ACAT inhibitors derived from hetero-Diels-Alder cycloadducts of thioaldehydes

Acyl-CoA:cholesterol acyltransferase (ACAT) is the enzyme largely responsible for intracellular cholesterol esterification. A systemic inhibitor of ACAT is believed to be able to slow or even reverse the atherosclerotic process. Towards that goal, a series of cyclic sulfides, derived from the hetero-Diels-Alder reaction of thioaldehydes with 1,3-dienes, and bearing carboxamide substituents, were prepared and evaluated for in vitro (in several tissues and species) and ex vivo ACAT inhibition. Minor changes in subsequent structure were found to have a significant effect in optimization of the biological activity of this series of compounds.     

The lived experience of nursing students in caring for suffering individuals

Most nursing school curricula address the pathologic nature of illness, the nursing care of clients who are ill, the prevention of illness, and the promotion of health. There seems to be minimal discussion, however, both in nursing curricula and in textbooks, of the alleviation of suffering or of how nurses know that someone is suffering. The article describes a phenomenologic analysis of 12 nursing students' lived experiences of caring for individuals who were suffering. The voices of the students as they chronicled their experiences are exemplars of clinical scholarship as described in the literature.     

Haemolytic activity of Aeromonas species isolated in Libya

Twenty seven Aeromonas strains (5A. hydrophila, 8A. sobria and 14A. caviae) isolated from children with diarrhoea and 34 Aeromonas strains (9A. hydrophila, 7A. sobria an 18A. caviae) isolated from children without diarrhoea were tested from haemolysin production. The results obtained showed that haemolysin production using human, horse or sheep erythrocytes was significantly associated with A.hydrophila and A sobria but not with A.caviae, regardless of whether these strains were isolated from children with or without diarrhoea. Human or horse rather than sheep erythrocytes are recommended for use in the haemolysin assay.     

Analysis of a 2(9) full factorial chemical library

Robotic synthesis is making possible the synthesis of large, systematically designed sets of compounds. We analyze a 512-compound set that is a 2(9) full factorial experimental design using a recursive partitioning algorithm, FIRM, and a high-dimension visualization tool, TempleMVV. These techniques are used to quickly and easily identify the main trends in the data set and also identify unusual observations. We show that analytical and visualization methods can be used synergistically to analyze a large, complex, high-dimensional data set. We also show that a fractional factorial design of 128 compounds would give essentially the same information.     

Tissue fixation security in transosseous rotator cuff repairs: a mechanical comparison of simple versus mattress sutures

The primary purpose of this investigation was to compare tissue fixation security by simple sutures versus mattress sutures in transosseous rotator cuff repair. These two repair techniques were each performed in 17 human cadaver shoulders, with two bone tunnels being used for the repair by two simple sutures and two other bone tunnels being used for the repair by one mattress suture. The repairs were loaded to failure in a servohydraulic materials test system. Rotator cuff repair by simple sutures was found to be significantly stronger than repair by mattress sutures (P = .0007). The average ultimate load to failure for the simple suture construct (189.62 N) was 39.72% greater than that for the mattress suture construct (135.71 N). Most of the failures occurred by suture breakage at the knot. Load-sharing by multiple suture tails and multiple knots in the simple suture configuration likely contributed to its superior strength characteristics compared with the mattress suture configuration.     

An analysis of pH tolerance and substrate preference of isolated skeletal muscle mitochondria from Bufo marinus and Rana catesbeiana

1. The effects of varying pH and substrate on isolated skeletal muscle mitochondria from Bufo marinus and Rana catesbeiana were investigated. 2. For both species, VO2 max significantly decreased at all pH < 7.3 (P < 0.05), while maximum values were observed at a pH range of 7.3-7.6 with B. marinus maintaining a greater VO2 max than R. catesbeiana. 3. Respiratory control values (RCR) decreased significantly at all pH < 6.9 for both species (P < 0.05). 4. Isolated mitochondria from both species were maintained at pH = 7.2 and O2 consumption measured under five separate substrate conditions. 5. A rank preference was established based upon state 3 and RCR values. 6. Substrate preference was identical for both species and interspecific comparisons revealed differences in state 3 respiration and coupling.     

Dissecting cAMP binding domain A in the RIalpha subunit of cAMP-dependent protein kinase. Distinct subsites for recognition of cAMP and the catalytic subunit

The two gene-duplicated cAMP binding domains in the regulatory subunits of cAMP dependent protein kinase are each comprised of an A helix, an eight-stranded beta-barrel, and a B and C helix (1). The A domain is required for high affinity binding to C, while the B domain regulates access to the A domain. Using a combination of a yeast two-hybrid screen coupled with deletion analysis, cAMP binding domain A of RI was dissected into two structurally and functionally distinct subsites, one that binds cAMP and another that binds the C subunit. The minimum stable subdomain required for binding to C in the 1-3 micromolar range is composed of residues 94-169, while residues 236-244, mapped to the C helix of cAMP binding domain A, were defined as a second surface necessary for high affinity (5-10 nanomolar) binding to C. This portion of the C helix, due to its position directly between the two subsites, serves as a molecular switch for either a cAMP-bound conformation or a C-bound conformation and can thus modulate interactions of cAMP binding domain A with cAMP, with C, and with cAMP binding domain B.