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Spoken and signed word production activated many of the same cortical regions, particularly those processing auditory and visual inputs; however, they activated different regions of sensorimotor cortex, and signing activated parietal cortex more than did speech. This study illustrates the utility of electrocorticographic gamma for studying the neuroanatomy and processing dynamics of human language.

Objectives: Clinical observations have demonstrated that copper levels elevate in several cancer types, and copper deprivation is shown to inhibit tumour angiogenesis and growth in both animal models and preclinical trials. However, the content of copper in pancreatic duct adenocarcinoma (PDAC) and whether it is a potential therapy target is still unknown. Materials and Methods:The levels of copper in PDAC specimens were detected by ICP-MS assays. Copper depletion in Panc-1 or MiaPaCa-2 cells was conducted via copper transporter 1 (SLC31A1) interference and copper chelator tetrathiomolybdate (TM) treatment. The effects of copper deprivation on cancer cells were evaluated by cell proliferation, migration, invasion, colony formation and cell apoptosis.The mechanism of copper deprivation-caused cancer cell quiescence was resolved through mitochondrial dysfunction tests and autophagy studies. The tumour-suppression experiments under the condition of copper block and/or autophagy inhibition were performed both in vitro and in xenografted mice.Results: SLC31A1-dependent copper levels are correlated with the malignant degree of pancreatic cancer. Blocking copper absorption could inhibit pancreatic cancer progression but did not increase cell death. We found that copper deprivation increased mitochondrial ROS level and decreased ATP level, which rendered cancer cells in a dormant state. Strikingly, copper deprivation caused an increase in autophagy to resist death of pancreatic cancer cells. Simultaneous treatment with TM and autophagy inhibitor CQ increased cell death of cancer cells in vitro and retarded cancer growth in vivo. Conclusions:These findings reveal that copper deprivation-caused cell dormancy and the increase in autophagy is a reason for the poor clinical outcome obtained from copper depletion therapies for cancers. Therefore, the combination of autophagy inhibition and copper depletion is potentially a novel strategy for the treatment of pancreatic cancer and other copper-dependent malignant tumours.

PurposePrevious studies have shown a bidirectional relationship between diabetes and pancreatic cancer (PC). In particular, new-onset diabetes might be induced by PC, and people with long-term diabetes might be at increased risk for the development of PC. The purpose of our study was to examine whether long-term diabetes represented an independent risk factor for PC development.MethodologyA literature search was performed by searching electronic databases for studies published before July 1, 2014, and relative risks (RRs) and corresponding 95% confidence intervals (CIs) were calculated. Data pertaining to diabetes were recorded at both individual and study levels, with RRs calculated separately to analyze the relationship between the duration of diabetes and the development of PC.ResultsForty-four studies were included in this meta-analysis, including 18 studies with a case-control design, 5 with a nested case-control design and 21 with a cohort design. The overall summary estimate for the relationship between the population with a duration of diabetes ≥2 years and PC was 1.64 (1.52-1.78). The pooled RR (95% CI) of PC for the population with a duration of diabetes ≥5 years was 1.58 (1.42-1.75). For the population with a duration of diabetes ≥10 years, the RR (95% CI) of PC was 1.50 (1.28-1.75).ConclusionsOur study suggests that long-term diabetes mellitus is associated with an increased risk of PC. However, the level of risk is negatively correlated with increasing diabetes mellitus duration.

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The impact of a central or peripheral visual field loss on the vision strategy used to guide walking was determined by measuring walking paths of visually impaired participants. An immersive virtual environment was used to dissociate the expected paths of the optic-flow and egocentric-direction strategies by offsetting the walker's point of view from the actual direction of walking. Environments consisted of a goal within a forest, the goal alone, or the forest alone following a brief presentation of the goal. The first two environments allowed an evaluation of the visual information used in a goal-directed task whereas the third environment investigated the information used in a memory-guided task. Participants had either a central (CFL) or peripheral visual field loss (PFL) or were fully sighted (FS). Results showed that, for the goal-directed task, the CFL group was less influenced by optic flow than was an age-matched FS group. Optic flow decreased heading error by only 1.3 degrees (16%) in the CFL group compared to 3.6 degrees (42%) in the FS group. The PFL group showed an optic-flow influence (2.4 degrees or 26%) comparable to an older, age-matched FS group (2.9 degrees or 31%). For the memory-guided task, all but the PFL group had heading errors comparable to those obtained in the goal-alone scene, demonstrating the ability to use an egocentric-direction strategy with a stored representation of either the goal's position or an offset relative to a landmark instead of a visible goal. The paths of the PFL group veered significantly from the predicted paths of both the optic-flow and egocentric-direction strategies. The findings of this study suggest that central vision is important for using optic flow to guide walking, whereas peripheral vision is important for establishing and/or updating an accurate representation of spatial structure for navigation.

