BiP maintains the permeability barrier of the ER membrane by sealing the lumenal end of the translocon pore before and early in translocation

Secretory proteins are cotranslationally translocated across the mammalian ER membrane through an aqueous pore in the translocon while the permeability barrier is maintained by a tight ribosome-membrane junction. The lumenal end of the pore is also blocked early in translocation. Extraction of soluble lumenal proteins from microsomes and reconstitution with purified proteins demonstrate, by fluorescence collisional quenching, that BiP seals the lumenal end of this pore. BiP also seals translocons that are assembled but are not engaged in translocation. These ribosome-free translocons have smaller pores (9-15 A diameter versus 40-60 A in functioning translocons) and are generated when ribosomes dissociate from functioning translocons with large pores. BiP therefore maintains the permeability barrier by sealing both nontranslocating and newly targeted translocons.     

1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma

Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.     

Coupling protein stability and protein function in Escherichia coli CspA

Idiopathic thrombocytopenic purpura (ITP, also known as immune thrombocytopenic purpura) in adults is principally a disease of young women. Although in some patients the onset is acute and complete resolution occurs, in most patients, the onset is insidious and the course is chronic. In spite of the relative frequency of ITP, there are important unresolved issues in its diagnosis and management. For this reason, the American Society of Hematology (ASH) chose ITP as the disease topic for its initial sponsored practice guideline in 1993. A major conclusion of the published guideline was the lack of firm evidence on which to base diagnostic procedures and management strategies. This review describes the clinical features of ITP in adults, emphasizes the principal unresolved issues in diagnosis and management, and outlines the critical areas for future research.     

Prevention of T cell anergy by signaling through the gamma c chain of the IL-2 receptor

When stimulated through their antigen receptor without requisite costimulation, T cells enter a state of antigen-specific unresponsiveness termed anergy. In this study, signaling through the common gamma chain of the interleukin-2 (IL-2), IL-4, and IL-7 receptors in the presence of antigen was found to be sufficient to prevent the induction of anergy. After culture with IL-2, IL-4, or IL-7, Jak3 kinase was tyrosine-phosphorylated, which correlated with the prevention of anergy. Therefore, a signal through the common gamma chain may regulate the decision of T cells to either clonally expand or enter a state of anergy.     

Shivering in patients recovering from CABG

Thirty-eight patients diagnosed as having continuous schizophrenia progrediens, 35 patients with shift-like schizophrenia and six patients with hypertoxic (feverish) schizophrenia were studied. The examinees displayed a marked increase in the blood content of lipid peroxidation products, such as malonic dialdehyde and conjugated dienes, together with an enhancement of the degree of erytrocytolysis, which events are particularly noticeable in hypertoxic- and continuous schizophrenia. Blood catalase activity gets higher, that of superoxide dismutase is on the decrease, which facts suggest to us some faults in the system of antioxidant defence.     

A new metal-binding site in photosynthetic bacterial reaction centers that modulates QA to QB electron transfer

Isolated reaction centers (RCs) from Rhodobacter sphaeroides were found to bind Zn(II) stoichiometrically and reversibly in addition to the 1 equiv of non-heme Fe(II). Metal and EPR analyses confirm that Zn(II) is ligated to a binding site that is distinct from the Fe site. When Zn(II) is bound to this site, electron transfer between the quinones QA and QB (QA-QB --> QAQB-) is slowed and the room-temperature kinetics become distributed across the microsecond to millisecond time domain. This effect of metal binding on the kinetics is similar to the more global effect of cooling RCs to 2 degreesC in the absence of Zn(II). This suggests that Zn(II) binding alters localized protein motions that are necessary for rapid QA-QB --> QAQB- electron transfer. Inspection of the RC crystal structure suggests a cluster of histidine ligands located beneath the QB binding pocket as a potential binding site.