Multi-Target Directed Ligands (MTDLs) Binding the σ1 Receptor as Promising Therapeutics: State of the Art and Perspectives

The sigma-1 (σ₁) receptor is a ‘pluripotent chaperone’ protein mainly expressed at the mitochondria–endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the σ₁ receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward σ₁ receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the σ₁ protein (as off-target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the σ₁ receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies.     

Correlations Among Neutron Yield and Dynamical Discharge Characteristics Obtained from Electrical Signals in a 400?J Plasma Focus

Dynamical discharge characteristics and their relation with the total neutron yield emitted from a 400 J plasma focus operating in deuterium gas are presented. The dynamical nature of the plasma focus is obtained merely from the analysis of the voltage and current electrical signals without considering any particular geometry for the plasma sheath. It is calculated that large neutron yields are obtained when plasma inductance, mechanical energy and plasma voltage at pinching time have larger values. In contrast, no correlations are found among neutron yields either with plasma propagation velocities or quantities at the beginning of the radial phase. There is also found that the current sheath geometry changes according to the gas pressure, having larger curvature for lower pressures. The calculations also provide estimations of sheath thicknesses at the detachment from the insulator in the range of 0.5–1 mm, being thicker for larger neutron yield.     

Genetic approach helps to speed classical Price algorithm for global optimization

In this paper is presented an hybrid algorithm for finding the absolute extreme point of a multimodal scalar function of many variables. The algorithm is suitable when the objective function is expensive to compute, the computation can be affected by noise and/or partial derivatives cannot be calculated. The method used is a genetic modification of a previous algorithm based on the Prices method. All information about behavior of objective function collected on previous iterates are used to chose new evaluation points. The genetic part of the algorithm is very effective to escape from local attractors of the algorithm and assures convergence in probability to the global optimum. The proposed algorithm has been tested on a large set of multimodal test problems outperforming both the modified Prices algorithm and classical genetic approach.     

Effect of formulation and process variables on the release behavior of amoxicillin matrix tablets

The sustained release of amoxicillin is desired to be confined to the upper gastrointestinal tract to treat certain kind of infections. In vitro dissolution, at pH 1.2, of amoxicillin sustained release tablets has been studied varying the proportion of Carbopol 971P NF and sodium alginate as well as the ethanol/water proportion in the granulation fluid. M_t, the amount of drug released at time (t) and defined in terms of the total drug released over a long time period (M_inf), was described by M_t/M_inf = ktⁿ. Matrices with increasing proportions of sodium alginate showed increasing values of the exponent indicative of the release mechanism (n) and increasing release constant values (k). This is attributed to a drop in the coherence of the polymeric matrix with increasing alginate proportions that produces an increasing polymer relaxation and erosion. Decreasing Carbopol 971P NF proportions reduce the amount of dissolved polymer during granulation, producing a lesser obstruction of amoxicillin dissolution. Alginate proportions of 80% produce near zero order release profiles. Granules obtained with increasing ethanol proportions showed increasing release constant values and a minor change in the exponent (n) values. This is considered a result of lower polymer dissolution during granulation that allows a lesser matrix coherence and a greater amoxicillin dissolution. Alginate matrices granulated with different ethanol/water proportions showed no significant changes in the amoxicillin release profile. There is a trend toward increasing floating times with increasing Carbopol 971P NF proportions.     

Behavioral and Chemical Analysis of Venom Gland Secretion of Queens of the Ant Solenopsis geminata

Bioassays in a Y-tube olfactometer showed that workers of Solenopsis geminata (Hymenoptera: Formicidae) were attracted to venom gland extracts of queens. Gas chromatography coupled mass spectrometry analysis of individual glands of queens of S. geminata showed that the secretion is composed mainly of a large amount of 2-alkyl-6-methylpiperidine alkaloids and a tiny amount of a -lactone and a -pyrone, which have been earlier identified as components of the queen attractant pheromone of Solenopsis invicta Buren. However, additional small amounts of a mixture of sesquiterpenes and pentadecene were found. The possible function of the sesquiterpenoid compounds is discussed.     

