Synapse elimination and learning rules co-regulated by MHC class I H2-Db.

The formation of precise connections between retina and lateral geniculate nucleus (LGN) involves the activity-dependent elimination of some synapses, with strengthening and retention of others. Here we show that the major histocompatibility complex (MHC) class I molecule H2-D(b) is necessary and sufficient for synapse elimination in the retinogeniculate system. In mice lacking both H2-K(b) and H2-D(b) (K(b)D(b)(-/-)), despite intact retinal activity and basal synaptic transmission, the developmentally regulated decrease in functional convergence of retinal ganglion cell synaptic inputs to LGN neurons fails and eye-specific layers do not form. Neuronal expression of just H2-D(b) in K(b)D(b)(-/-) mice rescues both synapse elimination and eye-specific segregation despite a compromised immune system. When patterns of stimulation mimicking endogenous retinal waves are used to probe synaptic learning rules at retinogeniculate synapses, long-term potentiation (LTP) is intact but long-term depression (LTD) is impaired in K(b)D(b)(-/-) mice. This change is due to an increase in Ca(2+)-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Restoring H2-D(b) to K(b)D(b)(-/-) neurons renders AMPA receptors Ca(2+) impermeable and rescues LTD. These observations reveal an MHC-class-I-mediated link between developmental synapse pruning and balanced synaptic learning rules enabling both LTD and LTP, and demonstrate a direct requirement for H2-D(b) in functional and structural synapse pruning in CNS neurons

Early Endarterectomy Carries a Lower Procedural Risk Than Early Stenting in Patients With Symptomatic Stenosis of the Internal Carotid Artery: Results From 4 Randomized Controlled Trials.

BACKGROUND AND PURPOSE: Patients undergoing carotid endarterectomy (CEA) for symptomatic stenosis of the internal carotid artery benefit from early intervention. Heterogeneous data are available on the influence of timing of carotid artery stenting (CAS) on procedural risk. METHODS: We investigated the association between timing of treatment (0-7 days and >7 days after the qualifying neurological event) and the 30-day risk of stroke or death after CAS or CEA in a pooled analysis of individual patient data from 4 randomized trials by the Carotid Stenosis Trialists' Collaboration. Analyses were done per protocol. To obtain combined estimates, logistic mixed models were applied. RESULTS: Among a total of 4138 patients, a minority received their allocated treatment within 7 days after symptom onset (14% CAS versus 11% CEA). Among patients treated within 1 week of symptoms, those treated by CAS had a higher risk of stroke or death compared with those treated with CEA: 8.3% versus 1.3%, risk ratio, 6.7; 95% confidence interval, 2.1 to 21.9 (adjusted for age at treatment, sex, and type of qualifying event). For interventions after 1 week, CAS was also more hazardous than CEA: 7.1% versus 3.6%, adjusted risk ratio, 2.0; 95% confidence interval, 1.5 to 2.7 (P value for interaction with time interval 0.06). CONCLUSIONS: In randomized trials comparing stenting with CEA for symptomatic carotid artery stenosis, CAS was associated with a substantially higher periprocedural risk during the first 7 days after the onset of symptoms. Early surgery is safer than stenting for preventing future stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00190398; URL: http://www.controlled-trials.com. Unique identifier: ISRCTN57874028; Unique identifier: ISRCTN25337470; URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732

The Extended Environment of M17: A Star Formation History

M17 is one of the youngest and most massive nearby star-formation regions in the Galaxy. It features a bright H II region erupting as a blister from the side of a giant molecular cloud (GMC). Combining photometry from the Spitzer GLIMPSE survey with complementary infrared (IR) surveys, we identify candidate young stellar objects (YSOs) throughout a 1.5 deg x 1 deg field that includes the M17 complex. The long sightline through the Galaxy behind M17 creates significant contamination in our YSO sample from unassociated sources with similar IR colors. Removing contaminants, we produce a highly-reliable catalog of 96 candidate YSOs with a high probability of association with the M17 complex. We fit model spectral energy distributions to these sources and constrain their physical properties. Extrapolating the mass function of 62 intermediate-mass YSOs (M >3 Msun), we estimate that >1000 stars are in the process of forming in the extended outer regions of M17. From IR survey images from IRAS and GLIMPSE, we find that M17 lies on the rim of a large shell structure ~0.5 deg in diameter (~20 pc at 2.1 kpc). We present new maps of CO and 13CO (J=2-1) emission, which show that the shell is a coherent, kinematic structure associated with M17 at v = 19 km/s. The shell is an extended bubble outlining the photodissociation region of a faint, diffuse H II region several Myr old. We provide evidence that massive star formation has been triggered by the expansion of the bubble. The formation of the massive cluster ionizing the M17 H II region itself may have been similarly triggered. We conclude that the star formation history in the extended environment of M17 has been punctuated by successive waves of massive star formation propagating through a GMC complex.Comment: 31 pages, 15 figures, accepted for publication in ApJ. For a version with higher-quality figures, see http://www.astro.wisc.edu/glimpse/Povich2009_M17.pd

