Involvement of the Src homology 2-containing tyrosine phosphatase SHP-2 in growth hormone signaling

Growth hormone (GH) signaling requires activation of the GH receptor (GHR)-associated tyrosine kinase, JAK2. JAK2 activation by GH is believed to facilitate initiation of various pathways including the Ras, mitogen-activated protein kinase, STAT, insulin receptor substrate (IRS), and phosphatidylinositol 3-kinase systems. In the present study, we explore the biochemical and functional involvement of the Src homology 2 (SH2)-containing protein-tyrosine phosphatase, SHP-2, in GH signaling. GH stimulation of murine NIH 3T3-F442A fibroblasts, cells that homologously express GHRs, resulted in tyrosine phosphorylation of SHP-2. As assessed specifically by anti-SHP-2 coimmunoprecipitation and by affinity precipitation with a glutathione S-transferase fusion protein incorporating the SH2 domains of SHP-2, GH induced formation of a complex of tyrosine phosphoproteins including SHP-2, GHR, JAK2, and a glycoprotein with properties consistent with being a SIRP-alpha-like molecule. A reciprocal binding assay using IM-9 cells as a source of SHP-1 and SHP-2 revealed specific association of SHP-2 (but not SHP-1) with a glutathione S-transferase fusion incorporating GHR cytoplasmic domain residues 485-620, but only if the fusion was first rendered tyrosine-phosphorylated. GH-dependent tyrosine phosphorylation of SHP-2 was also observed in murine 32D cells (which lack IRS-1 and -2) stably transfected with the GHR. Further, GH-dependent anti-SHP-2 coimmunoprecipitation of the Grb2 adapter protein was detected in both 3T3-F442A and 32D-rGHR cells, indicating that biochemical involvement of SHP-2 in GH signaling may not require IRS-1 or -2. Finally, GH-induced transactivation of a c-Fos enhancer-driven luciferase reporter in GHR- and JAK2-transfected COS-7 cells was significantly reduced when a catalytically inactive SHP-2 mutant (but not wild-type SHP-2) was coexpressed; in contrast, expression of a catalytically inactive SHP-1 mutant allowed modestly enhanced GH-induced transactivation of the reporter in comparison with that found with expression of wild-type SHP-1. Collectively, these biochemical and functional data imply a positive role for SHP-2 in GH signaling.     

The effects of DSM-IV cluster B personality disorder symptoms on the termination and continuation of psychotherapy.

This study investigates the relationship between therapy attendance with DSM-IV criteria for the cluster B personality disorders (antisocial [ANPD]; borderline [BPD]; histrionic [HPD]; and narcissistic [NPD]). Ninety patients who were found to meet DSM-IV criteria for an Axis II disorder (cluster A personality disorders?=?10; ANPD?=?20, BPD?=?25, HPD?=?5, NPD?=?14; cluster C personality disorders?=?16). Total number of DSM-IV criteria for BPD (r?=?.33, p?=?.001) and ANPD (r?=?–.22, p?=?.04) were significantly related to the number of psychotherapy sessions attended by a patient. Stepwise regression indicated that the 5 individual criteria BPD-1, NPD-4, BPD-8, HPD-8, and ANPD-7 (in order of entry into the regression equation) were independent and nonredundant predictors that explained 31% of variance found in the number of psychotherapy sessions attended by patients. The presence or absence of 3 of these individual criteria provided a good balance of positive predictive power (.78–.95) and overall correct classification rate (.53–.69) for therapy continuation. Clinical and research implications of personality characteristics are discussed in relation to the termination and continuation of psychotherapy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Efficient approaches to testing VHDL DSP models

