The 2.35 A crystal structure of the inactivated form of chicken Src: a dynamic molecule with multiple regulatory interactions

The Src protein tyrosine kinase plays a critical role in a variety of signal transduction pathways. Strict regulation of its activity is necessary for proper signalling. We present here the crystal structure of chicken Src which is phosphorylated at Tyr527 and represents its least active form. Our structure, similar to the recently reported human Hck and Src structures, contains the SH3, SH2 and the kinase domains and the C-terminal regulatory tail but not the N-terminal unique domain. The SH3 domain uses its hydrophobic surface to coordinate the SH2-kinase linker such that residues Gln251 and Leu255 specifically interact with side chains in the beta2-beta3 and the alphaC-beta4 loops of the N-terminal lobe opposite of the kinase active site. This position of the SH3 domain and the coordination of the SH2-kinase linker also optimally places the SH2 domain such that the phosphorylated Tyr527 in the C-terminal tail interacts with the SH2 binding pocket. Analogous to Cdk2 kinase, the position of the Src alphaC-helix in the N-terminal lobe is swung out disrupting the position of the active site residues. Superposition of other protein kinases including human Hck and Src onto chicken Src indicate that the alphaC-helix position is affected by the relative position of the N-terminal lobe with respect to the C-terminal lobe of the kinase and that the presence of the SH3/SH2-kinase linker/N-terminal lobe interactions restricts the kinase lobes and alphaC-helix access to the active conformation. These superpositions also suggest that the highly conserved alphaC-beta4 loop restricts the conformational freedom of the N-terminal lobe by anchoring it to the C-terminal lobe. Finally, based on sequence alignments and conservation of hydrophobic residues in the Src SH2-kinase linker as well as in the alphaC-beta4 and beta2-beta3 loops, we propose that the Src-related kinases, Abl, Btk and Csk, share the same quaternary structure.     

Extracellular cellulase system of a thermotolerant streptomycete: Streptomyces albaduncus

In this study we compared viewer-centered (VC) with object-centered (OC) mental exploration of an imagined clock drawn on the ground. An upper case F portrayed on a computer screen was to be imagined standing up in the center of the clock. In Expt. 1, an adjustment task was used to verify that the discrimination of clock directions rendered by this perspective drawing was quite accurate. Precision was not affected by the imaginary size of the clock. In Expt. 2, subjects either (1) indicated the clock location pointed by the F given their viewing position (VC condition), or (2) their location at the periphery of the clock given the location pointed by the F (OC condition). Response latencies were proportional to the explored imaginary distance and increased with the size of the imagined environment. We found an additional mean processing time of at least 2 s in the OC condition with respect to the VC condition. Results are interpreted within Kosslyn's (Kosslyn, S.M., A cognitive neuroscience of visual cognition: further developments. In: R.H. Logie and M. Denis (Eds.), Mental Images in Human Cognition, Elsevier Science Publishers, Amsterdam, 1991, pp. 351-381 [17]) framework of cognitive neuroscience.     

Late displacement of a fracture dislocation at the lumbosacral junction. A case study

STUDY DESIGN: This is a retrospective single-patient case report with a literature review. OBJECTIVE: To report on an uncommon injury: traumatic fracture-dislocation of the lumbosacral junction with delayed displacement. SUMMARY OF BACKGROUND DATA: Only 31 cases of traumatic fracture-dislocation of the lumbosacral junction were found in the English literature. Only three previous reports refer to this injury occurring with a posterior displacement. This is the first report of this type of injury displacing in a delayed manner. METHODS: Chart review. RESULTS: Open reduction, Arbeitsgemeinschaft fur Osteosynthesefargen instrumentation, and interbody fusion resulted in a satisfactory clinical result with no neurologic impairment. CONCLUSIONS: The present study reports a very rare injury consisting of traumatic dislocation of the lumbosacral joint, presenting with displacement 2 months after injury. The patient was treated successfully with surgery even though the injury displaced in a delayed fashion.     

Hereditary cancer risk notification and testing: how interested is the general population?