Intrinsically Red Sources Observed by Spitzer in the Galactic Midplane

We present a highly reliable flux-limited census of 18,949 point sources in the Galactic midplane that have intrinsically red mid-infrared colors. These sources were selected from the Spitzer Space Telescope Galactic Legacy Infrared Midplane Survey Extraordinaire (GLIMPSE) I and II surveys of 274 deg2 of the Galactic midplane, and consist mostly of high- and intermediate-mass young stellar objects (YSOs) and asymptotic giant branch (AGB) stars. The selection criteria were carefully chosen to minimize the effects of position-dependent sensitivity, saturation, and confusion. The distribution of sources on the sky and their location in the Infrared Array Camera and the Multiband Image Photometer for Spitzer 24 μm color-magnitude and color-color space are presented. Using this large sample, we find that YSOs and AGB stars can be mostly separated by simple color-magnitude selection criteria into approximately 50%-70% of YSOs and 30%-50% of AGB stars. Planetary nebulae and background galaxies together represent at most 2%-3% of all the red sources. 1004 red sources in the GLIMPSE II region, mostly AGB stars with high mass-loss rates, show significant (≥0.3 mag) variability at 4.5 and/or 8.0 μm. With over 11,000 likely YSOs and over 7000 likely AGB stars, this is to date the largest uniform census of AGB stars and high- and intermediate-mass YSOs in the Milky Way Galaxy

Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke:A meta-analysis of individual patient data from randomised trials

Background Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. Methods We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. Findings Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35-2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05-1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95-1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01-7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98-12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3-6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. Interpretation Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. Funding UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh

Gender and Age Interact to Affect Early Outcome after Intracerebral Hemorrhage

BackgroundIntracerebral hemorrhage (ICH) is a common and devastating form of cerebrovascular disease. In ICH, gender differences in outcomes remain relatively understudied but have been examined in other neurological emergencies. Further, a potential effect of age and gender on outcomes after ICH has not been explored. This study was designed to test the hypothesis that age and gender interact to modify neurological outcomes after ICH.MethodsAdult patients admitted with spontaneous primary supratentorial ICH from July 2007 through April 2010 were assessed via retrospective analysis of an existing stroke database at Duke University. Univariate analysis of collected variables was used to compare gender and outcome. Unfavorable outcome was defined as discharge to hospice or death. Using multivariate regression, the combined effect of age and gender on outcome after ICH was analyzed. ResultsIn this study population, women were younger (61.1+14.5 versus 65.8+17.3 years, p=0.03) and more likely to have a history of substance abuse (35% versus 8.9%, p<0.0001) compared to men. Multivariable models demonstrated that advancing age had a greater effect on predicting discharge outcome in women compared to men (p=0.02). For younger patients, female sex was protective; however, at ages greater than 60 years, female sex was a risk factor for discharge to hospice or death.ConclusionWhile independently associated with discharge to hospice or death after ICH, the interaction effect between gender and age demonstrated significantly stronger correlation with early outcome after ICH in a single center cohort. Prospective study is required to verify these findings

Interactions ofras-GAP with viral and cellular Src and other oncogenic tyrosine kinases.

Cellular Ras proteins act downstream of receptor and non-receptor protein tyrosine kinases in signal transduction pathways. The GTPase-activating protein of c-Ras, GAP, regulates c-Ras activity by enhancing its ability to hydrolyze GTP. GAP is thought to have an additional role as an effector protein. Here I show that the oncogenic non-receptor tyrosine kinase, v-Src, phosphorylates GAP directly on tyrosine and complexes with it to a low extent. The cellular homolog of v-Src, c-Src, can form more stable complexes with GAP in fibroblasts, although GAP is not phosphorylated. Mutational analysis demonstrates that complex formation of c-Src with GAP is dependent on the regulatory Tyr 527, which is normally phosphorylated. Results indicate that the SH2 region of c-Src also contributes to stable c-Src/GAP complex formation. SH2 and SH3 regions do not appear to be important for the ability of v-Src to phosphorylate GAP. These regions appear to be important, however, for phosphorylation of GAP-associated proteins and for full Src-mediated cell transformation. In general, we find that tyrosine phosphorylation of GAP correlates with the oncogenic potential and kinase activity of the Src kinase. Analysis of GAP interactions with other oncogenic tyrosine kinases demonstrates that v-Yes, v-Fps, and an activated ErbB protein all induce phosphorylation of GAP on tyrosine in chicken embryo fibroblasts, but at lower levels than does v-Src. In addition, v-Yes and v-Fps can be observed to associate with GAP to a small extent. v-Ros, on the other hand, does not detectably induce phosphorylation or form complexes with GAP. These studies are consistent with a model in which many tyrosine kinases phosphorylate GAP, causing it to form novel associations with other cellular proteins, and resulting in a change in GAP activities. Although GAP is not observed to be phosphorylated to high levels in cells expressing many oncogenic tyrosine kinases, formation of subcellular microenvironments around activated tyrosine kinases may result in transmission of a strong intracellular signal, leading to cellular transformation.Ph.D.Microbiology and ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/105856/1/9226855.pdfDescription of 9226855.pdf : Restricted to UM users only

Mek2 Is Dispensable for Mouse Growth and Development

MEK is a dual-specificity kinase that activates the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase upon agonist binding to receptors. The ERK/MAP kinase cascade is involved in cell fate determination in many organisms. In mammals, this pathway is proposed to regulate cell growth and differentiation. Genetic studies have shown that although a single Mek gene is present in Caenorhabditis elegans, Drosophila melanogaster, and Xenopus laevis, two Mek homologs, Mek1 and Mek2, are present in the mammalian cascade. The inactivation of the Mek1 gene leads to embryonic lethality and has revealed the unique role played by Mek1 during embryogenesis. To investigate the biological function of the second homolog, we have generated mice deficient in Mek2 function. Mek2 mutant mice are viable and fertile, and they do not present flagrant morphological alteration. Although several components of the ERK/MAP kinase cascade have been implicated in thymocyte development, no such involvement was observed for MEK2, which appears to be nonessential for thymocyte differentiation and T-cell-receptor-induced proliferation and apoptosis. Altogether, our findings demonstrate that MEK2 is not necessary for the normal development of the embryo and T-cell lineages, suggesting that the loss of MEK2 can be compensated for by MEK1