Effects of Distal Mutations on the Structure, Dynamics and Catalysis of Human Monoacylglycerol Lipase

An understanding of how conformational dynamics modulates function and catalysis of human monoacylglycerol lipase (hMGL), an important pharmaceutical target, can facilitate the development of novel ligands with potential therapeutic value. Here, we report the discovery and characterization of an allosteric, regulatory hMGL site comprised of residues Trp-289 and Leu-232 that reside over 18 Å away from the catalytic triad. These residues were identified as critical mediators of long-range communication and as important contributors to the integrity of the hMGL structure. Nonconservative replacements of Trp-289 or Leu-232 triggered concerted motions of structurally distinct regions with a significant conformational shift toward inactive states and dramatic loss in catalytic efficiency of the enzyme. Using a multimethod approach, we show that the dynamically relevant Trp-289 and Leu-232 residues serve as communication hubs within an allosteric protein network that controls signal propagation to the active site, and thus, regulates active-inactive interconversion of hMGL. Our findings provide new insights into the mechanism of allosteric regulation of lipase activity, in general, and may provide alternative drug design possibilities

Policy Carry-Over for Mobility in Software Defined Networks

Due to increase in the number of mobile devices that are connected to a network, it is getting harder by the day to manage these devices while they hop between different networks. Network management often involves implementation of policies that are generic to all the devices connected to the network as well as the ones that are specific to individual devices. In order to support this type of network management, static policies have to be set up across the networks using middle box technologies like firewalls, network policy servers, authentication servers etc. These middle boxes control the activity of the devices connected to the network using the policies but are often home for a huge number policies that complicate the network setup and make policy management a herculean task. In recent years, the development of Software Defined Networking practices has made it simple and intuitive to instantiate programmable networks and automate different network functions. We propose a solution to automate the process of network policy management for mobility in a Software Defined Network. Using this approach, we can implement a solution that can dynamically carry the policies across the network as a host or device moves from one place to another in a network, without any action from the network administrator. Also, with the help of this implementation, we can automate the process of policy repair in the case of network changes or errorsEngineering Technology, Department o

Microwave sintering studies on low loss (Zn, Mg)TiO₃ dielectric resonator materials

Low dielectric loss Zn0.7Mg0.3TiO3 and MgTiO3 microwave dielectric resonators were prepared by the conventional solid state reaction method. The microwave interaction with these materials has been studied using both single-mode and multimode microwave furnaces operating at a frequency of 2.45 GHz. Microwave sintering could be achieved using a multimode microwave furnace only, whereas, interaction with a single-mode furnace showed plasma generation. Phase formation was observed by X-ray diffraction. Microwave dielectric characteristics such as dielectric constant (s’), quality factor (Q*f) and temperature coefficient of resonant frequency (t/) of microwave sintered samples were measured using a vector network analyzer and compared with conventional sintered ones. Microstructure of all the conventional and microwave sintered samples was observed using high resolution scanning electron microscope. Although s’ and t/ of the conventional and microwave sintered samples are found to be comparable, the quality factor (the vital characteristic of dielectric resonators) of microwave sintered samples are observed to be much lower than those obtained by conventional sintering. The difference in these values is discussed with respect to the grain size

Translational strategies for therapeutic development in nicotine addiction: Rethinking the conventional bench to bedside approach

International audienceTobacco produces an impressive burden of disease resulting in premature death in half of users. Despite effective smoking cessation medications (nicotine replacement therapies, bupropion and varenicline), there is a very high rate of relapse following quit attempts. The use of efficient strategies for the development of novel treatments is a necessity. A 'bench to bedside strategy' was initially used to develop cannabinoid CB1 receptor antagonists for the treatment of nicotine addiction. Unfortunately, after being tested on experimental animals, what seemed to be an interesting approach for the treatment of nicotine addiction resulted in serious unwanted side effects when tested in humans. Current research is focusing again on pre-clinical models in an effort to eliminate unwanted side effects while preserving the initially observed efficacy. A 'bed side to bench strategy' was used to study the role of the insula (part of the frontal cortex) in nicotine addiction. This line of research started based on clinical observations that patients suffering stroke-induced lesions to the insula showed a greater likelihood to report immediate smoking cessation without craving or relapse. Subsequently, animal models of addiction are used to explore the role of insula in addiction. Due to the inherent limitations existing in clinical versus preclinical studies, the possibility of close interaction between both models seems to be critical for the successful development of novel therapeutic strategies for nicotine dependence

Blockade of CB1 or Activation of CB2 Cannabinoid Receptors Is Differentially Efficacious in the Treatment of the Early Pathological Events in Streptozotocin-Induced Diabetic Rats

