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.     

Temperature acclimation in the crayfish: Effects on phospholipid fatty acids

Acclimation to different temperatures by a poikilothermous animal must include modification of its membrane lipids to maintain the proper physical properties. The simplest way to achieve this acclimation would seem to be by modification of the phospholipid fatty acids. In a freshwater cray-fish,Procambarus clarkii, rapid changes in the degree of unsaturation of newly synthesized phospholipid fatty acids were correlated with changes in environmental temperature, both in whole animals and in slices of hepatopancreas tissue. At 5 C, the rate of fatty acid synthesis was about half that occurring at 23 C. Hepatopancreas tissue from animals acclimated to either 5 C or 23 C, when incubated for 2 hr at 5 C, incorporated a higher percentage of exogenous [1-¹⁴C] acetate into polyunsaturated acids (27–38% of the radioactivity in total fatty acids) than when incubated at 23 C (12–14%); conversely, more saturated fatty acids were synthesized at 23 C (73–80% vs 51–73%). The higher average unsaturation of the fatty acids biosynthesized at 5 C constitutes an effective response to the animal's need for modification of lipids to maintain adequate membrane function at the lower environmental temperature. Presented at the AOCS meeting in Mexico City, Mexico, April 27–May 2, 1974. Work done at the Laboratory of Nuclear Medicine and Radiation Biology, University of California, Los Angeles, CA 90024.     

Lipid labeling with32P-orthophosphate and14C-acetate in marine copepods

Freshly collectedCalanus pacificus were maintained in sea water containing 25 μCi/ml [³²P]orthophosphate or 1 μCi/ml [¹⁴C]acetate at 10 C for 24 hr. The animals took up label from the environment and incorporated it into various lipid fractions. After incubation with [¹⁴C]acetate the order of specific activity of the different lipid classes was: phospholipids > free fatty acids > wax esters > triglycerides. Argentation thin layer chromatography of the fatty acid methyl esters showed that ca. 50% of the activity was in saturated fatty acids and 34% in polyunsaturated acids. When the animals were exposed to [³²P]orthophosphate, lysophosphatidyl choline became most heavily labeled, followed by lysophosphatidyl ethanolamine, sphingomyelin, phosphatidyl ethanolamine, and phosphatidyl choline. Comparison of the data obtained with those available for decapods and mammals revealed striking similarities between these phylogenetically distant groups. It is believed that labeling the lipids of marine and freshwater planktonic crustaceans in this way will provide much information about the metabolism of lipids in these organisms.     

Fullerene Research in the Czech Republic

Abstract

Fullerene Science and Technology, both the field and the journal, have observed considerable progress during the last few years. The field has continued to mature as witnessed by the many new and interesting results published in thousands of journal articles (1-3) and in a multitude of books and conference proceedings. The recognition of fullerene sciences as a self-containing field of research has been culminating in the awarding of the 1996 Chemistry Nobel Prize to Professors Robert S. Curl, Harold W. Kroto, and Richard E. Smailey.     

Delineation of Subsea Freshwater Extension by Marine Geoelectromagnetic Soundings (SE Mediterranean Sea)

This study presents a novel application of marine geoelectromagnetic technique, in an attempt to delineate freshwater extension of the coastal sub-aquifers beneath the SE Mediterranean Sea, along central Israel. The novel marine Ex-Bz time domain electromagnetic (TDEM) geophysical method was applied, demonstrating high sensitivity to the presence of sub-seafloor electrically resistive structures up to several kilometers offshore (shallow marine environment). The study included 19 marine measurements located offshore between Ashdod in the south to Tel-Aviv in the north, where a previous onshore study detected fresh groundwater below seawater intrusion at the coast line. The offshore measurements were conducted to distances of up to 3 km from the shoreline. It was found that the lower sub-aquifer contains fresh groundwater (resistivity >10 Ω-m) to a distance of 2.8 km offshore along the 30 km strip, and is probably constrained by lateral geo-facial changes.     

Finite element analysis of a polymer composite subjected to a sliding steel asperity Part I Normal fibre orientation

FE micro-models have been developed in order to determine contact, stress and strain conditions produced by a steel asperity sliding on the surface of a normally oriented fibre-reinforced polymer composite. A displacement coupling technique was introduced to model a micro-environment as part of a macro-environment and to get more realistic simulation results about the failure conditions in the composite structure, in comparison to the so far widely applied anisotropic analytical or numerical macro-models. On the basis of the results, conclusions may be drawn for the possible wear mechanisms of the fibre-reinforced polymer composite. Stress results in the vicinity of the fibers in the contact area show high shear loading of the matrix leading to the formation of stretched-out matrix wear debris. In addition, high repeated compression-tension stresses at the fibre/matrix interface near the surface can lead to fibre debonding phenomena. Considering the fibre ends in the contact region, high compression stresses at their rear edges can produce fibre cracking features. To study the wear mechanisms experimentally, a single asperity scratch test was also performed showing shear failure events of the polymer matrix, fibre/matrix debonding and fibre cracking effects, as expected from the modelling studies.     

Occurrence and type of traumatic experiences among young Bosnian refugees in Denmark

Prior research has shown that young refugees may be especially traumatised. The study includes 123 young Bosnian refugees, living at two Bosnian boarding-schools in Denmark who were given a revised version of the Harvard Trauma Questionnaire (HTQ). The subjects themselves have on average experienced seven traumatic events, and have either witnessed or had a family member experience an additional six events. Three-quarters have been shot at, have lost their homes and private possession and have been exposed to violence in the form of harassment or humiliation. Two-thirds have lost friends. Three-fifths have lived with uncertainty as to whether friends and family were alive or dead. More than half have seen dead and wounded people, have had their lives threatened and have thought that they would die. More than a third have lost close family members, have been wounded and have had their homes destroyed. Just under a third have been exposed to physical violence or have witnessed somebody being killed. A quarter have starved and been ill without being able to receive treatment. About a fifth have experienced captivity, torture and forced labour. 6% have been raped or exposed to other forms of sexual abuse. It is concluded that the young Bosnians examined are a multitraumatised group. Use of the HTQ increased the number of traumatic events quite considerably compared to the case notes.