Potent inhibitors of secretory phospholipase A2: synthesis and inhibitory activities of indolizine and indene derivatives

Phospholipase A2 is an enzyme which hydrolyzes the sn-2 position of certain cellular phospholipids. The liberated lysophospholipid and arachidonic acid are precursors in the biosynthesis of various biologically active products. As human nonpancreatic sPLA2 is present in high levels in the blood of patients in several pathological conditions, the potent sPLA2 inhibitors have been suggested to be useful drugs. Here we describe the synthesis, structure-activity relationship, and inhibitory activities of indolizine and indene derivatives. 1-(Carbamoylmethyl)indolizine derivatives and 1-oxamoylindolizine derivatives exhibited very potent inhibitory activity. The former was unstable to air oxidation, but the latter exhibited an improvement both in stability and in potency. Some compounds approached the stoichiometric limit of the chromogenic assay.     

A 0.8-dB insertion-loss, 17.4-dBm power-handling, 5-GHz transmit/receive switch with DETs in a 0.18-/spl mu/m CMOS process

An optimized single-pole double-throw (SPDT) transmit/receive (T/R) switch has been fabricated using depletion-layer-extended transistors (DETs) in a 0.18 /spl mu/m CMOS process. The switch features the highest performance to date of any switch using a CMOS process, of a 0.8 dB insertion-loss, 23 dB isolation and 17.4 dBm power-handling capability at 5 GHz. The low insertion-loss has been achieved with the effects of junction capacitance decrease and substrate resistance increase in the DET, the adoption of low-loss shielded-pads, and several layout optimizations. The high power-handling capability is owing to the combined effect of the adoption of the source/drain dc biasing scheme and the high substrate resistance in the DET.     

Accumulation of genetic alterations and their significance in each primary human cancer and cell line

Analyses of multiple genetic alterations accumulated in each cancer cell is expected to provide useful information to elucidate the molecular mechanisms involved in tumorigenesis. Here, we summarized the results of studies on aberrations of oncogenes and tumor suppressor genes by ourselves and other groups. DNAs analyzed were from particular sets of surgical specimens from human tumors and cancer cell lines derived from non-small cell lung cancers, pancreatic cancers, hepatocellular carcinomas and gliomas. Tumors could be grouped into two types based on the genetic alterations detected. Tumors in group 1 had mutations in genes encoding proteins involved in a limited number of signal transduction cascades such as p16-cyclin D1/CDK4-RB or MDM2-p53-p21, where the aberration of one component seems to be sufficient to cause dysfunction of the cascade. Group 2 contained a subset of tumors in which no alteration was detected in the genes analyzed, even in the advanced stage or established cancer cells, indicating the involvement of completely different oncogenic pathways.     

Evaluation of learning and memory dysfunction and histological findings in rats with chronic stage contusion and diffuse axonal injury

Enantiomer separations of various acidic racemates were performed by capillary electrophoresis (CE) using a commercial cationic beta-cyclodextrin (beta-CD), quaternary ammonium beta-CD (QA-beta-CD), and a commercial amphoteric beta-CD (AM-beta-CD) as chiral selectors. Eleven acidic racemates were successfully separated using QA-beta-CD by changing the CD concentration and the buffer pH. These enantiomer separations were compared with the results using five neutral CD derivatives. Although most racemates were separated with some of the neutral CDs, relatively high CD concentrations were required to obtain baseline separations. In contrast, when QA-beta-CD was employed, the enantiomer separations were successful at low concentrations below 5 mM. Enantiomers of five acidic racemates and ten dansylated amino acids (Dns-amino acids) were separated using AM-beta-CD. Although the baseline separation of racemic 4-chloromandelic acid was not achieved with either QA-beta-CD or five neutral CDs, AM-beta-CD showed complete resolution. Furthermore, the simultaneous enantiomer separation of eight Dns-amino acids was also achieved with AM-beta-CD. Both QA-beta-CD and AM-beta-CD were analyzed by CE and mass spectrometry (MS) in order to identify their compositions because they consisted of a mixture having different degrees of substitution. QA-beta-CD consisted of six components having from one to six quaternary ammonium groups. The composition of AM-beta-CD, however, was very complicated and could not be identified.     

The lubricating ability of biomembrane models with dipalmitoyl phosphatidylcholine and gamma-globulin

This paper describes the process of involving health professions students in research in rural primary care and how their research has contributed to the development and expansion of a rural community health center. Since 1978 over 400 students have completed rotations at the center, and more than 200 have been health profession students, including medical, nursing, physician assistant, pharmacy, and health administration students. A total of 96 research projects were completed. These projects lie in two main areas: medical services and community outreach. Those related to medical services include measures of access to care, quality of care audits, clinical guideline development, practice patterns, prevalence studies, and qualitative research. Projects focusing on community outreach include community surveys, screening follow-ups, program evaluation, and program development. Principles that guide the selection and conduct of research projects include: Projects should be directly related to important work of the practice and reflect an interest of the student; projects are structured to include some or all of the following: literature search, data analysis, a visual display of quantitative information (table or graph), and application of relevant statistical tools; the student has a project supervisor; the student is a participant rather than an independent investigator; and a research flow sheet is used to orient students and NRHA staff to the larger research effort. Students are expected to present results, conclusions and recommendations to an appropriate group. Student research has made a significant contribution to both practice activities and practice policies.     

Analysis of a 36.2 kb DNA sequence including the right telomere of chromosome VI from Saccharomyces cerevisiae

The nucleotide sequence of a 36.2-kb distal region containing the right telomere of chromosome VI was determined. Both strands of DNA cloned into cosmid clone 9965 and plasmid clone pEL174P2 were sequenced with an average redundancy of 7.9 per base pair, by both dye primer and dye terminator cycle sequencing methods. The G+C content of the sequence was found to be 37.9%. Eighteen open reading frames (ORFs) longer than 100 amino acids were detected. Four of these ORFs (9965orfR017, 9965orfF016, 9965orfR009 and 9965orfF003) were found to encode previously identified genes (YMR31, PRE4, NIN1 and HXK1, respectively). Six ORFs (9965orfR013, 9965orfF018, 9965orfF006, 9965orfR014, 9965orfF013 and 9965orfR020) were found to be homologous to hypothetical 121.4-kDa protein in the BCK 5' region, Bacillus subtilis DnaJ protein, hypothetical Trp-Asp repeats containing protein in DBP3-MRPL27, putative mitochondrial carrier YBR291C protein, Salmonella typhimurium nicotinate-nucleotide pyrophosphorylase, and Escherichia coli cystathionine beta-lyase, respectively. The putative proteins encoded by 9965orfF018, 9965orfR014 and 9965orfR020 were found to be, respectively, a new member of the family of DnaJ-like proteins, the mitochondrial carrier protein and cystathionine lyase.