q-RASTR modelling for prediction of diverse toxic chemicals towards T. pyriformis.

A series of diverse organic compounds impose serious detrimental effects on the health of living organisms and the environment. Determination of the structural aspects of compounds that impart toxicity and evaluation of the same is crucial before public usage. The present study aims to determine the structural characteristics of compounds for Tetrahymena pyriformis toxicity using the q-RASTR (Quantitative Read Across Structure-Toxicity Relationship) model. It was developed using RASTR and 2-D descriptors for a dataset of 1792 compounds with defined endpoint (pIGC50) against a model organism, T. pyriformis. For the current study, the whole dataset was divided based on activity/property into the training and test sets, and the q-RASTR model was developed employing six descriptors (three latent variables) having r2, Q2F1 and Q2 values of 0.739, 0.767, and 0.735, respectively. The generated model was thoroughly validated using internationally recognized internal and external validation criteria to assess the model's dependability and predictability. It was highlighted that high molecular weight, aromatic hydroxyls, nitrogen, double bonds, and hydrophobicity increase the toxicity of organic compounds. The current study demonstrates the applicability of the RASTR algorithm in QSTR model development for the prediction of toxic chemicals (pIGC50) towards T. pyriformis.

Intuitionistic Fuzzy Weighted Least Squares Twin SVMs.

Fuzzy membership is an effective approach used in twin support vector machines (SVMs) to reduce the effect of noise and outliers in classification problems. Fuzzy twin SVMs (TWSVMs) assign membership weights to reduce the effect of outliers, however, it ignores the positioning of the input data samples and hence fails to distinguish between support vectors and noise. To overcome this issue, intuitionistic fuzzy TWSVM combined the concept of intuitionistic fuzzy number with TWSVMs to reduce the effect of outliers and distinguish support vectors from noise. Despite these benefits, TWSVMs and intuitionistic fuzzy TWSVMs still suffer from some drawbacks as: 1) the local neighborhood information is ignored among the data points and 2) they solve quadratic programming problems (QPPs), which is computationally inefficient. To overcome these issues, we propose a novel intuitionistic fuzzy weighted least squares TWSVMs for classification problems. The proposed approach uses local neighborhood information among the data points and also uses both membership and nonmembership weights to reduce the effect of noise and outliers. The proposed approach solves a system of linear equations instead of solving the QPPs which makes the model more efficient. We evaluated the proposed intuitionistic fuzzy weighted least squares TWSVMs on several benchmark datasets to show the efficiency of the proposed model. Statistical analysis is done to quantify the results statistically. As an application, we used the proposed model for the diagnosis of Schizophrenia disease.

Connection between quasisymmetric magnetic fields and anisotropic pressure equilibria in fusion plasmas.

The stellarator as a concept of magnetic confinement fusion requires careful design to confine particles effectively. A design possibility is to equip the magnetic field with a property known as quasisymmetry. Though it is generally believed that a steady-state quasisymmetric equilibrium can only be exact locally (unless the system has a direction of continuous symmetry such as the tokamak), we suggest in this work that a change in the equilibrium paradigm can ameliorate this limitation. We demonstrate that there exists a deep physical connection between quasisymmetry and magnetostatic equilibria with anisotropic pressure, extending beyond the isotropic pressure equilibria commonly considered.

Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia: a genetic and functional study.

OBJECTIVE: To study genetic variants and their function within genes coding for complement receptors in pre-eclampsia. DESIGN: A case-control study. SETTING: Pre-eclampsia is a common vascular disease of pregnancy. The clearance of placenta-derived material is one of the functions of the complement system in pregnancy. POPULATION: We genotyped 500 women with pre-eclamptic pregnancies and 190 pregnant women without pre-eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre-eclamptic pregnancies and 1905 controls from the national FINRISK cohort. METHODS: The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS-1 cells. MAIN OUTCOME MEASURES: Allele frequencies were compared between pre-eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. RESULTS: The most significantly pre-eclampsia-linked CR3 variant M441K (P = 4.27E-4, OR = 1.401, 95% CI = 1.167-1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. CONCLUSIONS: Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. TWEETABLE ABSTRACT: Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre-eclampsia.

