Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model

The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP.     

The Histidine Phosphocarrier Kinase/Phosphorylase from Bacillus Subtilis Is an Oligomer in Solution with a High Thermal Stability

The histidine phosphocarrier protein (HPr) kinase/phosphorylase (HPrK/P) modulates the phosphorylation state of the HPr protein, and it is involved in the use of carbon sources by Gram-positive bacteria. Its X-ray structure, as concluded from crystals of proteins from several species, is a hexamer; however, there are no studies about its conformational stability, and how its structure is modified by the pH. We have embarked on the conformational characterization of HPrK/P of Bacillus subtilis (bsHPrK/P) in solution by using several spectroscopic (namely, fluorescence and circular dichroism (CD)) and biophysical techniques (namely, small-angle X-ray-scattering (SAXS) and dynamic light-scattering (DLS)). bsHPrK/P was mainly a hexamer in solution at pH 7.0, in the presence of phosphate. The protein had a high conformational stability, with an apparent thermal denaturation midpoint of ~70 °C, at pH 7.0, as monitored by fluorescence and CD. The protein was very pH-sensitive, precipitated between pH 3.5 and 6.5; below pH 3.5, it had a molten-globule-like conformation; and it acquired a native-like structure in a narrow pH range (between pH 7.0 and 8.0). Guanidinium hydrochloride (GdmCl) denaturation occurred through an oligomeric intermediate. On the other hand, urea denaturation occurred as a single transition, in the range of concentrations between 1.8 and 18 µM, as detected by far-UV CD and fluorescence.     

Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.     

Global insight into microwave stoneware firing: Macro and microstructural changes

Industrial competition and environmental concerns lead to the exploration of alternative and energy-efficient technologies for ceramic materials processing. The main objective of this work was to present microwave heating as a viable option for stoneware processing. Stoneware functional properties are presented and discussed, with emphasis on impact strength, water absorption, porosity, and color. Microstructure analyses show that microwave- and gas-fired samples have higher densifications than electrically fired samples. A relevant finding for processing conditions is that microwave firing requires temperatures approximately 100°C lower than those required by conventional firing. Microwave-fired samples’ rupture energies are approximately twice (0.57 ± 0.06 (J)) those of the reference samples (0.26 ± 0.03 (J)), and their water absorptions are approximately one-half (1.5% at 1170°C and 0.8% at 1190°C) of those of the reference samples (2.0%), whereas the water absorption of electrically fired samples at 1180°C has been estimated to be 7.5%. Color analysis also evidences a shift to lower microwave firing temperatures, what is attributed to the enhanced transformations promoted by microwave heating when comparing with the transformations promoted by conventional (gas or electric) heating.     

Initial stages of tin electrodeposition from sulfate baths in the presence of gluconate

Tin electrodeposition in its initial stages in acid sulfate/gluconate baths was studied with varying tin and gluconate concentrations using potential-controlled electrochemical techniques. The deposit morphology was observed by scanning electron microscopy (SEM). A comparison with tin electrodeposition from acid sulfate baths in the absence of gluconate was also carried out. Use of a highly acidic bath leads to nonuniform deposits, even in the presence of gluconate; at pH 4 deposits are uniform, brilliant and suitable for finishing applications. Tin crystallites have a well defined morphology which depends on bath agitation conditions. In the absence of agitation, the crystallites have the same tetragonal shape as in a sulfate bath without gluconate.     

The role of the surface free energy in the selection of a suitable excipient in the course of a wet-granulation method

Pellets containing metronidazole were produced in a centrifugal granulator, with hydroxypropylcellulose (Klucel LF®) as binding agent, and corn starch, microcrystalline cellulose (Vivapur 101®) and lactose as excipients. The wettability of the pharmaceutical powders was assessed by means of contact angle measurements, and the dispersive and polar surface energies were determined. The spreading coefficients, the work of adhesion and the work of cohesion were calculated and correlated with the pellet properties (friability, bulk and tapped density, and porosity). The aim was to investigate the role of the surface free energy of one- and two-component powder compositions in pellet production. The interactions between the particles were found to be connected with the measured pellet parameters. It was concluded that, in the course of the growth of the pellets, the particle sizes of the pharmaceutical powders and the interactions between them are important. If the work of cohesion of the binder is lower than the work of cohesion of the substrate and the work of adhesion, then the optimal amount of the binding agent is that which coats the particles uniformly in minimal quantity and in continuous layer.     

