Early preventive strategies and CNS meningioma – Is this feasible? : A comprehensive review of literature

Acknowledgements We are grateful to Dr. Thamizhmaran Sundararajan for his contribution to our comprehensive review. His graphical representation of our results has enhanced the clarity of our findings.Peer reviewedPublisher PD

A computational modeling and molecular dynamics study of the Michaelis complex of human protein Z-dependent protease inhibitor (ZPI) and factor Xa (FXa)

Protein Z-dependent protease inhibitor (ZPI) and antithrombin III (AT3) are members of the serpin superfamily of protease inhibitors that inhibit factor Xa (FXa) and other proteases in the coagulation pathway. While experimental structural information is available for the interaction of AT3 with FXa, at present there is no structural data regarding the interaction of ZPI with FXa, and the precise role of this interaction in the blood coagulation pathway is poorly understood. In an effort to gain a structural understanding of this system, we have built a solvent equilibrated three-dimensional structural model of the Michaelis complex of human ZPI/FXa using homology modeling, protein–protein docking and molecular dynamics simulation methods. Preliminary analysis of interactions at the complex interface from our simulations suggests that the interactions of the reactive center loop (RCL) and the exosite surface of ZPI with FXa are similar to those observed from X-ray crystal structure-based simulations of AT3/FXa. However, detailed comparison of our modeled structure of ZPI/FXa with that of AT3/FXa points to differences in interaction specificity at the reactive center and in the stability of the inhibitory complex, due to the presence of a tyrosine residue at the P1 position in ZPI, instead of the P1 arginine residue in AT3. The modeled structure also shows specific structural differences between AT3 and ZPI in the heparin-binding and flexible N-terminal tail regions. Our structural model of ZPI/FXa is also compatible with available experimental information regarding the importance for the inhibitory action of certain basic residues in FXa

The Guanine Nucleotide Exchange Factor ARNO mediates the activation of ARF and phospholipase D by insulin

BACKGROUND: Phospholipase D (PLD) is involved in many signaling pathways. In most systems, the activity of PLD is primarily regulated by the members of the ADP-Ribosylation Factor (ARF) family of GTPases, but the mechanism of activation of PLD and ARF by extracellular signals has not been fully established. Here we tested the hypothesis that ARF-guanine nucleotide exchange factors (ARF-GEFs) of the cytohesin/ARNO family mediate the activation of ARF and PLD by insulin. RESULTS: Wild type ARNO transiently transfected in HIRcB cells was translocated to the plasma membrane in an insulin-dependent manner and promoted the translocation of ARF to the membranes. ARNO mutants: ΔCC-ARNO and CC-ARNO were partially translocated to the membranes while ΔPH-ARNO and PH-ARNO could not be translocated to the membranes. Sec7 domain mutants of ARNO did not facilitate the ARF translocation. Overexpression of wild type ARNO significantly increased insulin-stimulated PLD activity, and mutations in the Sec7 and PH domains, or deletion of the PH or CC domains inhibited the effects of insulin. CONCLUSIONS: Small ARF-GEFs of the cytohesin/ARNO family mediate the activation of ARF and PLD by the insulin receptor

4D printing of smart polymer nanocomposites: integrating graphene and acrylate based shape memory polymers

The ever-increasing demand for materials to have superior properties and satisfy functions in the field of soft robotics and beyond has resulted in the advent of the new field of four-dimensional (4D) printing. The ability of these materials to respond to various stimuli inspires novel applications and opens several research possibilities. In this work, we report on the 4D printing of one such Shape Memory Polymer (SMP) tBA-co-DEGDA (tert-Butyl Acrylate with diethylene glycol diacrylate). The novelty lies in establishing the relationship between the various characteristic properties (tensile stress, surface roughness, recovery time, strain fixity, and glass transition temperature) concerning the fact that the print parameters of the laser pulse frequency and print speed are governed in the micro-stereolithography (Micro SLA) method. It is found that the sample printed with a speed of 90 mm/s and 110 pulses/s possessed the best batch of properties, with shape fixity percentages of about 86.3% and recovery times as low as 6.95 s. The samples built using the optimal parameters are further subjected to the addition of graphene nanoparticles, which further enhances all the mechanical and surface properties. It has been observed that the addition of 0.3 wt.% of graphene nanoparticles provides the best results