Direct Observations of Particle Dynamics in Magnetized Collisionless Shock Precursors in Laser-Produced Plasmas.

We present the first laboratory observations of time-resolved electron and ion velocity distributions in magnetized collisionless shock precursors. Thomson scattering of a probe laser beam was used to observe the interaction of a laser-driven, supersonic piston plasma expanding through an ambient plasma in an external magnetic field. From the Thomson-scattered spectra we measure time-resolved profiles of electron density, temperature, and ion flow speed, as well as spatially resolved magnetic fields from proton radiography. We observe direct evidence of the coupling between piston and ambient plasmas, including the acceleration of ambient ions driven by magnetic and pressure gradient electric fields, and deformation of the piston ion flow, key steps in the formation of magnetized collisionless shocks. Even before a shock has fully formed, we observe strong density compressions and electron heating associated with the pileup of piston ions. The results demonstrate that laboratory experiments can probe particle velocity distributions relevant to collisionless shocks, and can complement, and in some cases overcome, the limitations of similar measurements undertaken by spacecraft missions.

Genitourinary Fistula: A Curse to Neglected Pregnancy.

Genitourinary fistula is a psychophysiosocial distress that results in prolonged labour. Gradually, it has become a public health issue globally with advancing of its incidence day by day. A handsome number of mothers are also suffering in Bangladesh from genitourinary fistula. This study was done to observe the patterns of presentations of genitourinary fistula and their fetal outcome. One hundred sixteen (116) consecutive patients were enrolled in the study by purposive sampling as a diagnosed case of genitourinary fistula presented in Department of Obstetrics & Gynecology of Dhaka Medical College Hospital, Dhaka, Bangladesh from January 2017 to September 2017. It was a prospective observational cross-sectional study. A pre-structured, interview and observation based, peer reviewed data collection sheet was prepared. Data regarding sociodemographic, clinical and Obstetrical profile were recorded. Statistical analysis was done with SPSS version 23. Data were presented as mean and standard deviation, frequency and percentage with range. The mean age of the respondents was 27.27±4.21 (age range: 20-35 years). The mean height of the respondents was 150.26±13.28cm (range: 133-172cm). Among 106 mothers 69(65.1%) and 25(23.6%) were primiparous and multiparous respectively. On the contrary, 5(4.7%) each were grand multiparous and experienced fistula due to non obstetrics complications like malignancy, hysterectomy and radiotherapy. Mothers had 1, 2 and 3 fistulas in 98(92.5%), 6(5.7%) and 2(1.9%) respectively. Among 106 mothers, 99(93.4%) experienced only urinary incontinence whereas 5(4.7%) experienced fecal incontinence. Only 2(1.9%) experienced both urinary and fecal incontinence. Maximum vesicovaginal fistula was due to obstructed labour (65.09%) which was subsequently followed by trauma (14.15%). Vesicovaginal fistula was the commonest type which was subsequently followed by vesicocervical fistula. Among 106 mothers, 73(68.9%) and 25(23.6%) gave birth, still birth and alive babies respectively. On the contrary, 4(3.7%) neonate experienced death in neonatal period whereas 1(0.9%) each twin deliveries resulted in 'one dead and one alive' and 'Twin alive' respectively. In case of only 3(2.8%) mothers 'no information' regarding fetal outcome could be recorded. Prolonged labour is the principal culprit to develop genitourinary fistulas among which VVF is the commonest variety. Still birth is the frequently evident fetal outcome in case of this clinical disaster of pregnancy.

Biermann-Battery-Mediated Magnetic Reconnection in 3D Colliding Plasmas.