Land Use Effect on the CN Model Parameters in a Tropical Dry Environment

Dry tropical forests account for over 1,000,000 km², and there is still lack of knowledge on their hydrologic processes. The curve number (CN) hydrologic model developed by the Natural Resources Conservation Service (NRCS) is widely applied for runoff determination in various parts of the world, but not so in tropical semiarid regions. This study analyzes the impact of land use changes on the CN model in a tropical semiarid environment, in two catchments of native dry tropical forest and thinned dry tropical forest land use from 2009 to 2012. The CN model was calibrated and validated for the NRCS recommended initial abstraction ratio λ = 0.2, and for λ evaluated from rainfall and runoff data. A reliability analysis was performed using Monte Carlo simulation. Model goodness-of-fit was assessed with statistical criteria. A total of 42 and 40 rainfall-runoff events were analyzed for the native and thinned dry tropical forest, respectively. Characteristic λ values of 0.15 and 0.11 were determined for the two respective catchments. Although CN values were similar for both land uses, CN_λ=0.20 = 80 and CN_{median λ} = 77, the thinned catchment showed a higher CN model parameters variability. The CN model was more sensitive to variations of CN values than to those of λ. This study showed that no matter the vegetation management in a dry tropical forest environment, modeled runoff is not affected by λ, but rather affected by CN, which represents soil, landuse and management.     

Application of the classical levels of intelligence to structuring the control system in an automated distribution centre

Traditional management and control models can benefit from added levels of intelligence to increase their capability to adapt to the continuous changes in global markets. After reviewing the classical definition of intelligence and its levels, this paper provides a new approach to help increase the responsiveness of management and control to changes and disturbances in the manufacturing supply chain. The ancient concept of the “Tertium Quid” has inspired a three-level community of agents (MAS-TRIO) that is proposed to improve the coordination of all actors involved. The proposed model combines Multi-Agent Systems (MAS) with Radio-Frequency Identification (RFID) to make possible a certain level of Autonomous Intelligence in the decision-taking process. This paper analyses how these levels of intelligence can be applied to management and control, and the performance of the proposed model has been tested at low and mid-levels on an experimental platform representing the facilities of a distribution centre controlled by a network of programmable logic controllers (PLCs).     

In situ leaching method for determination of chloride in concrete pore water

In the in situ leaching (ISL) method, pore water ionic content is determined in small cavities drilled in mortar/concrete specimens. Prior investigations have demonstrated the ISL applicability to obtain pH and nitrite ion concentration in concrete/mortar pore water. The application of the method is extended here to determine pore water chloride ion concentration (and pH) within practical test times in mortars and concretes prepared in the laboratory and in concrete cores extracted from a bridge deck in deicing salt service. Spatial resolution for the determination of composition profiles is also illustrated. Modeling of the ISL process indicates that chloride binding accelerates the approach toward a terminal cavity concentration, reducing test duration to practical lengths for moderate permeability concretes. This acceleration can be attributed to maintaining a higher gradient of free chloride near the cavity wall due to the release, during leaching, of previously bound chloride. Consequently, there is a faster chloride buildup in the cavity water compared with the no-binding case. Experimental chloride and pH results obtained by the ISL test in mortar samples show good agreement with those from the pore water expression (PWE) method. Also, examples are presented of application of ISL data to obtain chloride binding isotherms, and pore water chloride to hydroxide ratio relevant to assessing conditions for corrosion of steel reinforcement. The ISL method presents a less costly and less disruptive alternative to PWE for pore water analysis. It is noted, however, that in a few instances ISL could not be implemented because of excessive absorption of cavity water by the surrounding medium.