that it is worthwhile also screening lymphedema patients for these two new candidate genes.

Background: The PROX1 gene is specifically expressed in a subpopulation of endothelial cells that, by budding and sprouting, give rise to the lymphatic system. It also plays a critical role in neurogenesis and during development of many organs, such as the eye lens, liver, and pancreas., Methods: We used next-generation sequencing (NGS) to sequence the DNA of a cohort of 246 Italian patients with lymphatic malformations. We first investigated 29 known disease-causing genes: 235 of 246 patients tested negative and were then retested for a group of candidate genes, including PROX1, selected from a database of mouse models. The aim of the study was to define these patients' genotypes and explore the role of the candidate gene PROX1 in lymphedema., Results: Two of 235 probands were found to carry rare heterozygous missense variants in PROX1. In silico analysis of these variants-p.(Leu590His) and p.(Gly106Asp)-indicates that the overall protein structure was altered by changes in interactions between nearby residues, leading to functional protein defects., Conclusions: Our results suggest that PROX1 is a new candidate gene for predisposition to lymphedema., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

TIE1 is a cell surface protein expressed in endothelial cells. Involved in angiogenesis and lymphangiogenesis, including morphogenesis of lymphatic valves, TIE1 is important for lymphatic system functional integrity. The main purpose of this study was to identify different variants in the TIE1 gene that could be associated with lymphatic malformations or dysfunction and predisposition for lymphedema. In a cohort of 235 Italian lymphedema patients, who tested negative for variants in known lymphedema genes, we performed a further test for new candidate genes, including TIE1 . Three probands carried different variants in TIE1 . Two of these segregated with lymphedema or lymphatic dysfunction in familial cases. Variants in TIE1 could contribute to the onset of lymphedema. On the basis of our findings, we propose TIE1 as a candidate gene for comprehensive genetic testing of lymphedema.

Background: ARAP3 is a small GTPase-activating protein regulator, which has important functions in lymphatic vessel organogenesis and modulation of cell adhesion and migration. Mutations in the ARAP3 gene are associated with impaired lymphatic vessel formation., Objective: The aim of our study was to determine the genotypes of lymphedema patients in relation to variants in the ARAP3 gene in order to explore its role in the development of lymphedema., Methods and Results: We applied next-generation sequencing to DNA samples of a cohort of 246 Italian patients with lymphatic malformations. When we tested probands for known lymphedema genes, 235 out of 246 were negative. Retrospectively, we tested the DNA of these 235 patients for new candidate lymphedema-associated genes, including ARAP3 . Three out of 235 probands proved to carry rare missense heterozygous variants in ARAP3 . In the case of two families, other family members were also tested and proved negative for the ARAP3 variant, besides being unaffected by lymphedema. According to in silico analysis, alterations due to these variants have a significant impact on the overall structure and stability of the resulting proteins., Conclusions: Based on our results, we propose that variants in ARAP3 could be included in genetic testing for lymphedema., Competing Interests: No competing financial interests exist., (Copyright © 2020 Maurizio Ricci et al.)

In swine, even though the pregnant sows were with iron abundance, the inborn iron reserve of piglets was compromised. This indicates the insufficiency of molecular machinery involved in local placental iron flux. Here, we investigated the expression of iron regulatory proteins like hepcidin and ferroportin and also their association with iron reserve, inflammation and oxidative stress in placenta of full-term pregnant sows (n = 6). Amplification and sequencing of placental DNA confirmed the presence of hepcidin (MN579557) and ferroportin (MN565887) sequences and their 100% identity with existing GenBank data. Real-time amplification of placental mRNA revealed significant higher expression of hepcidin (p < .05) than ferroportin. Western blot analysis of placental tissues revealed specific bands for both hepcidin (~8 kDa) and ferroportin (~62 kDa) molecules. Immunohistochemistry revealed the immunoreactivity for both proteins in the cytoplasm and membrane of trophoblastic cells of the placenta. Hepcidin and ferroportin expressions were positively associated with placental non-haem iron reserve (p < .0001; p = .033), lipid peroxidation (p = .0060; p < .0001) and reactive oxygen species level (p = .0092; p = .0292). Hepcidin expression was positively associated with interleukin - 6 (p = .0002) and interferon gamma (p < .0001) expressions but ferroportin expression was negatively associated with interleukin-6 (p = .0005), interleukin-1β (p = .0226) and interferon gamma (p = .0059) expressions. This indicates hepcidin and ferroportin may have a role in controlling the local placental iron flux by acting as a molecular bridge between iron trafficking and inflammation., (© 2020 Blackwell Verlag GmbH.)