Recent experiments have demonstrated magnetic reconnection between colliding plasma plumes, where the reconnecting magnetic fields were self-generated in the plasma by the Biermann-battery effect. Using fully kinetic 3D simulations, we show the full evolution of the magnetic fields and plasma in these experiments, including self-consistent magnetic field generation about the expanding plume. The collision of the two plasmas drives the formation of a current sheet, where reconnection occurs in a strongly time- and space-dependent manner, demonstrating a new 3D reconnection mechanism. Specifically, we observe a fast, vertically localized Biermann-mediated reconnection, an inherently 3D process where the temperature profile in the current sheet coupled with the out-of-plane ablation density profile conspires to break inflowing field lines, reconnecting the field downstream. Fast reconnection is sustained by both the Biermann effect and the traceless electron pressure tensor, where the development of plasmoids appears to modulate the contribution of the latter. We present a simple and general formulation to consider the relevance of Biermann-mediated reconnection in general astrophysical scenarios.

The feasibility of putrescible components of municipal solid waste for biomethane production at Hyderabad, Pakistan.

This study analyzes the feasibility of putrescible components of municipal solid waste (PCMSW) such as food waste (FW) and yard waste (YW) for methane production in Pakistan. The batch experiments have been conducted at two different inoculums to substrate ratios (ISRs) by using various inoculums under mesophilic condition. The highest methane yield of FW and YW is achieved to be 428 Nml g-1 volatile solids (VS) added and 304 Nml g-1 VS added respectively by using buffalo dung inoculum at ISR-5. While, lowest methane yield of FW and YW is obtained as 236 Nml g-1 VS added and 151Nml g-1 VS added respectively by using effluent from a continuous stirrer tank reactor as inoculum at ISR-3. The first order decay model has been introduced, which gives best fit for methane potential of PCMSW with buffalo dung inoculum. Additionally, the feasibility of PCMSW in terms of power generation potential has been analyzed. About 60.63 million m3/year energy can be generated by converting PCMSW into methane gas leading to power generation. The finding of this study concludes that the replacement of imported energy and reduction up to 1.62% in other primary energy sources would be achieved, if PCMSW are properly converted into energy through anaerobic digestion in Pakistan.

Comparison of paclitaxel-cetuximab chemotherapy versus metronomic chemotherapy consisting of methotrexate and celecoxib as palliative chemotherapy in head and neck cancers.

BACKGROUND: The present match pair analysis was planned to compare the efficacy of cetuximab-paclitaxel-based chemotherapy versus metronomic therapy. MATERIALS AND METHODS: Sixty patients with metastatic/recurrent head and neck squamous cell cancer treated with weekly paclitaxel (80 mg/m2) and cetuximab were matched with sixty patients treated with oral metronomic chemotherapy consisting of methotrexate and celecoxib. The progression-free survival (PFS) and overall survival (OS) between the cohorts were compared using log-rank test. Cox proportional regression model was used to identify independent factors affecting PFS and OS. RESULTS: The median OS was 191 days (95% confidence interval [CI]: 122.2-259.8 days) in metronomic cohort and 256 days (95% CI 177.0-334.9 days) in cetuximab cohort (hazard ratio: 0.58, 95% CI: 0.35-0.95, P = 0.031). On Cox proportional hazard model, Eastern Cooperative Oncology Group Performance Status (0-1 vs. 2) and therapy (cetuximab versus metronomic) had a statistically significant impact on OS. CONCLUSION: Cetuximab-based chemotherapy leads to a significant improvement in OS in the match pair analysis in comparison to metronomic chemotherapy.

Retrospective analysis of palliative metronomic chemotherapy in head and neck cancer.