Calmodulin (CaM) is implicated in regulation of Ca(2+) channels as a Ca(2+) sensor. The effect of CaM on rundown of L-type Ca(2+) channels in inside-out patch form was investigated in guinea pig ventricular myocytes. Ca(2+) channel activity disappeared within 1-3 min and did not reappear when the patch was excised and exposed to an artificial intracellular solution. However, application of CaM (0.03, 0.3, 3 microM) + 3 mM ATP to the intracellular solution within 1 min after patch excision resulted in dose-dependent activation of channel activity. Channel activity averaged 11.2%, 94.7%, and 292.9%, respectively, of that in cell-attached mode. Channel activity in inside-out patch mode was induced by CaM + ATP at nanomolar Ca(2+) concentrations ([Ca(2+)]); however, increase to micromolar [Ca(2+)] rapidly inactivated the channel activity induced, revealing that the effect of CaM on the channel was Ca(2+) dependent. At the 2nd, 4th, 6th, 8th, and 10th minutes after patch excision, CaM (0.75 microM) + ATP induced Ca(2+) channel activity to 150%, 100%, 96.9%, 29.3%, and 16.6%, respectively, revealing a time-dependent action of CaM on the channel. CaM added with adenosine 5'-(beta,gamma-imido)triphosphate (AMP-PNP) also induced channel activity, although with much lower potency and shorter duration. Protein kinase inhibitors KN-62, CaM-dependent protein kinase (CaMK)II 281-309, autocamtide-related CaMKII inhibitor peptide, and K252a (each 1-10 microM) did not block the effect of CaM, indicating that the effect of CaM on the Ca(2+) channel was phosphorylation independent. Neither CaM nor ATP alone induced Ca(2+) channel activity, showing a cooperative effect of CaM and ATP on the Ca(2+) channel. These results suggest that CaM is a crucial regulatory factor of Ca(2+) channel basal activity.

This article is available online at http://www.jlr.org to form a series of biologically active lipid mediators ( 1, 2 ). In the CNS, 12/15-LOX expression has been described throughout the cerebrum, basal ganglia, and hippocampus ( 3, 4 ). Arachidonic acid (AA) is an important component of membrane lipids that can activate several signaling pathways directly by itself or by its metabolites ( 5 ). In nervous tissue, the major enzymatic route for AA metabolism is the 12/15-LOX pathway, and the principal metabolites are 12(S)-HETE and 15(S)-HETE ( 3, 4, 6, 7 ). The biological signifi cance of these metabolites of AA is that they have been proposed to play roles as second messengers in synaptic transmission and they are thought to be involved in learning and memory processes ( 8 ). In addition, 12(S)-HETE is known to act as an inhibitory neuromodulator by reducing voltage-sensitive calcium channel activity ( 9 ) and attenuating glutamate release and affi nity to its receptors ( 10-12 ).Brain ischemia triggers the massive release of free fatty acids from membrane stores, such as AA and DHA, and then the accumulation of lipid peroxides. 12/15-LOX is thought to be damaging because of its lipid-oxidizing properties, and the detrimental effects of 12/15-LOX have been documented by demonstrating the protection in the ischemic brain through 12/15-LOX inhibition or gene deletion ( 13-15 ). Several metabolites of 12/15-LOX, however, have neuroprotective and anti-infl ammatory qualities during brain ischemia. For example, 12/15-LOX metabolites derived from DHA and other -3 fatty acids inhibit cerebral ischemia-induced injury (16)(17)(18). This suggests 12/15-LOX and its metabolites may differ in their effects following cerebral ischemia.PPAR ␥ is a member of the nuclear hormone receptor family of ligand-dependent transcription factors. This work was supported by grants from the National Natural Science Foundation of China (number 81070968 to L.S. and number 81401023 to Y-W.X.) and from the Tianjin Municipal Science and Technology Commission (number 13ZCZDSY01900 to Y.C.). The authors declare no confl icts of interest. Manuscript received 15 July 2014 and in revised form 12(S)-and 15(S)-HETE activate PPAR ␥ in ischemic brain 503animals survived the MCAO surgical procedure. Rats that did not demonstrate neurological defi cits during 90 min MCAO were excluded from further study. Animals dying prematurely during the reperfusion period or having subarachnoid hemorrhage at postmortem examination were also excluded. Measurements derived from these animals were not included in the present study. Drug treatmentEicosanoids, 12(S)-HETE and 15(S)-HETE, were products of Cayman Chemical (Ann Arbor, MI) and given 30 min before the onset of MCAO by icv injection. 12(S)-and 15(S)-HETE, supplied in ethanol at 1 mg/ml, were air-dried under a stream of nitrogen and dissolved in a 30% DMSO and 70% isotonic saline solution ( 35 ). Animals received either vehicle (30% DMSO-0.9% saline) or a single dose of 12(S)-or 15(S)-HETE at 10, 15, or 20 g ( ‫...