Generation of test benches for large DSP behavioral models is a complicated, labor intensive task. Also, tests generated manually satisfy no formal definition of completeness. To address these needs, high level approaches to test bench development are employed which relieve the modeler of the details of this task. High level design tools are used to develop the test bench VHDL code. The test bench code models sensors which drive the Model Under Test (MUT). Data files which can also drive the MUT are prepared by environmental data generators. The system specification values are linked to the testbench via requirements capture tools and test plans. Intelligent interfaces are used to control the development and simulation of the test bench. The approach is applicable to the testing of any DSP system modeled in the VHDL language. It provides the modeler with the capability to rapidly test DSP models and adjust the model test environment to frequent changes in system requirements.Material in this paper was previously presented at the 1 st Annual RASSP Conference, Arlington, Virginia, August 16, 1994, at the 2nd Annual RASSP Conference, Arlington, VA, July 1995, and at the Spring 1995 VHDL International Users Forum in San Diego, CA.     

Mechanism of activation for Zap-70 catalytic activity

There is a growing body of evidence, including data from human genetic and T-cell receptor function studies, which implicate a zeta-associated protein of M(r) 70,000 (Zap-70) as a critical protein tyrosine kinase in T-cell activation and development. During T-cell activation, Zap-70 becomes associated via its src homology type 2 (SH2) domains with tyrosine-phosphorylated immune-receptor tyrosine activating motif (ITAM) sequences in the cytoplasmic zeta chain of the T-cell receptor. An intriguing conundrum is how Zap-70 is catalytically activated for downstream phosphorylation events. To address this question, we have used purified Zap-70, tyrosine phosphorylated glutathione S-transferase (GST)-Zeta, and GST-Zeta-1 cytoplasmic domains, and various forms of ITAM-containing peptides to see what effect binding of zeta had upon Zap-70 tyrosine kinase activity. The catalytic activity of Zap-70 with respect to autophosphorylation increased approximately 5-fold in the presence of 125 nM phosphorylated GST-Zeta or GST-Zeta-1 cytoplasmic domain. A 20-fold activity increase was observed for phosphorylation of an exogenous substrate. Both activity increases showed a GST-Zeta concentration dependence. The increase in activity was not produced with nonphosphorylated GST-Zeta, phosphorylated zeta, or phosphorylated ITAM-containing peptides. The increase in Zap-70 activity was SH2 mediated and was inhibited by phenylphosphate, Zap-70 SH2, and an antibody specific for Zap-70 SH2 domains. Since GST-Zeta and GST-Zeta-1 exist as dimers, the data suggest Zap-70 is activated upon binding a dimeric form of phosphorylated zeta and not by peptide fragments containing a single phosphorylated ITAM. Taken together, these data indicate that the catalytic activity of Zap-70 is most likely activated by a trans-phosphorylation mechanism.     

Sigmund Koch (1917–1996): Obituary.

Memorializes Sigmund Koch. Although dismissive of grand systems, on both principled and empirical grounds, Koch indicated ways in which psychologists can realize the kind of sensibility-based, context-dependent, finely textured insights that can result from authentic probing of human experience. His own inquiries into a perceptual theory of definition, the nature of objective value-properties, and the processes of creative activity in the arts illustrate the sort of qualitative, philosophically informed, and empirically grounded investigations that should be central to what he christened "the psychological studies." (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Psychiatric comorbidity, health status, and functional impairment associated with alcohol abuse and dependence in primary care patients: Findings of the PRIME MD-1000 study.

The psychiatric comorbidity, health, and functioning of primary care patients with alcohol abuse and dependence (AAD) was investigated in a sample of 1,000 patients. Psychiatric symptomatology was assessed with the Primary Care Evaluation of Mental Disorders (PRIME-MD) diagnostic system. Health and functional status was assessed with the Medical Outcomes Study Short Form General Health Survey (SF-20). Results indicated that use of the PRIME-MD system brought about a 71% increase in physician recognition of AAD. AAD patients were diagnosed with substantial psychiatric comorbidity, and they reported poorer health and functioning than did patients without any psychiatric disorders. However, they reported less impairment and psychiatric comorbidity than did patients with other psychiatric disorders. Results also indicated that AAD patients' health and functioning were associated with the presence or absence of psychiatric comorbidity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)