The Midcontinent rift system is a 1.1‐b.y.‐old structure extending from Kansas, through the Lake Superior region, and into southern Michigan. The rift is filled with thick sequences of basaltic volcanic rocks and clastic sediments. For most of its extent it is buried beneath Paleozoic rocks but can be traced by its strong gravity and magnetic anomalies. The rocks of the rift system are exposed only in the Lake Superior region and comprise the Keweenawan Supergroup. Much of the geology of the Keweenawan is beneath Lake Superior and has only been inferred from potential field studies and seismic refraction studies and extrapolation from on‐shore geology. Seismic reflection surveys by the Great Lakes International Multidisciplinary Program on Crustal Evolution in 1986 imaged much of the deep structure of the rift beneath the lake in detail. The reflection profiles across the rift reveal a deep, asymmetrical central graben whose existence and magnitude was not previously documented. They show that, in addition to crustal sagging documented by previous investigations, normal faulting played a major role in subsidence of the axial region of the rift. A sequence of volcanic and sedimentary rocks, in places greater than 30 km thick, fills the graben. Thinner volcanic and sedimentary units lie on broad flanks of the rift outside of the graben. Near the axis, the prerift crust is thinned to about one fourth of its original thickness, apparently by a combination of low‐angle extensional faulting and ductile stretching or distributed shear. The sense of asymmetry of the central graben changes along the trend of the rift, documenting the segmented nature of the structure and suggesting the existence of accommodation zones between the segments. The location of the accommodation zones is inferred from abrupt disruptions in the Bouguer gravity signature of the rift. Uplift of the central graben occurred when the original graben‐bounding normal faults were reactivated as high‐angle reverse faults with throws of 5 km or more in places. The Midcontinent rift has some striking similarities to some younger passive continental margins. We propose that it preserves a record of nearly complete continental separation which, had it not been arrested, would have created a Middle Proterozoic ocean basin.

Skeletal muscle mass and function are regulated by motor innervation, and denervation results in muscle atrophy. The activity of mammalian target of rapamycin complex 1 (mTORC1) is substantially increased in denervated muscle, but its regulatory role in denervation-induced atrophy remains unclear. At early stages after denervation of skeletal muscle, a pathway involving class II histone deacetylases and the transcription factor myogenin mediates denervation-induced muscle atrophy. We found that at later stages after denervation of fast-twitch muscle, activation of mTORC1 contributed to atrophy and that denervation-induced atrophy was mitigated by inhibition of mTORC1 with rapamycin. Activation of mTORC1 through genetic deletion of its inhibitor TSC1 (tuberous sclerosis complex 1) sensitized mice to denervation-induced muscle atrophy and suppressed the kinase activity of Akt, leading to activation of FoxO transcription factors and increasing the expression of genes encoding E3 ubiquitin ligases atrogin [also known as MAFbx (muscle atrophy F-box protein)] and MuRF1 (muscle-specific ring finger 1). Rapamycin treatment of mice restored Akt activity, suggesting that the denervation-induced increase in mTORC1 activity was producing feedback inhibition of Akt. Genetic deletion of the three FoxO isoforms in skeletal muscle induced muscle hypertrophy and abolished the late-stage induction of E3 ubiquitin ligases after denervation, thereby preventing denervation-induced atrophy. These data revealed that mTORC1, which is generally considered to be an important component of anabolism, is central to muscle catabolism and atrophy after denervation. This mTORC1-FoxO axis represents a potential therapeutic target in neurogenic muscle atrophy.

Mechanical ventilation (MV) is a life-saving measure in many critically ill patients. However, prolonged MV results in diaphragm dysfunction that contributes to the frequent difficulty in weaning patients from the ventilator. The molecular mechanisms underlying ventilator-induced diaphragm dysfunction (VIDD) remain poorly understood. We report here that MV induces myonuclear DNA fragmentation (3-fold increase; P<0.01) and selective activation of caspase 9 (P<0.05) and Bcl2-interacting mediator of cell death (Bim; 2- to 7-fold increase; P<0.05) in human diaphragm. MV also statistically significantly down-regulates mitochondrial gene expression and induces oxidative stress. In cultured muscle cells, we show that oxidative stress activates each of the catabolic pathways thought to underlie VIDD: apoptotic (P<0.05), proteasomal (P<0.05), and autophagic (P<0.01). Further, silencing Bim expression blocks (P<0.05) oxidative stress-induced apoptosis. Overlapping the gene expression profiles of MV human diaphragm and H₂O₂-treated muscle cells, we identify Fos, FoxO1, and Stat3 as regulators of Bim expression as well as of expression of the catabolic markers atrogin and LC3. We thus identify a novel Fos/FoxO1/Stat3-Bim intrinsic apoptotic pathway and establish the centrality of oxidative stress in the development of VIDD. This information may help in the design of specific drugs to prevent this condition.

Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age‐related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3's phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age‐related muscle atrophy, and GDF signaling is a proposed mechanism.