Physical activity patterns and gestational diabetes outcomes – The wings project

AbstractObjectiveTo compare physical activity (PA) patterns in pregnant woman with and without gestational diabetes (GDM) and to assess the effects of an exercise intervention on change in PA patterns, blood glucose levels and pregnancy outcomes in GDM women.MethodsFor the first objective, PA patterns were studied in 795 pregnant women with and without GDM. For the second objective, the Women in India with Gestational Diabetes Strategy-Model of Care (WINGS-MOC) intervention were evaluated in 151 women out of 189 with GDM. PA was assessed using a validated questionnaire and a pedometer. Changes in PA patterns, glycemic parameters and neonatal outcomes were evaluated.ResultsOverall, only 10% of pregnant women performed recommended levels of PA. Women with GDM were significantly more sedentary compared to those without GDM (86.2 vs. 61.2%, p<0.001). After the MOC was implemented in women with GDM, there was a significant improvement in PA and a decrease in sedentary behaviour amongst women (before MOC, moderate activity: 15.2%, sedentary: 84.8% vs. after MOC-moderate: 26.5%, sedentary: 73.5%; p<0.001), and an increase in their daily step count from 2206/day to 2476/day (p<0.001). Fasting 1 and 2-h postprandial glucose values significantly decreased (p<0.001 for all). Sedentary behaviour was associated with a fourfold higher risk (p=0.02), and recreational walking with 70% decreased risk, of adverse neonatal outcomes (p=0.04) after adjusting for potential confounders.ConclusionsPA levels are inadequate amongst this group of pregnant women studied i.e. those with and without GDM. However, a low-cost, culturally appropriate MOC can bring about significant improvements in PA in women with GDM. These changes are associated with improved glycemic control and reduction in adverse neonatal outcomes

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation &lt;92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p&lt;0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p&lt;0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Executable embedded web objects and internet security

The number of Internet hosts and users are reported to be doubling every year. Executable content in the form of dynamic web pages is the common source of information on the World Wide Web. As more and more people turn to the web for their information needs, two important technologies are competing to be in the forefront of this executable objects era. Java Applets and ActiveX Controls are the two widely implemented executable objects on the Web.Master of Science (Communication and Network Systems

ARF proteins mediate insulin-dependent activation of phospholipase D

AbstractBackground: ADP-ribosylation factors (ARFs) have been shown to activate phospholipase D (PLD), an enzyme modulated by extracellular signals, including several growth factors and, in particular, insulin. We have tested the hypothesis that ARF proteins are involved specifically in insulin-induced activation of PLD.Results: We found that in membranes obtained from HIRcB cells, a cell line derived from Rat-1 fibroblasts that overexpresses normal human insulin receptors, binding of the GTP analogue GTPγS to purified bovine or recombinant ARF was enhanced in the presence of insulin. Membranes obtained from cells that overexpressed a mutated, nonfunctional insulin receptor failed to stimulate ARF activation. Insulin promoted the association of ARF proteins with membranes in the presence of GTPγS in permeabilized cells. Insulin activated PLD in permeabilized HIRcB cells by a process that required GTPγS and ARF. Azido–γ[32P]-GTP labelling of immunoprecipitated receptors revealed the presence of a unique 19 kD band; ARF proteins are approximately this size, and analysis using specific monoclonal antibodies demonstrated that ARF proteins coimmunoprecipitated with the insulin receptor. Coimmunoprecipitation of ARF with the receptor was inhibited by guanine nucleotides and stimulated by insulin. No evidence of the coprecipitation of ARF with mutant receptors could be obtained using azido–γ[32P]-GTP or anti-ARF antibodies.Conclusions: The activation of ARF proteins is stimulated by insulin and this process plays an important role in insulin-mediated regulation of PLD