Oxidative stress, neurodegeneration, neuroinflammation, and vascular leakage are believed to play a key role in the early stage of diabetic retinopathy (ESDR). The aim of this study was to investigate the blockade of cannabinoid receptor 1 (CB1R) and activation of cannabinoid receptor 2 (CB2R) as putative therapeutics for the treatment of the early toxic events in DR. Diabetic rats [streptozotocin (STZ)-induced] were treated topically (20 μL, 10 mg/mL), once daily for fourteen days (early stage DR model), with SR141716 (CB1R antagonist), AM1710 (CB2R agonist), and the dual treatment SR141716/AM1710. Immunohistochemical-histological, ELISA, and Evans-Blue analyses were performed to assess the neuroprotective and vasculoprotective properties of the pharmacological treatments on diabetes-induced retinal toxicity. Activation of CB2R or blockade of CB1R, as well as the dual treatment, attenuated the nitrative stress induced by diabetes. Both single treatments protected neural elements (e.g., RGC axons) and reduced vascular leakage. AM1710 alone reversed all toxic insults. These findings provide new knowledge regarding the differential efficacies of the cannabinoids, when administered topically, in the treatment of ESDR. Cannabinoid neuroprotection of the diabetic retina in ESDR may prove therapeutic in delaying the development of the advanced stage of the disease

Blockade of CB1 or Activation of CB2 Cannabinoid Receptors Is Differentially Efficacious in the Treatment of the Early Pathological Events in Streptozotocin-Induced Diabetic Rats

Oxidative stress, neurodegeneration, neuroinflammation, and vascular leakage are believed to play a key role in the early stage of diabetic retinopathy (ESDR). The aim of this study was to investigate the blockade of cannabinoid receptor 1 (CB1R) and activation of cannabinoid receptor 2 (CB2R) as putative therapeutics for the treatment of the early toxic events in DR. Diabetic rats [streptozotocin (STZ)-induced] were treated topically (20 μL, 10 mg/mL), once daily for fourteen days (early stage DR model), with SR141716 (CB1R antagonist), AM1710 (CB2R agonist), and the dual treatment SR141716/AM1710. Immunohistochemical-histological, ELISA, and Evans-Blue analyses were performed to assess the neuroprotective and vasculoprotective properties of the pharmacological treatments on diabetes-induced retinal toxicity. Activation of CB2R or blockade of CB1R, as well as the dual treatment, attenuated the nitrative stress induced by diabetes. Both single treatments protected neural elements (e.g., RGC axons) and reduced vascular leakage. AM1710 alone reversed all toxic insults. These findings provide new knowledge regarding the differential efficacies of the cannabinoids, when administered topically, in the treatment of ESDR. Cannabinoid neuroprotection of the diabetic retina in ESDR may prove therapeutic in delaying the development of the advanced stage of the disease

Effect of grain size on the microwave dielectric characteristics of high-energy ball-milled zinc magnesium titanate ceramics

Using solid-state reaction route and high-energy ball milling technique Zn1−xMgxTiO3 (x = 0–0.5) compositions were synthesized. These ball milled samples were sintered at 1100°C for 2 h and microwave dielectric properties such as dielectric constant (ε’), quality factor (Q) and temperature coefficient of resonant frequency (τf) were studied. Significant improvement in quality factor of ∼ 65% was observed for x = 0.3. To understand the effect of sintering duration on the microwave dielectric properties, single phase Zn0.7Mg0.3TiO3 samples were sintered at 1100°C for different durations from 2 to 20 h. The grain size increases with sintering duration and it influences to enhance the microwave dielectric properties and as a result, the quality factor further improved by three times. The dielectric constant and temperature coefficient of resonant frequency showed a slight improvement of ∼ 10%–15% with sintering duration

Effect of Grain Size on the Microwave Dielectric Characteristics of High-Energy Ball-Milled Zinc Magnesium Titanate Ceramics

Using solid-state reaction route and high-energy ball milling technique Zn1−xMgxTiO3 (x = 0–0.5) compositions were synthesized. These ball milled samples were sintered at 1100°C for 2 h and microwave dielectric properties such as dielectric constant (ε’), quality factor (Q) and temperature coefficient of resonant frequency (τf) were studied. Significant improvement in quality factor of ∼ 65% was observed for x = 0.3. To understand the effect of sintering duration on the microwave dielectric properties, single phase Zn0.7Mg0.3TiO3 samples were sintered at 1100°C for different durations from 2 to 20 h. The grain size increases with sintering duration and it influences to enhance the microwave dielectric properties and as a result, the quality factor further improved by three times. The dielectric constant and temperature coefficient of resonant frequency showed a slight improvement of ∼ 10%–15% with sintering duration