SummaryThe cellular basis of age-related tissue deterioration remains largely obscure. The ability to activate compensatory mechanisms in response to environmental stress is an important factor for survival and maintenance of cellular functions. Autophagy is activated both under short and prolonged stress and is required to clear the cell of dysfunctional organelles and altered proteins. We report that specific autophagy inhibition in muscle has a major impact on neuromuscular synaptic function and, consequently, on muscle strength, ultimately affecting the lifespan of animals. Inhibition of autophagy also exacerbates aging phenotypes in muscle, such as mitochondrial dysfunction, oxidative stress, and profound weakness. Mitochondrial dysfunction and oxidative stress directly affect acto-myosin interaction and force generation but show a limited effect on stability of neuromuscular synapses. These results demonstrate that age-related deterioration of synaptic structure and function is exacerbated by defective autophagy.

The transcription factor SOX2 (3q26.3-q27) is a key regulator of foregut development and an embryonic stem cell factor cooperating during induction of pluripotency in terminally differentiated somatic cells. Recently, we found SOX2 to be amplified in a subset of squamous cell lung and esophageal cancers. The aim of this study was to explore the prognostic role of SOX2 in a large series of squamous cell carcinomas and adenocarcinomas of the lung. A total of 891 samples from two independent population-based cohorts were assessed by fluorescence in situ hybridization and immunohistochemistry. Furthermore, we assessed for associations between SOX2 amplification/upregulation and clinicopathological features. Similar results were found in the two cohorts. Within squamous cell carcinoma cases, 8% high-level as well as 68 and 65% low-level SOX2 amplifications occurred in the two cohorts, respectively. In adenocarcinomas, no high-level amplification was found and low-level amplification occurred in 6% of the two cohorts. Within squamous cell carcinomas of one cohort, SOX2 amplification was associated with lower tumor grade, while higher levels of SOX2 expression were related to younger age, smaller tumor size, and lower probability of angiolymphatic invasion and metastasis. High SOX2 expression levels proved to be a marker for prolonged overall survival among patients with squamous cell carcinomas. In conclusion, SOX2 amplification and upregulation are frequent events in squamous cell carcinomas of the lung and are associated with indicators of favorable prognosis. Modern Pathology (2011) 24, 944-953;

The distribution and function of sympathetic innervation in skeletal muscle have largely remained elusive. Here we demonstrate that sympathetic neurons make close contact with neuromuscular junctions and form a network in skeletal muscle that may functionally couple different targets including blood vessels, motor neurons, and muscle fibers. Direct stimulation of sympathetic neurons led to activation of muscle postsynaptic β2-adrenoreceptor (ADRB2), cAMP production, and import of the transcriptional coactivator peroxisome proliferator-activated receptor γ-coactivator 1α (PPARGC1A) into myonuclei. Electrophysiological and morphological deficits of neuromuscular junctions upon sympathectomy and in myasthenic mice were rescued by sympathicomimetic treatment. In conclusion, this study identifies the neuromuscular junction as a target of the sympathetic nervous system and shows that sympathetic input is crucial for synapse maintenance and function

The kinematic properties of t t events are studied in the Wϩmultijet channel using data collected with the CDF detector during the 1992-1995 runs at the Fermilab Tevatron collider corresponding to an integrated luminosity of 109 pb Ϫ1 . Distributions of a variety of kinematic variables chosen to be sensitive to different aspects of t t production are compared with those expected from Monte Carlo calculations. A sample of 34 events rich in t t pairs is obtained by requiring at least one jet identified by the silicon vertex detector ͑SVX͒ as having a displaced vertex consistent with the decay of a b hadron. The data are found to be in good agreement with predictions of the leading order t t matrix element with color coherent parton shower evolution. ͓S0556-2821͑99͒04007-2͔

We have observed bottom-charm mesons via the decay mode B-c(+/-) --> J/psi l(+/-)v in 1.8 TeV p (p) over bar collisions using the CDF detector at the Fermilab Tevatron. A fit of background and signal contributions to the J/psi l mass distribution yielded 20.4(-5.5)(+6.2) events from B-c mesons. A fit to the same distribution with background alone was rejected at the level of 4.8 standard deviations. We measured the B-c(+) mass to be 6.40 +/- 0.39(stat) +/- 0.13(syst) GeV/c(2) and the B-c(+) lifetime to be 0.46(-0.16)(+0.18)(stat) +/- 0.03(syst) ps. Our measured yield (production cross section times branching ratio) for B-c(+) --> J/psi l(+)v relative to that for B+ --> J/psi K+ is 0.132(-0.037)(+0.041)(stat) +/- 0.031 (syst)(-0.020)(+0.032)(lifetime)