Background: Estrogen Receptors (ER) are members of the nuclear intracellular receptors family. ER once activated by estrogen, it binds to DNA via translocating into the nucleus and regulates the activity of various genes. Withaferin A (WA) - an active compound of a medicinal plant Withania somnifera was reported to be a very effective anti-cancer agent and some of the recent studies has demonstrated that WA is capable of arresting the development of breast cancer via targeting estrogen receptor., Objective: The present study is aimed at understanding the molecular level interactions of ER and Tamoxifen in comparison to Withaferin A using In-silico approaches with emphasis on Withaferin A binding capability with ER in presence of point mutations which are causing de novo drug resistance to existing drugs like Tamoxifen., Methods: Molecular modeling and docking studies were performed for the Tamoxifen and Withaferin A with the Estrogen receptor. Molecular docking simulations of estrogen receptor in complex with Tamoxifen and Withaferin A were also performed., Results: Amino acid residues, Glu353, Arg394 and Leu387 was observed as crucial for binding and stabilizing the protein-ligand complex in case of Tamoxifen and Withaferin-A. The potential of Withaferin A to overcome the drug resistance caused by the mutations in estrogen receptor to the existing drugs such as Tamoxifen was demonstrated., Conclusion: In-silico analysis has elucidated the binding mode and molecular level interactions which are expected to be of great help in further optimizing Withaferin A or design / discovery of future breast cancer inhibitors targeting estrogen receptor., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

PECAM1 is a member of the immunoglobulin superfamily and is expressed in monocytes, neutrophils, macrophages and other types of immune cells as well as in endothelial cells. PECAM1 function is crucial for the development and maturation of B lymphocytes. The aim of this study was to link rare PECAM1 variants found in lymphedema patients with the development of lymphatic system malformations. Using NGS, we previously tested 246 Italian lymphedema patients for variants in 29 lymphedema-associated genes and obtained 235 negative results. We then tested these patients for variants in the PECAM1 gene. We found three probands with rare variants in PECAM1. All variants were heterozygous missense variants. In Family 1, the unaffected mother and brother of the proband were found to carry the same variant as the proband. Lymphoscintigraphy was performed to determine possible lymphatic malformations and showed that in both cases a bilateral slight reduction in the speed and lymphatic clearance of the lower limbs. PECAM1 function is important for lymphatic vasculature formation. We found variants in PECAM1 that may be associated with susceptibility to lymphedema., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

We report molecular characterization of the kisspeptin receptor (kiss1r), an essential gatekeeper for reproduction and onset of puberty in vertebrates. The full-length cDNA sequence of kiss1r is 1786bp which consist of 5' UTR (untranslated region) 261bp, 3' UTR of 424bp and open reading frame of 1101 encoding a putative protein of 366 amino acids. Basal tissue expression pattern of kiss1r mRNA revealed that it is mainly expressed in the brain and testis. We also report the structure of the kiss1r, along with plausible activation mechanism of this receptor by kisspeptin using computational modelling and dynamic simulation approach of multiple 100ns of timescale. A present modelling and simulations studies shed light on the molecular level of interaction, suggesting that direct hydrogen bonds between ASN4, SER5, GLY7, ARG9 and PHE10 of kisspeptin and TRP7, ASN8, GLU11, ILE17, ASN19 and TYR183 of kiss1r could be crucial role players in initial binding of receptor and the kisspeptin towards allosteric modulatory effects of kisspeptin on the receptor. To the best our knowledge, this is the first report on computational modelling and molecular dynamic simulations of kiss1r in animals shedding light on its possible mode of activation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Glycogen synthase kinase-3 (GSK-3) is a multitasking serine/threonine protein kinase, which is associated with the pathophysiology of several diseases such as diabetes, cancer, psychiatric and neurodegenerative diseases. Tideglusib is a potent, selective, and irreversible GSK-3 inhibitor that has been investigated in phase II clinical trials for the treatment of progressive supranuclear palsy and Alzheimer's disease. In the present study, we performed pharmacophore feature-based virtual screening for identifying potent targetspecific GSK-3 inhibitors. We found 64 compounds that show better GSK-3 binding potentials compared with those of Tideglusib. We further validated the obtained binding potentials by performing 20-ns molecular dynamics simulations for GSK-3 complexed with Tideglusib and with the best compound found via virtual screening in this study. Several interesting molecular-level interactions were identified, including a covalent interaction with Cys199 residue at the entrance of the GSK-3 active site. These findings are expected to play a crucial role in the binding of target-specific GSK-3 inhibitors.

Indoleamine-2,3-dioxygenase (IDO) an immunoregulatory enzyme and emerging as a new therapeutic drug target for the treatment of cancer. Carboranes, an icosahedral arrangement of eleven boron atoms plus one carbon atom with unique pharmacological properties such low toxicity, isosterism with phenyl ring and stability to hydrolysis. On the other hand, carboranes are known to increase the interaction of ligand with non-polar region of the protein provides an excellent platform to explore these carboranes towards designing and development of novel, potent and target specific drug candidates with further enhanced binding affinities. Despite of their many potential applications, molecular modeling studies of carborane-substituted ligands with macromolecules have been rarely reported. Previously, we have demonstrated the promising high binding affinity of Withaferin-A (WA) for IDO. In this present study, we investigated the effect of carborane substitutions on WA compound towards developing novel analogs for target specific IDO inhibition with better potency. Interesting docked poses and molecular interactions for the carborane substituted WA ligands were elucidated. Based on our In-silico studies, carborane substituted at various position of WA has shown enhanced binding affinity towards IDO, worth of considering for further studies.

Congenital heart defects (CHD) presented as structural defects in the heart and blood vessels during birth contribute an important cause of childhood morbidity and mortality worldwide. Many Single nucletotide polymorphisms (SNPs) in different genes have been associated with various types of congenital heart defects. NKX 2-5 gene is one among them, which encodes a homeobox-containing transcription factor that plays a crucial role during the initial phases of heart formation and development. Mutations in this gene could cause different types of congenital heart defects, including Atrial septal defect (ASD), Atrial ventricular block (AVB), Tetralogy of fallot and ventricular septal defect. This highlights the importance of studying the impact of different SNPs found within this gene that might cause structural and functional modification of its encoded protein. In this study, we retrieved SNPs from the database (dbSNP), followed by identification of potentially deleterious Non-synonymous single nucleotide polymorphisms (nsSNPs) and prediction of their effect on proteins by computational screening using SIFT and Polyphen. Furthermore, we have carried out molecular dynamic simulation (MDS) in order to uncover the SNPs that would cause the most structural damage to the protein altering its biological function. The most important SNP that was found using our approach was rs137852685 R161P, which was predicted to cause the most damage to the structural features of the protein. Mapping nsSNPs in genes such as NKX 2-5 would provide valuable information about individuals carrying these polymorphisms, where such variations could be used as diagnostic markers.

Epidermal growth factor receptors (EGFR) are critical for the growth of many tumors and expressed at high levels in about one third of epithelial cancers. Hence, blockade of the binding sites for EGFR has been hypothesized as an effective anti-cancer therapy. Chalcone derivative compounds have been shown to be highly effective anti-cancer agents, however there are still so many novel derivatives possible, one of which might get us the best targeted EGFR inhibitor. In this effort directed towards the discovery of novel, potent anti-tumor agents for the treatment of cancer, in the present study a library of novel chalcone series of compounds has been designed and evaluated for their anti-cancer activity targeting EGFR kinase domain using various computational approaches. Among the twenty five novel designed chalcone series of compounds, all of them have found to be successfully docking inside the active binding domain of EGFR receptor target with a binding energy in a range of -6.10 to -9.25 Kcal/mol with predicted IC50 value range of 33.50 micor molar to 164.66 nano molar respectively. On the other hand, calculated 2DQSAR molecular descriptor properties of the compounds showed promising ADME parameters and found to be well in compliance with Lipinski׳s rule of five. Among all the twenty five compounds tested, compound 21 ((2E)-3-(anthracen-9-yl)-1-phenylprop-2-2n-1- one) was found to be the best lead like molecule with a binding energy of -9.25 kcal/mol with predicted IC50 value of 164.66 nano molar. Conclusively, novel designed compound 21 of the present study have shown promising anti-cancer potential worth considering for further evaluations.

Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic drug target for the treatment of cancer characterized by pathological immune suppression. IDO catalyzes the rate-limiting step of tryptophan degradation along the kynurenine pathway. Reduction in local tryptophan concentration and the production of immunomodulatory tryptophan metabolites contribute to the immunosuppressive effects of IDO. Presence of IDO on dentritic cells in tumor-draining lymph nodes leading to the activation of T cells toward forming immunosuppressive microenvironment for the survival of tumor cells has confirmed the importance of IDO as a promising novel anticancer immunotherapy drug target. On the other hand, Withaferin A (WA) - active constituent of Withania Somnifera ayurvedic herb has shown to be having a wide range of targeted anticancer properties. In the present study conducted here is an attempt to explore the potential of WA in attenuating IDO for immunotherapeutic tumor arresting activity and to elucidate the underlying mode of action in a computational approach. Our docking and molecular dynamic simulation results predict high binding affinity of the ligand to the receptor with up to -11.51 kcal/mol of energy and 3.63 nM of IC50 value. Further, de novo molecular dynamic simulations predicted stable ligand interactions with critically important residues SER167; ARG231; LYS377, and heme moiety involved in IDO's activity. Conclusively, our results strongly suggest WA as a valuable small ligand molecule with strong binding affinity toward IDO.

Background: Herpes viruses are important human pathogens that can cause mild to severe lifelong infections with high morbidity. They remain latent in the host cells and can cause recurrent infections that might prove fatal. These viruses are known to infect the host cells by causing the fusion of viral and host cell membrane proteins. Fusion is achieved with the help of conserved fusion machinery components, glycoproteins gB, heterodimer gH-gL complex along with other non-conserved components. Whereas, another important glycoprotein gD without which viral entry to the cell is not possible, acts as a co-activator for the gB-gH-gL complex formation. Thus, this complex formation interface is the most promising drug target for the development of novel anti-herpes drug candidates. In the present study, we propose a model for binding of gH-gL to gB glycoprotein leading from pre to post conformational changes during gB-gH-gL complex formation and reported the key residues involved in this binding activity along with possible binding site locations. To validate the drug targetability of our proposed binding site, we have repositioned some of the most promising in vitro, in vivo validated anti-herpes molecules onto the proposed binding site of gH-gL complex in a computational approach., Methods: Hex 6.3 standalone software was used for protein-protein docking studies. Arguslab 4.0.1 and Accelrys® Discovery Studio 3.1 Visualizer softwares were used for semi-flexible docking studies and visualizing the interactions respectively. Protein receptors and ethno compounds were retrieved from Protein Data Bank (PDB) and Pubchem databases respectively. Lipinski's Filter, Osiris Property Explorer and Lazar online servers were used to check the pharmaceutical fidelity of the drug candidates., Results: Through protein-protein docking studies, it was identified that the amino acid residues VAL342, GLU347, SER349, TYR355, SER388, ASN395, HIS398 and ALA387 of gH-gL complex play an active role in its binding activity with gB. Semi flexible docking analysis of the most promising in vitro, in vivo validated anti-herpes molecules targeting the above mentioned key residues of gH-gL complex showed that all the analyzed ethno medicinal compounds have successfully docked into the proposed binding site of gH-gL glycoprotein with binding energy range between -10.4 to -6.4 K.cal./mol., Conclusions: Successful repositioning of the analyzed compounds onto the proposed binding site confirms the drug targetability of gH-gL complex. Based on the free binding energy and pharmacological properties, we propose (3-chloro phenyl) methyl-3,4,5 trihydroxybenzoate as worth a small ethno medicinal lead molecule for further development as potent anti-herpes drug candidate targeting gB-gH-gL complex formation interface.

