Nonperturbative studies of supersymmetric matrix quantum mechanics with 4 and 8 supercharges at finite temperature

We investigate thermodynamic properties of one-dimensional U(N) supersymmetric gauge theories with 4 and 8 supercharges in the planar large-N limit by Monte Carlo calculations. Unlike the 16 supercharge case, the threshold bound state with zero energy is widely believed not to exist in these models. This led A.V. Smilga to conjecture that the internal energy decreases exponentially at low temperature instead of decreasing with a power law. In the 16 supercharge case, the latter behavior was predicted from the dual black 0-brane geometry and confirmed recently by Monte Carlo calculations. Our results for the models with 4 and 8 supercharges indeed support the exponential behavior, revealing a qualitative difference from the 16 supercharge case.Comment: 16 pages, 7 figures, LaTeX2e, minor corrections in section 3, final version accepted in JHE

Progress in Understanding and Treating SCN2A-Mediated Disorders

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel NaV1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders

New Insights in the Contribution of Voltage-Gated Nav Channels to Rat Aorta Contraction

BACKGROUND: Despite increasing evidence for the presence of voltage-gated Na(+) channels (Na(v)) isoforms and measurements of Na(v) channel currents with the patch-clamp technique in arterial myocytes, no information is available to date as to whether or not Na(v) channels play a functional role in arteries. The aim of the present work was to look for a physiological role of Na(v) channels in the control of rat aortic contraction. METHODOLOGY/PRINCIPAL FINDINGS: Na(v) channels were detected in the aortic media by Western blot analysis and double immunofluorescence labeling for Na(v) channels and smooth muscle alpha-actin using specific antibodies. In parallel, using real time RT-PCR, we identified three Na(v) transcripts: Na(v)1.2, Na(v)1.3, and Na(v)1.5. Only the Na(v)1.2 isoform was found in the intact media and in freshly isolated myocytes excluding contamination by other cell types. Using the specific Na(v) channel agonist veratridine and antagonist tetrodotoxin (TTX), we unmasked a contribution of these channels in the response to the depolarizing agent KCl on rat aortic isometric tension recorded from endothelium-denuded aortic rings. Experimental conditions excluded a contribution of Na(v) channels from the perivascular sympathetic nerve terminals. Addition of low concentrations of KCl (2-10 mM), which induced moderate membrane depolarization (e.g., from -55.9+/-1.4 mV to -45.9+/-1.2 mV at 10 mmol/L as measured with microelectrodes), triggered a contraction potentiated by veratridine (100 microM) and blocked by TTX (1 microM). KB-R7943, an inhibitor of the reverse mode of the Na(+)/Ca(2+) exchanger, mimicked the effect of TTX and had no additive effect in presence of TTX. CONCLUSIONS/SIGNIFICANCE: These results define a new role for Na(v) channels in arterial physiology, and suggest that the TTX-sensitive Na(v)1.2 isoform, together with the Na(+)/Ca(2+) exchanger, contributes to the contractile response of aortic myocytes at physiological range of membrane depolarization

Review for the generalist: evaluation of pediatric hip pain

Hip pathology may cause groin pain, referred thigh or knee pain, refusal to bear weight or altered gait in the absence of pain. A young child with an irritable hip poses a diagnostic challenge. Transient synovitis, one of the most common causes of hip pain in children, must be differentiated from septic arthritis. Hip pain may be caused by conditions unique to the growing pediatric skeleton including Perthes disease, slipped capital femoral epiphysis and apophyseal avulsion fractures of the pelvis. Hip pain may also be referred from low back or pelvic pathology. Evaluation and management requires a thorough history and physical exam, and understanding of the pediatric skeleton. This article will review common causes of hip and pelvic musculoskeletal pain in the pediatric population

Macoilin, a Conserved Nervous System–Specific ER Membrane Protein That Regulates Neuronal Excitability

Genome sequence comparisons have highlighted many novel gene families that are conserved across animal phyla but whose biological function is unknown. Here, we functionally characterize a member of one such family, the macoilins. Macoilins are characterized by several highly conserved predicted transmembrane domains towards the N-terminus and by coiled-coil regions C-terminally. They are found throughout Eumetazoa but not in other organisms. Mutants for the single Caenorhabditis elegans macoilin, maco-1, exhibit a constellation of behavioral phenotypes, including defects in aggregation, O2 responses, and swimming. MACO-1 protein is expressed broadly and specifically in the nervous system and localizes to the rough endoplasmic reticulum; it is excluded from dendrites and axons. Apart from subtle synapse defects, nervous system development appears wild-type in maco-1 mutants. However, maco-1 animals are resistant to the cholinesterase inhibitor aldicarb and sensitive to levamisole, suggesting pre-synaptic defects. Using in vivo imaging, we show that macoilin is required to evoke Ca2+ transients, at least in some neurons: in maco-1 mutants the O2-sensing neuron PQR is unable to generate a Ca2+ response to a rise in O2. By genetically disrupting neurotransmission, we show that pre-synaptic input is not necessary for PQR to respond to O2, indicating that the response is mediated by cell-intrinsic sensory transduction and amplification. Disrupting the sodium leak channels NCA-1/NCA-2, or the N-,P/Q,R-type voltage-gated Ca2+ channels, also fails to disrupt Ca2+ responses in the PQR cell body to O2 stimuli. By contrast, mutations in egl-19, which encodes the only Caenorhabditis elegans L-type voltage-gated Ca2+ channel α1 subunit, recapitulate the Ca2+ response defect we see in maco-1 mutants, although we do not see defects in localization of EGL-19. Together, our data suggest that macoilin acts in the ER to regulate assembly or traffic of ion channels or ion channel regulators