BACKGROUND: Metronomic chemotherapy has shown promising results in selected patients of head and neck cancer in a small randomized study. This retrospective analysis was done to see whether the efficacy of metronomic chemotherapy in an unselected cohort of head and neck cancer patients is similar to that reported in the randomized study and the influence of the site and subsite of head and neck cancer on survival. MATERIALS AND METHODS: This was a retrospective analysis of head and neck cancer patients who received palliative metronomic chemotherapy between January 2013 and February 2015. The data of these patients were collected from our palliative chemotherapy database maintained in medical oncology outpatient department. The overall survival (OS) was calculated in days from the date of start of chemotherapy to the date of death. Patients who had not expired at last follow-up were censored during estimation of OS by Kaplan-Meier method. Factors affecting OS were identified by COX regression analysis. RESULTS: Over the stipulated time period, 340 patients received palliative metronomic chemotherapy. The median age of these patients was 48 years (22-90 years). The sites of tumor origin were oral cavity in 281 patients (82.6%), oropharynx in 33 patients (9.7%), larynx in seven patients (2.1%), hypopharynx in 12 patients (3.5%), and maxilla in seven patients (2.1%). Previous treatment was received by 286 patients (84.1%). The median time to failure was 3.5 months (interquartile range 2.0-6.0 months). The overall median survival was 155 days (95% confidence interval 140.2-169.8 days). Failure within 6 months of previous treatment was the most important factor influencing OS. There was a trend toward lower OS in patients with oral cancers (139 days vs. 210 days). Among the various oral cancer subsites, oral tongue primary had a lower OS. CONCLUSION: Oral metronomic chemotherapy has promising results when used in a selected cohort of patients but has dismal results in patients who failed within 6 months of previous treatment.

Development and validation of a predictive score, for identifying poor eastern cooperative oncology group performance status (performance status 3-4) advanced nonsmall cell lung cancer patients who are likely to benefit from tyrosine kinase inhibitors.

BACKGROUND: One of the ten advanced lung cancer patients presents with poor eastern cooperative oncology group performance status (ECOG PS). There are no clear guidelines about management of these patients. The benefit of tyrosine kinase inhibitors (TKI) in this patient population remains questionable. Hence, in this study, we attempted to develop and validate a predictive score which would predict benefit from oral TKI. METHODS: This was a prospective observational study done at Tata Memorial Hospital, India. Patients with nonsmall cell lung cancer with ECOG PS 3-4 were included in this study. All these patients had received oral TKI on compassionate grounds and were followed up till death. The overall survival (OS) was calculated from date of start of TKI to date of death. R software was used for development and validation of the predictive model. RESULTS: The median survival duration of the discovery cohort and validation cohort were 170.5 and 115 days, respectively. The model predicted OS accurately, within ±2 months in 72.1% and within ±3 months in 81.7% of patients. CONCLUSION: The current model can predict OS in poor PS patients treated with TKI within a satisfactory clinical range and can be used for decision-making of these patients.

Generation and Evolution of High-Mach-Number Laser-Driven Magnetized Collisionless Shocks in the Laboratory.

We present the first laboratory generation of high-Mach-number magnetized collisionless shocks created through the interaction of an expanding laser-driven plasma with a magnetized ambient plasma. Time-resolved, two-dimensional imaging of plasma density and magnetic fields shows the formation and evolution of a supercritical shock propagating at magnetosonic Mach number M_{ms}≈12. Particle-in-cell simulations constrained by experimental data further detail the shock formation and separate dynamics of the multi-ion-species ambient plasma. The results show that the shocks form on time scales as fast as one gyroperiod, aided by the efficient coupling of energy, and the generation of a magnetic barrier between the piston and ambient ions. The development of this experimental platform complements present remote sensing and spacecraft observations, and opens the way for controlled laboratory investigations of high-Mach number collisionless shocks, including the mechanisms and efficiency of particle acceleration.

Binding of small molecules at interface of protein-protein complex - A newer approach to rational drug design.

Protein-protein interaction is a vital process which drives many important physiological processes in the cell and has also been implicated in several diseases. Though the protein-protein interaction network is quite complex but understanding its interacting partners using both in silico as well as molecular biology techniques can provide better insights for targeting such interactions. Targeting protein-protein interaction with small molecules is a challenging task because of druggability issues. Nevertheless, several studies on the kinetics as well as thermodynamic properties of protein-protein interactions have immensely contributed toward better understanding of the affinity of these complexes. But, more recent studies on hot spots and interface residues have opened up new avenues in the drug discovery process. This approach has been used in the design of hot spot based modulators targeting protein-protein interaction with the objective of normalizing such interactions.

