Interaction between serine phosphorylated IRS-1 and beta1-integrin affects the stability of neuronal processes

Tumor necrosis factor-alpha (TNFalpha) released in the brain by HIV-activated macrophages/microglia is suspected to compromise neuronal survival. Previously, we have demonstrated that activated receptor for insulin-like growth factor I (IGF-IR) protects neurons from TNFalpha-induced neuronal damage (Wang et al. [ 2006] J. Neurosci. Res. 83:7-18). Because TNFalpha triggers phosphorylation of insulin receptor substrate 1 (IRS-1) on serine residues (pS-IRS-1; Rui et al. [ 2001] J. Clin. Invest. 107:181-189), and pS-IRS-1 binds integrins (Reiss et al. [ 2001] Oncogene 20:490-500), we asked how these events affect neuronal processes. We show that beta1-integrin and pS-IRS-1 colocalize in PC12 cells and in primary cortical neurons. TNFalpha treatment elevated membrane-associated pS-IRS-1, enhanced pS-IRS-1 interaction with beta1-integrin, and attenuated cell attachment to collagen IV. In contrast, IGF-I inhibited pS-IRS-1-beta1-integrin complexes and improved cell attachment. The domain of IRS-1 involved in beta1-integrin binding mapped between amino acids 426 and 740, and the expression of 426-740/IRS-1 mutant attenuated neuronal outgrowth. Our results indicate that TNFalpha facilitates the interaction of pS-IRS-1 and beta1-integrin and destabilizes neuronal processes. IGF-I counteracts TNFalpha-mediated accumulation of pS-IRS-1-beta1-integrin complexes supporting the stability of neuronal processes.     

An important risk factor in idiopathic generalized epilepsies

15q13.3 microdeletions increase risk of idiopathic generalized epilepsy
Helbig et al. (2009)
Nature Genetics 41(2):160–162     

Pachygyriclike changes: topographic appearance at MR imaging and CT and correlation with neurologic status

Studies of 23 pediatric patients with pachygyriclike changes (PLCs) examined with computed tomography (CT) and magnetic resonance (MR) imaging were reviewed to determine topographic patterns and correlate them with various clinical syndromes and degrees of neurologic impairment. Three types of topographic distributions were identified: unilateral, diffuse, and bilateral nondiffuse (of which eight of 10 showed frontotemporal predominance). PLCs were an isolated finding in seven patients, were associated with various congenital syndromes in nine patients, and were associated with congenital infection in seven patients, six of whom showed marked white matter abnormalities. Although most patients had severe developmental delay, three with nondiffuse PLCs had less severe impairment, permitting less required care.     

Colonic adenocarcinomas: near-infrared microcatheter imaging of smart probes for early detection--study in mice

PURPOSE: To prospectively evaluate the ability of micro-fiberoptic catheters, which simultaneously record white light and near-infrared (NIR) images, to reveal colonic neoplasms after the intravenous administration of activatable "smart" probes that increase in NIR fluorescence subsequent to protease activation. MATERIALS AND METHODS: The institutional animal care committee approved all animal experiments. CT26 tumor cells were orthotopically implanted into the descending colon of C57BL6/J mice (n=10). Thirteen days later, mice intravenously received either 2 nmol of a protease-sensing probe that had cathepsin B as a major activator (n=5) or saline (control animals [n=5]). One day later, animals were noninvasively examined to the point of the splenic flexure by using microcatheter imaging. Excised colons were subsequently evaluated with epifluorescence imaging, histologic examination, and cathepsin B immunohistochemistry. Student t test was used for statistical analysis, with P<.05 considered to indicate a significant difference. RESULTS: Results with fiberoptic imaging demonstrated that all tumors were visible with the protease-activatable probe, even when they were not readily apparent at white light imaging. A target-to-background ratio (TBR) of 8.86 for tumor to adjacent normal mucosa was achieved in the NIR channel after probe administration (P=.001), whereas white light images resulted in a TBR of 1.14 (P>.5) based on luminosity. The tumoral NIR fluorescence intensity was more than 30-fold greater in probe-injected animals than in control animals, indicating that essentially all of the signal recorded in lesions was from activatable probe administration. Results of immunohistochemistry confirmed cathepsin B overexpression in the tumor compared with adjacent mucosa. CONCLUSION: The use of NIR imaging microcatheters combined with protease-activatable smart probes results in a beacon effect that highlights tumors with high TBRs; this technique thus may be a potentially useful adjunct to white light colonoscopy in the future.