Voltage Gated Calcium Channels Negatively Regulate Protective Immunity to Mycobacterium tuberculosis

Mycobacterium tuberculosis modulates levels and activity of key intracellular second messengers to evade protective immune responses. Calcium release from voltage gated calcium channels (VGCC) regulates immune responses to pathogens. In this study, we investigated the roles of VGCC in regulating protective immunity to mycobacteria in vitro and in vivo. Inhibiting L-type or R-type VGCC in dendritic cells (DCs) either using antibodies or by siRNA increased calcium influx in an inositol 1,4,5-phosphate and calcium release calcium activated channel dependent mechanism that resulted in increased expression of genes favoring pro-inflammatory responses. Further, VGCC-blocked DCs activated T cells that in turn mediated killing of M. tuberculosis inside macrophages. Likewise, inhibiting VGCC in infected macrophages and PBMCs induced calcium influx, upregulated the expression of pro-inflammatory genes and resulted in enhanced killing of intracellular M. tuberculosis. Importantly, compared to healthy controls, PBMCs of tuberculosis patients expressed higher levels of both VGCC, which were significantly reduced following chemotherapy. Finally, blocking VGCC in vivo in M. tuberculosis infected mice using specific antibodies increased intracellular calcium and significantly reduced bacterial loads. These results indicate that L-type and R-type VGCC play a negative role in M. tuberculosis infection by regulating calcium mobilization in cells that determine protective immunity

A promising method for identifying cross-cultural differences in patient perspective: the use of Internet-based focus groups for content validation of new Patient Reported Outcome assessments

OBJECTIVES: This proof of concept (POC) study was designed to evaluate the use of an Internet-based bulletin board technology to aid parallel cross-cultural development of thematic content for a new set of patient-reported outcome measures (PROs). METHODS: The POC study, conducted in Germany and the United States, utilized Internet Focus Groups (IFGs) to assure the validity of new PRO items across the two cultures – all items were designed to assess the impact of excess facial oil on individuals' lives. The on-line IFG activities were modeled after traditional face-to-face focus groups and organized by a common 'Topic' Guide designed with input from thought leaders in dermatology and health outcomes research. The two sets of IFGs were professionally moderated in the native language of each country. IFG moderators coded the thematic content of transcripts, and a frequency analysis of code endorsement was used to identify areas of content similarity and difference between the two countries. Based on this information, draft PRO items were designed and a majority (80%) of the original participants returned to rate the relative importance of the newly designed questions. FINDINGS: The use of parallel cross-cultural content analysis of IFG transcripts permitted identification of the major content themes in each country as well as exploration of the possible reasons for any observed differences between the countries. Results from coded frequency counts and transcript reviews informed the design and wording of the test questions for the future PRO instrument(s). Subsequent ratings of item importance also deepened our understanding of potential areas of cross-cultural difference, differences that would be explored over the course of future validation studies involving these PROs. CONCLUSION: The use of IFGs for cross-cultural content development received positive reviews from participants and was found to be both cost and time effective. The novel thematic coding methodology provided an empirical platform on which to develop culturally sensitive questionnaire content using the natural language of participants. Overall, the IFG responses and thematic analyses provided a thorough evaluation of similarities and differences in cross-cultural themes, which in turn acted as a sound base for the development of new PRO questionnaires

GABA Maintains the Proliferation of Progenitors in the Developing Chick Ciliary Marginal Zone and Non-Pigmented Ciliary Epithelium

GABA is more than the main inhibitory neurotransmitter found in the adult CNS. Several studies have shown that GABA regulates the proliferation of progenitor and stem cells. This work examined the effects of the GABAA receptor system on the proliferation of retinal progenitors and non-pigmented ciliary epithelial (NPE) cells. qRT-PCR and whole-cell patch-clamp electrophysiology were used to characterize the GABAA receptor system. To quantify the effects on proliferation by GABAA receptor agonists and antagonists, incorporation of thymidine analogues was used. The results showed that the NPE cells express functional extrasynaptic GABAA receptors with tonic properties and that low concentration of GABA is required for a baseline level of proliferation. Antagonists of the GABAA receptors decreased the proliferation of dissociated E12 NPE cells. Bicuculline also had effects on progenitor cell proliferation in intact E8 and E12 developing retina. The NPE cells had low levels of the Cl–transporter KCC2 compared to the mature retina, suggesting a depolarising role for the GABAA receptors. Treatment with KCl, which is known to depolarise membranes, prevented some of the decreased proliferation caused by inhibition of the GABAA receptors. This supported the depolarising role for the GABAA receptors. Inhibition of L-type voltage-gated Ca2+ channels (VGCCs) reduced the proliferation in the same way as inhibition of the GABAA receptors. Inhibition of the channels increased the expression of the cyclin-dependent kinase inhibitor p27KIP1, along with the reduced proliferation. These results are consistent with that when the membrane potential indirectly regulates cell proliferation with hyperpolarisation of the membrane potential resulting in decreased cell division. The increased expression of p27KIP1 after inhibition of either the GABAA receptors or the L-type VGCCs suggests a link between the GABAA receptors, membrane potential, and intracellular Ca2+ in regulating the cell cycle