Connexin-hemichannels are Involved in Acidosis-induced ATP Release from Skeletal Myocytes

Oral PresentationATP is an important extracellular signalling molecule which contributes to exercise vasodilation. We have previously shown that the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in acidosis-induced ATP release from skeletal muscle. However, it is still unknown whether ATP is released through CFTR itself or whether CFTR regulates a separate ATPrelease channel. So we investigated: (1) the pathway responsible for CFTR activation in myocytes at low pH; (2) whether connexin (Cx) hemichannels were involved in the acidosis-induced ATP release from skeletal muscle. Lactic acid (10 mM) increased the intracellular cAMP and the extracellular ATP in L6 skeletal myocytes. Similarly, the cAMP-elevating agent, forskolin, increased extracellular ATP. The phosphodiesterase inhibitor, IBMX, increased extracellular ATP in the absence or presence of lactic acid. CFTR phosphorylation was increased by the addition of forskolin alone, and further increased by forskolin plus dibutyryl-cAMP and IBMX, but the forskolininduced increase in CFTR phosphorylation was inhibited by the PKA inhibitor, KT5720. Whereas KT5720 inhibited acidosis-induced ATP release from myocytes. These data suggest that skeletal muscle CFTR is activated through the cAMP/PKA pathway at low pH. RT-PCR indicated that cultured rat L6 skeletal myocytes expressed mRNA for both Cx40 and Cx43, but Cx40 was expressed only weakly in western blot, whereas Cx43 was strongly expressed. Co-immunoprecipitation results showed that CFTR and Cx43 were associated with each other in the cell membrane. A Cx43 over-expression model was created by transfecting myocytes with a Cx43 plasmid: Cx43 over-expression was confirmed using western blot. Cx43 over-expressing myocytes released significantly more ATP than control myocytes at pH 6.8, suggesting that Cx43 may be involved in acidosis-induced ATP release, whereas silencing Cx43 expression using siRNA inhibited the acidosis-induced ATP release. Over-expression of CFTR alone did not alter ATP release from myocytes, whereas co-over-expression of CFTR with Cx43 increased ATP release significantly more than over-expression of Cx43 alone. These data suggest that Cx43 co-localises with CFTR in the myocyte membrane, and that it may be involved in ATP release during acidosis; further investigation is required to determine whether and how CFTR interacts with Cx43 to induce ATP release.published_or_final_versio

cAMP/Protein Kinase A activates Cystic Fibrosis Transmembrane Conductance Regulator for ATP release from rat skeletal muscle during low pH or contractions

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Behavioral activation for dementia caregivers: scheduling pleasant events and enhancing communications

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Experimental measurement-based quantum computing beyond the cluster-state model

The paradigm of measurement-based quantum computation opens new experimental avenues to realize a quantum computer and deepens our understanding of quantum physics. Measurement-based quantum computation starts from a highly entangled universal resource state. For years, clusters states have been the only known universal resources. Surprisingly, a novel framework namely quantum computation in correlation space has opened new routes to implement measurement-based quantum computation based on quantum states possessing entanglement properties different from cluster states. Here we report an experimental demonstration of every building block of such a model. With a four-qubit and a six-qubit state as distinct from cluster states, we have realized a universal set of single-qubit rotations, two-qubit entangling gates and further Deutsch's algorithm. Besides being of fundamental interest, our experiment proves in-principle the feasibility of universal measurement-based quantum computation without using cluster states, which represents a new approach towards the realization of a quantum computer.Comment: 26 pages, final version, comments welcom

Beliefs about the Minds of Others Influence How We Process Sensory Information

Attending where others gaze is one of the most fundamental mechanisms of social cognition. The present study is the first to examine the impact of the attribution of mind to others on gaze-guided attentional orienting and its ERP correlates. Using a paradigm in which attention was guided to a location by the gaze of a centrally presented face, we manipulated participants' beliefs about the gazer: gaze behavior was believed to result either from operations of a mind or from a machine. In Experiment 1, beliefs were manipulated by cue identity (human or robot), while in Experiment 2, cue identity (robot) remained identical across conditions and beliefs were manipulated solely via instruction, which was irrelevant to the task. ERP results and behavior showed that participants' attention was guided by gaze only when gaze was believed to be controlled by a human. Specifically, the P1 was more enhanced for validly, relative to invalidly, cued targets only when participants believed the gaze behavior was the result of a mind, rather than of a machine. This shows that sensory gain control can be influenced by higher-order (task-irrelevant) beliefs about the observed scene. We propose a new interdisciplinary model of social attention, which integrates ideas from cognitive and social neuroscience, as well as philosophy in order to provide a framework for understanding a crucial aspect of how humans' beliefs about the observed scene influence sensory processing

A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells

The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the anti-apoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.published_or_final_versio

A posterior epidural mass causing paraparesis in a 20-year-old healthy individual

We present a case of a posterior epidural abscess at the thoracic vertebral level causing paraparesia in a young, healthy individual with no otherwise predisposing factors, with normal laboratory findings, as diagnosed using fat-suppressed MR imaging. Spinal epidural abscess is a rare condition, encountered mostly in the midthoracic or lower lumbar vertebral levels of elderly patients, that has a high mortality and morbidity (18-31%) when diagnosis and treatment is delayed. It is rarely spontaneous and is usually accompanied by spinal osteomyelitis. Diagnosis is rather easy in cases of vertebral osteomyelitis or when classical clinical, laboratory and imaging findings are present. However, cases of spontaneous development, with no predisposing factors, and lack of abscess suggesting clinical and laboratory findings may be a diagnostic challenge. In such cases, other posterior epidural masses such as schwannoma, neurofibroma, meningioma and hematoma should be considered in the differential diagnosis. Both the clinician and the radiology physician should have a high suspicion of epidural abscesses, because their early diagnosis and treatment is important. In addition to routine MR images, fat-suppressed MR images prove helpful in the diagnosis of spontaneous epidural abscesses by showing the inflammatory changes in the paraspinal area

Electronic Structures of S-Doped Capped C-SWNT from First Principles Study

The semiconducting single-walled carbon nanotube (C-SWNT) has been synthesized by S-doping, and they have extensive potential application in electronic devices. We investigated the electronic structures of S-doped capped (5, 5) C-SWNT with different doping position using first principles calculations. It is found that the electronic structures influence strongly on the workfunction without and with external electric field. It is considered that the extended wave functions at the sidewall of the tube favor for the emission properties. With the S-doping into the C-SWNT, the HOMO and LUMO charges distribution is mainly more localized at the sidewall of the tube and the presence of the unsaturated dangling bond, which are believed to enhance workfunction. When external electric field is applied, the coupled states with mixture of localized and extended states are presented at the cap, which provide the lower workfunction. In addition, the wave functions close to the cap have flowed to the cap as coupled states and to the sidewall of the tube mainly as extended states, which results in the larger workfunction. It is concluded that the S-doped C-SWNT is not incentive to be applied in field emitter fabrication. The results are also helpful to understand and interpret the application in other electronic devices