PURPOSE: Great interest in predictive testing for hereditary cancer syndromes has been reported. Prior research has focused on testing for specific hereditary syndromes and/or among individuals at high risk for positive carrier status. Given anticipated expansion of both the range of hereditary syndromes for which testing will be available, as well as the clinical settings in which testing will occur, assessment of interest in hereditary cancer risk testing and notification in the general public is warranted. METHODS: As part of an annual statewide telephone survey, adults' (N = 654) interest in hereditary cancer risk testing and notification was assessed. RESULTS: Interest in both risk testing (82%) and risk notification (87%) was high. Logistic regression analyses indicated that disinterest in risk notification was associated with female sex, performance of fewer health protective behaviors, and better perceptions of personal health. Disinterest in risk testing was associated with these same variables as well as older age, less concern over developing cancer, and a more extensive history of cancer in first degree relatives. CONCLUSION: In the absence of risk-reducing behaviors with demonstrable efficacy, hereditary risk testing programs may have difficulty attracting the interest of those at greatest risk for carrier status. In contrast, many individuals at low risk for positive carrier status might seek testing, perhaps as a means of seeking reassurance regarding their low hereditary risk.     

Parenteral iron therapy: indications and safety

Bone marrow necrosis (BMN) is a relatively rare entity and has been associated with a poor prognosis. It is most commonly found in patients with neoplastic disorders, severe infections and sickle cell anemia. An unusual case of antiphospholipid syndrome (APS) with extensive bone marrow necrosis is described in a 27 year old woman. The patient presented with severe pancytopenia, some cognitive impairment resulting from a previous cerebrovascular accident, fever, hypertension, dyspnoea, tachycardia, hepatosplenomegaly, and vaginal bleeding. Her laboratory findings included a strongly positive Coombs' test (anti-IgG and anti-C3d), a prothrombin time of 23 seconds and an activated partial thromboplastin time of 45 seconds. Anticardiolipin antibody tests were positive. Antinuclear and anti-DNA antibodies were negative but the anti-SM test was positive. A bone marrow biopsy specimen was reported as showing extensive necrosis. The patient was treated with steroids, transfusion, and plasma exchange with some clinical improvement but her pancytopenia did not respond and necessitated frequent transfusions. This case lends further support to the association between APS and BMN.     

The proteins synaptotagmin and syntaxin are not general targets of Lambert-Eaton myasthenic syndrome autoantibody

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neuromuscular disease in which impairment of Ca2+ entry into the nerve ending and consequent impaired release of acetylcholine (ACh) results in muscle weakness. The identity of the primary antigenic target molecule(s) of the autoantibodies is uncertain. Electrophysiological studies and 45Ca2+ uptake studies implicate a direct effect on the Ca2+ channel complex at the motor nerve terminal. Some recent studies, however, suggest a more indirect interference caused by binding of autoantibodies to synaptotagmin or syntaxin, molecules presumed to be involved in docking and/or coupling the synaptic vesicles to the Ca2+ channels in the active zone for vesicle exocytosis and transmitter release. Western blot analyses of rat and human brain membrane proteins and pure recombinant synaptotagmin and syntaxin were used to examine directly the targets of LEMS autoantibodies and determine specifically whether or not synaptotagmin and/or syntaxin were general targets in LEMS. IgG from 14 patients with LEMS was used to probe western blots of gels containing synaptotagmin, syntaxin, rat synaptosomal proteins, and human brain membrane proteins. Several similar immunoreactive bands were observed using both rat and human brain membranes. These include high-molecular-weight protein bands whose size would be consistent with being components of Ca2+ channels. No reactive component was observed against either syntaxin or synaptotagmin in IgG of the 14 LEMS patients. However, both human and rat brain membranes contain proteins recognized by antibodies directed against synaptotagmin or syntaxin, indicating their immunologic relatedness and evolutionary conservation. These results suggest that large-molecular-weight proteins consistent with being Ca2+ channel subunits rather than syntaxin and synaptotagmin are general targets of LEMS autoantibodies.     

UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins

When nasoseptal dislocation or deviation contributes to nasal obstruction or external deformity, successful nasal surgery should include septal restructuring, maintenance or restoration of adequate nasal support, and stabilization of the reconstructed elements.