Determination of free fatty acids in foods by flow injection

A flow injection manifold has been developed for the spectrophotometric determination of free fatty acids (FFA) at 716 nm after continuous extraction into an organic phase of soaps formed by the reaction of copper acetate with the analytes. The carrier system stream was toluene and the reagent stream aqueous copper acetate-pyridine (50 g litre^?1). The calibration graph was linear over the range 1 × 10^?4 to 5 × 10^?3 M oleic acid using an injection volume of 115 μl. The injection rate was 75 samples h^?1 with a precision of 109% (RSD). Though this procedure does not permit the total recovery of short-chain fatty acids it is very effective in reflecting the total concentration of FFA. The system has been applied to the determination of total FFA in olive oil, milk fat and cocoa butter. Although the values obtained by the proposed method are lower than those obtained by the reference method (titration) and by chromatography, their comparison shows good linearity.     

Ferromagnetic Mn–Al–C L10 Formation by Electric Current Assisted Annealing

The ferromagnetic Mn–Al–C τ-phase (${\text{L1}}_0$ tetragonal structure) shows intrinsic potential to be developed as a permanent magnet; however, this phase is metastable and is easily decomposed to nonmagnetic stable phases, affecting negatively the magnetic properties. Giving the necessity to careful control of its synthesis, the use of a novel approach is investigated using electric current–assisted annealing to obtain pure τ-phase samples. The temperature and electrical resistance of the samples are monitored during annealing and it is shown that the change in resistance can be used to probe the phase transformation. Upon increase of electric current density, the required temperature for the ferromagnetic phase formation is reduced, reaching a maximum shift of 140 °C at 45 A mm⁻². Even though this noticeable shift is achieved, the magnetic properties are not affected showing coercivity of 0.13 T and magnetization of 90 Am² kg⁻¹, independently from the electric current density used during annealing. Microstructural investigation reveals the nucleation of the τ-phase at the grain boundaries of the parent ε-phase. In addition, the existence of twin boundaries upon nucleation and growth of the metastable phase for all evaluated annealing conditions is observed, resulting in similar extrinsic magnetic properties.     

Design,Synthesis, and Characterization of a Novel Fluoroprobe for Live Human Islet Cell Imaging of Serotonin 5-HT1A Receptor

Mounting evidence suggests that the serotonin system serves in signal transmission to regulate insulin secretion in pancreatic islets of Langerhans. Among the 5-HT receptor subtype found in pancreatic islets, serotonin receptor 1A (5-HT_1A) demonstrates a unique ability to inhibit β-cell insulin secretion. We report the design, synthesis, and characterization of two novel fluorescent probes for the 5-HT_1A receptor. The compounds were prepared by conjugating the scaffold of the 5-HT_1A receptor agonist 8-OH-DPAT with two fluorophores suitable for live-cell imaging. Compound 5a {5-(dimethylamino)-N-[5-[(8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino]pentyl]naphtalen-1-sulfonammide} showed high affinity for the 5-HT_1A receptor (K_i=1.8 nM). Fluoroprobe 5a was able to label the 5-HT_1A receptor in pancreatic islet cell cultures in a selective manner, as the fluorescence emission was significantly attenuated by co-administration of the 5-HT_1A receptor antagonist WAY-100635. Thus, fluoroprobe 5a showed useful properties to further characterize this unique receptor‘s role.     

Detecting the imprints of past clear-cutting on riparian forest plant communities along a Mediterranean river

In riparian forests, clear-cutting causes long-lasting changes in both riparian and aquatic biota. In this work, we examined if past clear-cutting events occurred at different times have imprints on riparian forests in a Mediterranean river in central Italy. We carried out a randomized, plot-based vegetation survey of riparian forests in systematically sampled 500 m-long sectors along the whole river, dividing the riparian zone into two internal and two external strips. From historical aerial photos, past clear-cutting events within plots were detected and classified in age classes: (i) cut in the past 8 years (recent); (ii) cut between 8 and 19 years ago (intermediate); (iii) no signs of clear-cutting in the last 19 years (distant). We analyzed the responses of vegetation to clear-cutting and strip position. Alien species richness was higher and woody species richness was lower in recently clear-cut areas compared to those with a distant clear-cutting event. Moreover, recently cut woods had more alien and synanthropic species. Intermediate clear-cut areas had higher levels of invasion by alien species compared to areas with distant cut. Riparian forests of internal strips are impacted by clear-cutting, but seem to recover in 8–19 years thanks to their natural resilience. Conversely, recent or intermediate clear-cutting events did not affect any of the investigated vegetation attributes in the external strips since such forests were already invaded by alien and synanthropic species after human disturbance. Our results confirm that clear-cutting events can have long-lasting effects on Mediterranean riparian forests, confirming the vulnerability of river ecosystems to clear-cutting and suggesting the need for more caution in management practices to improve the conservation status of riparian forests.