Target fishing of glycopentalone using integrated inverse docking and reverse pharmacophore mapping approach.

Glycopentalone isolated from Glycosmis pentaphylla (family Rutaceae) has cytotoxic and apoptosis inducing effects in various human cancer cell lines; however, its mode of action is not known. Therefore, target fishing of glycopentalone using a combined approach of inverse docking and reverse pharmacophore mapping approach was used to identify potential targets of glycopentalone, and gain insight into its binding modes against the selected molecular targets, viz., CDK-2, CDK-6, Topoisomerase I, Bcl-2, VEGFR-2, Telomere:G-quadruplex and Topoisomerase II. These targets were chosen based on their key roles in the progression of cancer via regulation of cell cycle and DNA replication. Molecular docking analysis revealed that glycopentalone displayed binding energies ranging from -6.38 to -8.35 kcal/mol and inhibition constants ranging from 0.758 to 20.90 µM. Further, the binding affinities of glycopentalone to the targets were in the order: Telomere:G-quadruplex > VEGFR-2 > CDK-6 > CDK-2 > Topoisomerase II > Topoisomerase I > Bcl-2. Binding mode analysis revealed critical hydrogen bonds as well as hydrophobic interactions with the targets. The targets were validated by reverse pharmacophore mapping of glycopentalone against a set of 2241 known human target proteins which revealed CDK-2 and VEGFR-2 as the most favorable targets. The glycopentalone was well mapped to CDK-2 and VEGFR-2 which involve six pharmacophore features (two hydrophobic centers and four hydrogen bond acceptors) and nine pharmacophore features (five hydrophobic, two hydrogen bond acceptors and two hydrogen bond donors), respectively. The present computational approach may aid in rational identification of targets for small molecules against large set of candidate macromolecules before bioassays validation.

Distribution of Class II integrons and their contribution to antibiotic resistance within Enterobacteriaceae family in India.

BACKGROUND: Integrons are the main contributors to the development of multidrug resistance (MDR) among Gram-negative bacilli. There is a lack of knowledge about the molecular relation between gene cassettes and antibiotic resistance in India. OBJECTIVE: In this study, we have investigated the occurrence of Class II integron and their cassette array among Enterobacteriaceae. MATERIALS AND METHODS: A total of 268 MDR non-duplicate strains of Enterobacteriaceae were collected from Silchar Medical College and Hospital, Silchar, Assam, India, during June 2012 to May 2013. Polymerase chain reaction was performed for detection of the integrase genes and gene cassettes within the Class II integron which were further analysed by sequencing. RESULTS: Class II integron was observed in 47 isolates. Four different gene cassette arrangements were detected: dfrA1-sat2-aadA1; dfrA1-sat2-aadA1-orfX-ybeA-ybfA-ybfB-ybgA; dfrA12-sat2-aadA1; and dfrA1-linF-aadA1. The most prevalent cassette combination was dfrA1-sat2-aadA1. This study has also identified a set of gene cassette associated with linF gene instead of sat2 gene. CONCLUSION: Further investigation is required to determine the current situation and important reservoir of Class II integron for the transmission of drug resistance among Enterobacteriaceae and their contribution to antimicrobial resistance in hospital environment .

Tolerance of weekly metronomic paclitaxel and carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer patients who are unlikely to tolerate 3 weekly paclitaxel and carboplatin.

