Potent piperazine hydroxyethylamine HIV protease inhibitors containing novel P3 ligands

The 2-isopropyl thiazolyl group is a highly optimized P3 ligand for C2 symmetry-based HIV protease inhibitors, as exemplified in the drug ritonavir. Here we report that incorporation of this P3 ligand into a piperazine hydroxyethylamine series also yielded novel, highly potent inhibitors. In tissue culture assays, the presence of human serum was less deleterious to the activity of these inhibitors than to that of ritonavir. Furthermore, potent activity against ritonavir resistant HIV was observed.     

Networking,Storytelling and Knowledge Production in First-Year Writing

As writing teachers, we seek to validate the knowledge that students bring to the classroom while introducing and cultivating new methods, strategies, techniques and technologies that may serve them now and in the future. In this article we describe an approach we take that integrates curricular and extracurricular co-apprenticeship strategies using public writing models in conjunction with social networking tools. With publication as a final goal, we urge students to move from expressing personal problems to addressing social issues, using a private, non-commercial learning network NoDiff <http://NoDiff.com> as a safe zone for skills development, knowledge production and social inquiry. In taking this approach, we resist dichotomies that place professional skills training in strict opposition to critical pedagogy. We argue that many of the so-called “extracurricular” composing activities that most of today's students engage in lay the groundwork for both professional and civic participation. Acknowledging that we as composition teachers are also beginners in the world of 21^st century communication, we emphasize both (1) the continual transference of skills and knowledge among teachers and learners; and (2) the importance of providing what is often lacking in skills-based ‘new literacy’ training, namely a critical pedagogical approach to learning as social engagement and critical intervention.     

Effects of early-postmortem glycolytic rate on beef tenderness

Electrical stimulation (ES) was applied at 500 V to one side from each of 60 beef carcasses at 30 to 40 min postmortem. Wide ranges of early-postmortem glycolytic and cooling rates were produced in the musculature by use of three different forms of ES (in addition to non-ES treatment of the contralateral sides) and application of chilling routines of four different degrees of severity. Panel and Warner-Bratzler shear evaluations of loin steaks from all 120 sides showed that tenderness was highest when glycolysis had proceeded at an intermediate rate (corresponding to the attainment of a 3-h pH of about 6·1) and was appreciably lower on both sides of this mid-value. The toughening effect of rapid glycolysis (relative to that of a moderately increased glycolytic rate) persisted through 14 days of aging at 2°C.

These observations appear to be incompatible with the view that lysosomal enzymes contribute significantly to ES-induced tenderization. They also indicate that the effect of ES on tenderness is highly dependent on the subsequent cooling rate, very slow chilling sometimes accelerating the already high rate of pH fall to such an extent that the tissue is significantly toughened. Finally, they suggest that the goal of maximizing the early-postmortem rate of pH decline in bovine muscle is misguided and, if attained, will cause sub-optimal tenderness.     

Effects of 2-Hz and 60-Hz electrical stimulation on the microstructure of beef

A comparative electron-microscope study was made of the structural changes brought about in bovine longissimus dorsi muscle by 2-Hz and 60-Hz electrical stimulation. Apart from the frequency difference, the two treatments were identical: 500V AC, 600 pulses (2Hz × 300s and 60 Hz × 10 s), and a time of application of about 40 min post mortem. The low-frequency current produced no detectable tissue disruption or irregularity in sarcomere length, whereas the 60-Hz treatment caused widespread supercontraction and the formation of contraction nodes; many sarcomeres in the internodal zones were stretched or fractured. The observations confirm and extend those of our earlier light-microscope study, and support the view that fiber disruption contributes significantly to the tenderizing effect of high-voltage electrical stimulation.     

Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

The discovery of novel intronic variants in the ABCA4 locus has contributed significantly to solving the missing heritability in Stargardt disease (STGD1). The increasing number of variants affecting pre-mRNA splicing makes ABCA4 a suitable candidate for antisense oligonucleotide (AON)-based splicing modulation therapies. In this study, AON-based splicing modulation was assessed for 15 recently described intronic variants (three near-exon and 12 deep-intronic variants). In total, 26 AONs were designed and tested in vitro using a midigene-based splice system. Overall, partial or complete splicing correction was observed for two variants causing exon elongation and all variants causing pseudoexon inclusion. Together, our results confirm the high potential of AONs for the development of future RNA therapies to correct splicing defects causing STGD1.     