Glycolysis is the initial step of glucose catabolism and is up-regulated in cancer cells (the Warburg Effect). Such shifts toward a glycolytic phenotype have not been explored widely in other biological systems, and the molecular mechanisms underlying the shifts remain unknown. With proteomics, we observed increased glycolysis in disused human diaphragm muscle. In disused muscle, lung cancer, and H(2)O(2)-treated myotubes, we show up-regulation of the rate-limiting glycolytic enzyme muscle-type phosphofructokinase (PFKm, >2 fold, P<0.05) and accumulation of lactate (>150%, P<0.05). Using microRNA profiling, we identify miR-320a as a regulator of PFKm expression. Reduced miR-320a levels (to ∼50% of control, P<0.05) are associated with the increased PFKm in each of these diverse systems. Manipulation of miR-320a levels both in vitro and in vivo alters PFKm and lactate levels in the expected directions. Further, miR-320a appears to regulate oxidative stress-induced PFKm expression, and reduced miR-320a allows greater induction of glycolysis in response to H(2)O(2) treatment. We show that this microRNA-mediated regulation occurs through PFKm's 3' untranslated region and that Ets proteins are involved in the regulation of PFKm via miR-320a. These findings suggest that oxidative stress-responsive microRNA-320a may regulate glycolysis broadly within nature.

Previous studies have suggested decreased N-methyl-D-aspartate (NMDA)-type glutamate receptor function may contribute to increased negative symptoms in patients with schizophrenia. Consistent with this hypothesis, glycine, a co-agonist at NMDA receptors, has been reported to improve negative symptoms associated with the illness. This study was performed to determine if plasma levels of glycine or its ratio to serine, a precursor of glycine, are decreased in patients with schizophrenia compared to normal control subjects or patients with major depression. We also tested the hypothesis that these amino acids were correlated with negative symptoms in subjects with schizophrenia. Plasma levels of glycine, serine, and their ratio, were compared in 144 patients with schizophrenia, 44 patients with major depression, and 49 normal control subjects. All subjects were medication-free. Psychopathology was evaluated using the Brief Psychiatric Rating Scale (BPRS). Plasma glycine levels and glycine/serine ratios were decreased in patients with schizophrenia relative to control subjects and patients with major depression. By contrast, serine levels were increased in patients with schizophrenia compared to normal subjects but not compared to major depression. Patients with major depression also had increased plasma serine levels and decreased glycine/serine ratios compared to normal controls, but glycine levels were not different from those of normal controls. In subjects with schizophrenia, glycine levels predicted the Withdrawal-Retardation score (BPRS), whereas no such correlation was found in subjects with major depression. These results provide additional evidence that decreased availability of glycine may be related to the pathophysiology of negative symptoms. The decreases in plasma glycine levels support the evidence for an abnormality in the glutamatergic system in schizophrenia, and provide additional support for efforts to improve negative symptoms by augmentation of antipsychotic drugs with agonists at the glycine site of the NMDA receptor.

INTRODUCTION Mechanical ventilation (MV) is an important component of modern medical practice which allows support of breathing in the intensive care unit (ICU) and during surgery requiring general anesthesia. Many patients, however, fail initial weaning from the ventilator and enter the difficult realm of prolonged ventilation. Patients who develop this ventilator dependence, though a diverse group, share the common underlying problem of substantial dysfunction of the major inspiratory muscle, the diaphragm (1-8). The development of ventilator-induced diaphragm dysfunction (VIDD) appears to be a major underlying cause of prolonged ventilator-dependence with its attendant dramatic increase in morbidity and mortality (9-14). The pathogenesis of VIDD includes both atrophy of diaphragmatic myofibers and loss of diaphragmatic contractile function (that is, specific force) unrelated to atrophy (15-17). In previous studies, MV with diaphragm inactivity has been shown to elicit significant dysfunction and/or atrophy of myofibers in the diaphragm of humans (18-21), rats (22), mice (23-25), rabbits (26) and piglets (27). With regard to the atrophy, several proteolytic events, such as activation of the ubiquitin proteasome system (UPS) (28-30), autophagy (24,25,31) and apoptosis (32-35), and upregulation of calpain (36), have been demonstrated in MV models. We and others have re

A unique set of high-quality downhole shallow subsurface well log data combined with industry standard 3D seismic data from the Alaminos Canyon area has enabled the first detailed description of a concentrated gas hydrate accumulation within sand in the Gulf of Mexico. The gas hydrate occurs within very fine grained, immature volcaniclastic sands of the Oligocene Frio sand. Analysis of well data acquired from the Alaminos Canyon Block 818 #1 (''Tigershark'') well shows a total gas hydrate occurrence 13 m thick, with inferred gas hydrate saturation as high as 80% of sediment pore space. Average porosity in the reservoir is estimated from log data at approximately 42%. Permeability in the absence of gas hydrates, as revealed from the analysis of core samples retrieved from the well, ranges from 600 to 1500 millidarcies. The 3-D seismic data reveals a strong reflector consistent with significant increase in acoustic velocities that correlates with the top of the gas-hydrate-bearing sand. This reflector extends across an area of approximately 0.8 km 2 and delineates the minimal probable extent of the gas hydrate accumulation. The base of the inferred gas-hydrate zone also correlates well with a very strong seismic reflector that indicates transition into units of significantly reduced acoustic velocity. Seismic inversion analyses indicate uniformly high gas-hydrate saturations throughout the region where the Frio sand exists within the gas hydrate stability zone. Numerical modeling of the potential production of natural gas from the interpreted accumulation indicates serious challenges for depressurization-based production in settings with strong potential pressure support from extensive underlying aquifers.