OBJECTIVE: There are little data regarding safety and effectiveness of neoadjuvant chemotherapy (NACT) in patients who are considered unfit for receiving 3 weekly paclitaxel and carboplatin. The aim of this study was to examine the toxicity and response rates of weekly paclitaxel and carboplatin as NACT in such cohort of patients. METHODS: Study population included advanced ovarian cancer patients who were unlikely to tolerate 3 weekly paclitaxel and carboplatin and hence received weekly paclitaxel (80 mg/m(2)) and carboplatin AUC-2 as NACT. The data regarding the baseline characteristics, chemotherapy tolerance, completion rates, toxicity (Common Terminology Criteria for Adverse Events version 4.02), and radiological response rates are presented. SPSS version 16 was used for analysis. Descriptive statistics is presented. RESULTS: Eleven patients received this schedule. Nine patients completed nine cycles of NACT. Except one, all patients completed NACT with an average relative dose intensity of >0.8. There was no chemotherapy-related mortality. Grade 3-4 life-threatening complications were seen in two patients. The post NACT response rate was 100%. CONCLUSIONS: Weekly paclitaxel and carboplatin chemotherapy is safe and efficacious in patients who are unsuitable for 3 weekly paclitaxel and carboplatin chemotherapy schedules.

Molecular docking of the anticancer bioactive compound proceraside with macromolecules involved in the cell cycle and DNA replication.

The bioactive compounds proceraside A, frugoside and calotropin, which were extracted from the root bark of Calotropis procera (Aiton) W.T. Aiton (family Asclepiadaceae), were recently reported to inhibit the growth of inhibition against various human cancer cell lines in vitro. However, their modes of action have not been clearly defined. Therefore, we attempted an in silico approach to gain insights into their binding modes against the following selected molecular targets: CDK-2, CDK-6, topoisomerase I, BCL-2, VEGFR-2, telomere: G-quadruplex, and topoisomerase II. These targets were selected based on their key roles in cancer progression via the regulation of the cell cycle and DNA replication. Molecular-docking analyses revealed that proceraside A was the best docked ligand against all the targets, with the exception of telomere-G: quadruplex. Furthermore, it displayed the lowest binding energies and inhibition constants, and critical hydrogen bonds and hydrophobic interactions with the targets were also revealed. The present study may aid in the identification of possible targets for proceraside A, and might provide a plausible explanation for its proven anti-tumor activities. Moreover, the result of this study may further guide structure-activity relationship studies used to generate more potent target-specific inhibitors.

Formation of current singularity in a topologically constrained plasma.

Recently a variational integrator for ideal magnetohydrodynamics in Lagrangian labeling has been developed. Its built-in frozen-in equation makes it optimal for studying current sheet formation. We use this scheme to study the Hahm-Kulsrud-Taylor problem, which considers the response of a 2D plasma magnetized by a sheared field under sinusoidal boundary forcing. We obtain an equilibrium solution that preserves the magnetic topology of the initial field exactly, with a fluid mapping that is non-differentiable. Unlike previous studies that examine the current density output, we identify a singular current sheet from the fluid mapping. These results are benchmarked with a constrained Grad-Shafranov solver. The same signature of current singularity can be found in other cases with more complex magnetic topologies.

Tolerance of weekly paclitaxel and carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer patients who are unlikely to tolerate 3 weekly paclitaxel and carboplatin.

OBJECTIVE: There are little data regarding safety and effectiveness of neoadjuvant chemotherapy (NACT) in patients who are considered unfit for receiving 3 weekly paclitaxel and carboplatin. The aim of this study was to study the toxicity and response rates of weekly paclitaxel and carboplatin as NACT in such cohort of patients. METHODS: Study population included advanced ovarian cancer patients who were unlikely to tolerate 3 weekly paclitaxel and carboplatin and hence received weekly paclitaxel (80 mg/m2) and carboplatin AUC-2 as NACT. The data regarding the baseline characteristics, chemotherapy tolerance, completion rates, toxicity (CTCAE version 4.02), and radiological response rates are presented. SPSS version 16 was used for analysis. Descriptive statistics is presented. RESULT: Eleven patients received this schedule. Nine patients completed nine cycles of NACT. Except one, all patients completed NACT with an average relative dose intensity of >0.8. There was no chemotherapy-related mortality. Grade 3-4 life-threatening complications were seen in two patients. The post NACT response rate was 100%. CONCLUSION: Weekly paclitaxel and carboplatin chemotherapy is safe and efficacious in patients who are unsuitable for 3 weekly paclitaxel and carboplatin chemotherapy schedules.