The effect of cavity-filling mutations on the thermostability of Bacillus stearothermophilus neutral protease

Cavities in the hydrophobic core of the neutral protease ofBacillus stearothermophilus were analyzed using a threedimensionalmodel that was inferred from the crystal structure of thermolysin,the highly homologous neutral protease of B.thermoproteolyticus(85% sequence identity). Site–directed mutagenesis wasused to fill some of these cavities, thereby improving hydrophobicpacking in the protein interior. The mutations had small effectson the thermostability, even after drastic changes, such asLeu284Trp and Met168Trp. The effects on T50, the temperatureat which 50% of the enzyme is irreversibly inactivated in 30min, ranged from 0.0 to +0.4°C. These results can be explainedby assuming that the mutations have positive and negative structuraleffects of approximately the same magnitude. Alternatively,it could be envisaged that the local unfolding steps, whichrender the enzyme susceptible towards autolysis and which arerate limiting in the process of thermal inactivation, are onlyslightly affected by alterations in the hydrophobic core.     

Carbonization and liquid-crystal (mesophase) development. 12. Mechanisms of the co-carbonization of coals with organic additives

In industrial situations, coals interact with solvents or additives to produce liquid fuels, solvent-refined coal, coal extract and metallurgical coke. In these processes there occurs a wide variation in effects or modifications of the coal by these additives. This paper describes the modifications which can occur, using a wide range of rank of coal, when these coals interact and are co-carbonized with a wide range of additives of different chemical properties. The optical texture of the resultant cokes is given special attention. The objective of the paper is to summarize the current state of knowledge of the mechanisms of these interactions. Possible mechanisms of interactions are summarized, kinetic and chemical structural aspects of reactions are outlined, the importance is mentioned of the formation of liquid phases enabling anisotropic optical textures in modified cokes to be created, and the industrial relevance of its possible development is discussed.     

Carbonization and liquid—crystal (mesophase) development. 19. Co-carbonization of oxidized coals with model organic compounds

This study examines further the phenomena of the modification of coal carbonizations by organic additives. Anthracene, pyrene and chrysene modify the carbonization in a closed system of coking coals as observed from increases in the size of optical textures of resultant cokes. Weakly caking coals are unaffected. Chrysene is the most efficient modifier probably because of its lowest calculated free valence. The co-additives tetralin and hydrogenated anthracene oil further enhance the modification processes so obviating the necessity to use hydrogenated additives. Co-carbonizations of oxidized coking and caking coals with decacyclene are effective in removing the effects of mild oxidation. Increased rates of carbonization enhance the sizes of optical textures of resultant cokes.     

Carbonization and liquid-crystal (mesophase) development. 8. The co-carbonization of coals with acenaphthylene and decacyclene

Several coals of different rank have been carbonized singly and also co-carbonized with acenaphthylene and decacyclene. The resultant cokes were mounted in resin and polished surfaces were examined for optical texture using a polarized-light optical microscope fitted with a half-wave retarder plate. The optical texture can be assessed qualitatively (visually) or quantitatively by a point-counting technique in terms of size and shape of constituent isochromatic anisotropic units. Some cokes from coals were Isotropic. Acenaphthylene was only able to exert a smaller influence than decacyclene on the optical texture of the resultant cokes from co-carbonizations. Decacyclene was able to modify the optical texture for both the low-rank non-fusible and the caking coals. The effects of changing the proportions of coal to additive were examined. Results are interpreted in terms of ‘depolymerization’ of the coal by the action of the additive (as solvent) and also by the action of the additive in modifying the processes of formation of semi-coke via nematic liquid crystals.     

Aspects of gasification and structure in cokes from coals

Cokes were prepared from nine coals of different rank and characterized by surface area measurement, reactivity to carbon dioxide at 1473K and Raman-laser spectroscopy. Rates of gasification of cokes on a unit surlface area basis (K¹ = g m^?2 min^?1) decreased with increasing rank of parent coal based on maximum oil reflectances. However rates of gasification could not be related to coke structure as measured by Raman-laser spectroscopy.