A new species of aquatic plant, Scutifolium jordanicum gen. et sp. nov., Taylor, Brenner & Basha, is described from the Albian of Jordan. The leaves are microphyllous with a symmetrical, elliptical to suborbiculate shape, convex to rounded apex and base, and actinodromous to palinactinodromous primary venation. The peltate, centrally attached petioles are narrow, elongate, and alternately arranged on similarly sized stems. The leaves appear to be thick and have aerenchyma. Comparisons to plants with centrally peltate leaves and palmate venation and to aquatic plants with floating leaves suggest that S. jordanicum belongs to the Cabombaceae lineage within the Nymphaeales. Cladistic analysis including the fossil and living members of the Nymphaeales shows that the S. jordanicum is basal to the living members of the family and has unique characters not found in any living genera. This is the oldest evidence of the Cabombaceae from the Old World. Inclusion of two other Early Cretaceous peltate leaf fossils in the phylogenetic analysis indicates their affinities to Cabombaceae and that some of the shared derived characters for the living members are progressively acquired in the fossils. These data show the Cabombaceae were widespread in Gondwana and Laurasia by the mid-Cretaceous.

Collagen is one of the best materials used for nerve guide preparation due to its biocompatibility and desirable tensile strength. In this work, we have compared regeneration and functional reinnervation after sciatic nerve resection with bioresorbable crosslinked collagen guides in 10 mm gap. The crosslinking was carried out either with glutaraldehyde (GTA) or microwave irradiation (MWI). The multilayered collagen membrane used for nerve guides are prepared by lamellar evaporation technique. Functional evaluations of the regenerated nerves were performed by measuring the sciatic functional index (SFI), nerve conduction velocity (NCV), and electromyography (EMG). Transmission electron microscopic studies showed growth of axonal cable with fewer myelinated axons, Schwann cells and more unmyelinated axons present in the case of group treated with uncrosslinked collagen tubes after 1 month of implantation. However, we have observed more myelinated axons in the case of autograft, GTA, and MWI crosslinked collagen tube implants across the gap of 1 cm after the same period of implantation. Smaller myelinated fiber diameter was observed in the case of GTA crosslinked collagen tube group when compared with the autograft and MWI collagen tube groups. There were more myelinated axons during the 3rd and 6th months postoperatively using these conduits as substantiated by light microscopic studies of the regenerated nerve. The conduction velocity and recovery index improved significantly after 5 months reaching the normal values in the autograft and MWI crosslinked collagen groups compared to GTA and uncrosslinked collagen tubes.

Neurotrophic factors play an important modulatory role in axonal sprouting during nerve regeneration involving the proliferation of hematogenous and Schwann cells in damaged tissue. We have exposed lesioned sciatic nerves to a collagen prosthesis with covalently bonded small cell adhesive peptides Arg-Gly-Asp-Ser (RGDS), Lys-Arg-Asp-Ser (KRDS), and Gly-His-Lys (GHK) to study local production of growth factors and cytokines in the regenerating tissues. Western/enzyme-linked immunosorbent assay (ELISA) studies were performed after 10 days of regeneration, when the tubular prosthesis is filled with fibrous matrix infiltrated by hematogenous cells and proliferating Schwann cells with growth factors produced locally. Regeneration was also analyzed by morphometrical methods after 30 days. The quantification of growth factors and proteins by ELISA revealed that there was an enhanced expression of the neurotrophic factors nerve growth factor (NGF) and neurotrophins (NT-3 and NT-4) in the regenerating tissues. This was further established by Western blot to qualitatively analyze the presence of the antigens in the regenerating tissues. Schwann cells were localized in the regenerating tissues using antibodies against S-100 protein. Other growth factors including growth-associated protein 43 (GAP-43), apolipoprotein E (Apo E), and pro-inflammatory cytokine like interleukin-1alpha (IL-1alpha) expression in the peptide groups were evaluated by ELISA and confirmed by Western blotting. Cell adhesive integrins in the proliferating cells were localized using integrin-alpha V. The combined results suggest that the early phase of regeneration of peripheral nerves in the presence of peptide-incorporated collagen tubes results in the enhanced production of trophic factors by the recruited hematogenous cells and Schwann cells, which in turn help in the secretion of certain vital trophic and tropic factors essential for early regeneration. Furthermore, hematogenous cells recruited within the first 10 days of regeneration help in the production of inflammatory mediators like interleukins that in turn stimulate Schwann cells to produce NGF for axonal growth.