Challenges in Discovering Drugs That Target the Protein–Protein Interactions of Disordered Proteins

Protein–protein interactions (PPIs) outnumber proteins and are crucial to many fundamental processes; in consequence, PPIs are associated with several pathological conditions including neurodegeneration and modulating them by drugs constitutes a potentially major class of therapy. Classically, however, the discovery of small molecules for use as drugs entails targeting individual proteins rather than targeting PPIs. This is largely because discovering small molecules to modulate PPIs has been seen as extremely challenging. Here, we review the difficulties and limitations of strategies to discover drugs that target PPIs directly or indirectly, taking as examples the disordered proteins involved in neurodegenerative diseases.     

SIZE EFFECTS ON THE THERMAL CONDUCTIVITY OF THIN METALLIC WIRES: MICROSCALE IMPLICATIONS

This study examines the influence of radial thickness on the thermal conductivity of thin metallic wires. While size effects on the electrical conductivity of thin wires have been discussed in the literature, research into size effects on thermal conductivity still requires investigation. At such small length scales, the assumption that the reduced electrical conductivity can be simply related to the reduced thermal conductivity through a Wiedemann-Franz relation is subject to question. This study uses the Boltzmann transport equation for electrons to determine the thermal conductivity of a thin wire directly. Electrons are treated as the primary heat carriers in a thin wire with a thermal gradient along the axis. A single-crystal, defect-free, metallic thin wire is considered in the derivation. An expression is presented which accounts for the radial size effects on axial thermal conductivity. The derived thermal conductivity is compared to expressions for the reduced electrical conductivity, and the applicability of the Wiedemann-Franz relation is discussed.     

Flow Properties of Tailored Net-Shape Thermoplastic Composite Preforms

A novel thermoplastic programmable preforming process, TP-P4, has been used to manufacture preforms for non-isothermal compression molding. Commingled glass and polypropylene yarns are deposited by robot onto a vacuum screen, followed by a heat-setting operation to stabilize the as-placed yarns for subsequent handling. After an optional additional preconsolidation stage, the preforms are molded by preheating and subsequent press forming in a shear edge tool. The in- and out-of-plane flow capabilities of the material were investigated, and compared to those of 40 _wt% Glass Mat Thermoplastics (GMTs). Although the TP-P4 material has a fiber fraction of 60 _wt%, the material could be processed to fill 77 mm deep ribs with a thickness of 3 mm, indicative of complex part production. The pressure requirements for out-of-plane flow were shown to depend on the fiber length and fiber alignment. Segregation phenomena were found to be less severe with TP-P4 than with GMT material.     

ANTIBACTERIAL EFFECT, HISTOLOGICAL IMPACT AND OXIDATIVE STRESS STUDIES FROM LAURUS NOBILIS EXTRACT

Laurus nobilis is one of the most broadly used spices in Moroccan gastronomy. Its antimicrobial activity against both gram-positive and gram-negative bacterial species was demonstrated. Likewise, its toxicity was investigated on Swiss albinos' mice . Daily, mice were treated orally with 0.003 and 0.3 mg during 7 days. Plasmatic markers and enzymatic systems were assessed and histological alterations were evaluated. A significant increase in creatine phosphokinase level was observed. The microscopic evaluation showed that L. nobilis induces morphological perturbation in mice's liver. The results also showed an inhibitory effect of glyceraldehydes 3-phosphate dehydrogenase and an important increase in the level of thiobarbituric acid reactive substances and succinate dehydrogenase and no change in catalase activities. The results showed that L. nobilis induces toxicity at 0.3 mg/g mouse and affects energy metabolism and oxidative stress.

PRACTICAL APPLICATIONS

The aim of the present study is to determine the antimicrobial effect of Laurus nobilis on pathogens for potential application as herbal medicine in infusion or oral preparation. The effect of the spice extract was investigated on the metabolic markers, stress biomarkers and clinical parameters. This study was completed with histological coupes. To our knowledge, this is the first report to demonstrate the laurel effect on energy metabolism and oxidative stress.     

α-Tocopherol alteration of soybean antiherbivory toTrichoplusia ni larvae

The antioxidant vitamin E, -tocopherol, was tested as a candidate elicitor of alterable antiherbivory in soybean plants against cabbage looper larvae. Although a nonspecific antioxidant, vitamin E proved elicitory to the involved sulfhydryl-dependent receptor-energy transducer protein in soybean plasma membrane. Effects of -tocopherol were dependent on dosage, time, and space in the plant. The observed elicited effects were all decreases in herbivory. The best negative phytochemical correlate of looper feeding was the percentage of increased total HPLC peak area of extractables from elicited as compared to nonelicited leaves. Some specific compounds, e.g., glyceollins, were quantitatively major components of the total profile of secondary metabolites.     

Chemical correlates of α-tocopherol (Vitamin E) alteredMalacosoma disstria herbivory inFraxinus pennsylvanica var.Subintegerrinia,green ash

The antioxidant -tocopherol (vitamin E), applied in a basal trunk band to the green ash tree,Fraxinus pennsylvanica var.subintergerrinia, elicited an alteration of foliar feeding byMalacosoma disstria larvae (Lepidoptera: Lasiocampidae). The bioassayed effects were dependent on the dosage of elicitor, the time after elicitation, and the position in the tree. Leaves for chemical analysis were collected from trees receiving two dosages and at two intervals after elicitation. Compounds in the ethyl acetate extractables from the ash tree leaves were separated by TLC and HPLC. TLC separations showed differences in the nonhydrolyzed extractables attributable to elicitor dosage and time after elicitation. TLC-resolved differences were also evident among acid-hydrolyzed samples. HPLC-resolved profiles revealed eight peaks in the nonhydrolyzed extractables that were quantitatively negatively correlated with larval feeding preference between elicited versus control foliage on at least one of the two sampling dates. Results from this study and other investigations reported in the literature indicate that the antioxidant-tocopherol (vitamin E) can function as an environmental-stress elicitor of alterable defensive chemistry in green ash and other plants.     

Lateral diffusion in planar lipid bilayers

Direct measurements by fluorescence correlation spectroscopy of lateral diffusion coefficients of fluorescent lipid analogs in lipid bilaryer membranes indicate self-diffusion coefficients D greater than 10(-7) square centimeters per second for various lipid systems above their reported transition temperatures. Cholesterol in egg lecithin at mole ratio of 1 : 2 reduces D by about twofold, while retained hydrocarbon solvent can increase it by two- to threefold.     

Intraventricular chemotherapy in neonatal meningitis

All of 16 infants with neonatal meningitis treated during a 30-month period were found to have accompanying ventriculitis at the time of the initial ventricular puncture. Fifteen of these infants were caused by gramm-negative organisms. All infants received antibiotics systemically and intraventricularly via an implanted ventriculostomy reservoir or by direct ventricular injection. Antibiotic concentrations within the ventricular fluid were monitored during chemotherapy; the complications encountered during treatment are discussed. Fifteen infants survived the infection; of these, seven infants were normal at follow-up examinations. In our experience intraventricular chemotherapy as an adjunct to systemic administration of antibiotics has greatly reduced the mortality rate in neonatal meningitis.