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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Diagnostic relevance of spatial orientation for vascular dementia: A case study

Background: Spatial orientation is emerging as an early and reliable cognitive biomarker of Alzheimer’s disease (AD) pathophysiology. However, no evidence exists as to whether spatial orientation is also affected in vascular dementia (VaD). Objective: To examine allocentric (map-based) and egocentric (viewpoint-based) spatial orientation in an early stage VaD case. Methods: A spatial test battery was administered following clinical and neuropsychological cognitive evaluation. Results: Despite the patient’s complaints, little evidence of episodic memory deficits were detected when cueing was provided to overcome executive dysfunction. Similarly, medial temporal lobe-mediated allocentric orientation was intact. By contrast, medial parietal-mediated egocentric orientation was impaired, despite normal performance on standard visuospatial tasks. Conclusion: To our knowledge, this is the first in-depth investigation of spatial orientation deficits in VaD. Isolated egocentric deficits were observed. This differs from AD orientation deficits which encompass both allocentric and egocentric orientation deficits. A combination of egocentric orientation and executive function tests could serve as a promising cognitive marker for VaD pathophysiology

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Which growth parameters can affect mortality in cerebral palsy?

BACKGROUND: The objective of this study was to identify growth parameters that can affect mortality of cerebral palsy (CP). METHOD: This was a birth cohort study based on the National Health Screening Program for Infants and Children database along with the National Health Insurance Service, which were linked using a personal identifier number. The birth cohort consisted of 2 191 956 subjects, representing 93.5% of live births from 2007-2011, with maximal 10-year follow-up (range, 5-10 years) until October 2016. Subjects with CP were identified. Growth parameters in terms of birth weight, underweight (weight-for-age below the 3rd percentile), rate of body weight gain were collected, along with all-cause mortality after the age of 1 year. RESULT: Prevalence of CP was 2.0 per 1000 live births (95% CI, 1.94-2.06). All-cause mortality after the age of 1 year was 0.09 deaths/1000 person-years (95% CI, 0.08-0.09) in the general population (GP) and 2.85 deaths/1000 person-years (95% CI, 2.32-3.50) in subjects with CP during the follow-up. Therefore, the incidence rate ratio for all-cause mortality was 32.15 (95% CI, 25.72-39.76) in subjects with CP compared to GP. Presence of underweight was significantly associated with higher mortality in both subjects with CP and GP, where the adjusted hazard ratio of death was 2.60 (95% CI, 1.93-3.50) at the age of 18-24 months, 3.12 at 30-36 months, 4.37 at 42-48 months, 5.12 at 54-60 months, and 4.17 at 66-71 months. Birth weight did not affect mortality in both subjects with CP and GP after the age of 1 year (p > 0.05). CONCLUSION: While subjects with CP shows higher mortality, underweight is an important growth parameter that affects all-cause mortality of both subjects with CP and GP. This study urges increased awareness that subjects with CP who are underweight require special care

Understanding and using comparative healthcare information; the effect of the amount of information and consumer characteristics and skills

<p>Abstract</p> <p>Background</p> <p>Consumers are increasingly exposed to comparative healthcare information (information about the quality of different healthcare providers). Partly because of its complexity, the use of this information has been limited. The objective of this study was to examine how the amount of presented information influences the comprehension and use of comparative healthcare information when important consumer characteristics and skills are taken into account.</p> <p>Methods</p> <p>In this randomized controlled experiment, comparative information on total hip or knee surgery was used as a test case. An online survey was distributed among 800 members of the NIVEL Insurants Panel and 76 hip- or knee surgery patients. Participants were assigned to one of four subgroups, who were shown 3, 7, 11 or 15 quality aspects of three hospitals. We conducted Kruskall-Wallis tests, Chi-square tests and hierarchical multiple linear regression analyses to examine relationships between the amount of information and consumer characteristics and skills (literacy, numeracy, active choice behaviour) on one hand, and outcome measures related to effectively using information (comprehension, perceived usefulness of information, hospital choice, ease of making a choice) on the other hand.</p> <p>Results</p> <p>414 people (47%) participated. Regression analysis showed that the amount of information slightly influenced the comprehension and the perceived usefulness of comparative healthcare information. It did not affect consumers’ hospital choice and ease of making this choice. Consumer characteristics (especially age) and skills (especially literacy) were the most important factors affecting the comprehension of information and the ease of making a hospital choice. For the perceived usefulness of comparative information, active choice behaviour was the most influencing factor.</p> <p>Conclusion</p> <p>The effects of the amount of information were not unambiguous. It remains unclear what the ideal amount of quality information to be presented would be. Reducing the amount of information will probably not automatically result in more effective use of comparative healthcare information by consumers. More important, consumer characteristics and skills appeared to be more influential factors contributing to information comprehension and use. Consequently, we would suggest that more emphasis on improving consumers’ skills is needed to enhance the use of comparative healthcare information.</p

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO