TDP-43 promotes the formation of neuromuscular synapses through the regulation of Disc-large expression in Drosophila skeletal muscles

Background: The ribonuclear protein TDP-43 has been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS), with genetic mutations being linked to the neurological symptoms of the disease. Though alterations in the intracellular distribution of TDP-43 have been observed in skeletal muscles of patients suffering from ALS, it is not clear whether such modifications play an active role in the disease or merely represent an expression of muscle homeostatic mechanisms. Also, the molecular and metabolic pathways regulated by TDP-43 in the skeletal muscle remain largely unknown. Here, we analyze the function of TBPH, the Drosophila melanogaster ortholog of TDP-43, in skeletal muscles. Results: We modulated the activity of TDP-43 in Drosophila muscles by means of RNA interference and observed that it is required to promote the formation and growth of neuromuscular synapses. TDP-43 regulated the expression levels of Disc-large (Dlg), and restoring Dlg expression either in skeletal muscles or in motoneurons was sufficient to suppress the locomotive and synaptic defects of TDP-43-null flies. These results were validated by the observation of a decrease in Dlg levels in human neuroblastoma cells and iPSC-differentiated motoneurons derived from ALS patients, suggesting similar mechanisms may potentially be involved in the pathophysiology of the disease. Conclusions: Our results help to unveil the physiological role of TDP-43 in skeletal muscles as well as the mechanisms responsible for the autonomous and non-autonomous behavior of this protein concerning the organization of neuromuscular synapses

Assessment of gastrointestinal dysfunction in selection of an effective method of nutritional support in patients with acute pancreatitis.

Potential mortality in acute pancreatitis (AP) is 5%. Patients with AP represent II type of intestinal insufficiency, which occurs on the background of dyspeptic syndrome and increased intra-abdominal pressure (IAP). IAP is a differentiated indicator. With the increase of IAP more than 10 mmHg, intra-abdominal hypertension (IAH) arises. Increasing IAP to this level is considered as safe. Monitoring of IAP level allows to achieve better clinical results. Totally 47 patients with acute pancreatitis were examined. Depending on the function of the gastrointestinal tract and the selected type of starting nutritional support (NS), they were divided into 2 groups. The first group consisted of IAH patients of I degree and dyspeptic syndrome who underwent parenteral nutrition (PN) with 3-component compounds begun on the 2nd day of disease and after restoration of gastrointestinal tract function a late enteral feeding (LEF) was performed. In the second group, patients with AP were initially diagnosed with elevated IAP at a safe level and dyspeptic syndrome. They were prescribed early enteral nutrition (EEN) with specialized blends from the 2nd day of disease. In 2 days a significant reduction in pain syndrome with the persistence of dyspeptic syndrome and intestinal insufficiency (II) was recorded. In patients with intra-abdominal hypertension, total parenteral nutrition is the effective method of nutritional support, against which, after 5 days manifestations of dyspeptic syndrome and IAP indices decrease to a safe level. Therefore in-time detection of high level of intra-abdominal pressure in patients with acute pancreatitis can help to choose a more rational method of nutritional support

Simultaneous multi-frequency observation of the unknown redshift blazar PG 1553+113 in March-April 2008

The blazar PG 1553+113 is a well known TeV gamma-ray emitter. In this paper, we determine its spectral energy distribution using simultaneous multi-frequency data in order to study its emission processes. An extensive campaign was carried out between March and April 2008, where optical, X-ray, high-energy (HE) gamma-ray, and very-high-energy (VHE) gamma-ray data were obtained with the KVA, Abastumani, REM, RossiXTE/ASM, AGILE and MAGIC telescopes, respectively. This is the first simultaneous broad-band (i.e., HE+VHE) gamma-ray observation, though AGILE did not detect the source. We combine data to derive source's spectral energy distribution and interpret its double peaked shape within the framework of a synchrotron self compton modelComment: 5 pages, 2 figures, publishe

MAGIC Upper Limits for two Milagro-detected, Bright Fermi Sources in the Region of SNR G65.1+0.6

We report on the observation of the region around supernova remnant G65.1+0.6 with the stand-alone MAGIC-I telescope. This region hosts the two bright GeV gamma-ray sources 1FGL J1954.3+2836 and 1FGL J1958.6+2845. They are identified as GeV pulsars and both have a possible counterpart detected at about 35 TeV by the Milagro observatory. MAGIC collected 25.5 hours of good quality data, and found no significant emission in the range around 1 TeV. We therefore report differential flux upper limits, assuming the emission to be point-like (<0.1 deg) or within a radius of 0.3 deg. In the point-like scenario, the flux limits around 1 TeV are at the level of 3 % and 2 % of the Crab Nebula flux, for the two sources respectively. This implies that the Milagro emission is either extended over a much larger area than our point spread function, or it must be peaked at energies beyond 1 TeV, resulting in a photon index harder than 2.2 in the TeV band.Comment: 8 pages, 3 figures, 1 tabl

Study of the reaction e^{+}e^{-} -->J/psi\pi^{+}\pi^{-} via initial-state radiation at BaBar

We study the process $e^+e^-\to J/\psi\pi^{+}\pi^{-}$ with initial-state-radiation events produced at the PEP-II asymmetric-energy collider. The data were recorded with the BaBar detector at center-of-mass energies 10.58 and 10.54 GeV, and correspond to an integrated luminosity of 454 $\mathrm{fb^{-1}}$. We investigate the $J/\psi \pi^{+}\pi^{-}$ mass distribution in the region from 3.5 to 5.5 $\mathrm{GeV/c^{2}}$. Below 3.7 $\mathrm{GeV/c^{2}}$ the $\psi(2S)$ signal dominates, and above 4 $\mathrm{GeV/c^{2}}$ there is a significant peak due to the Y(4260). A fit to the data in the range 3.74 -- 5.50 $\mathrm{GeV/c^{2}}$ yields a mass value $4244 \pm 5$ (stat) $\pm 4$ (syst)$\mathrm{MeV/c^{2}}$ and a width value $114 ^{+16}_{-15}$ (stat)$\pm 7$(syst)$\mathrm{MeV}$ for this state. We do not confirm the report from the Belle collaboration of a broad structure at 4.01 $\mathrm{GeV/c^{2}}$. In addition, we investigate the $\pi^{+}\pi^{-}$ system which results from Y(4260) decay

Cultural diversity teaching and issues of uncertainty: the findings of a qualitative study

BACKGROUND: There is considerable ambiguity in the subjective dimensions that comprise much of the relational dynamic of the clinical encounter. Comfort with this ambiguity, and recognition of the potential uncertainty of particular domains of medicine (e.g.--cultural factors of illness expression, value bias in diagnoses, etc) is an important facet of medical education. This paper begins by defining ambiguity and uncertainty as relevant to clinical practice. Studies have shown differing patterns of students' tolerance for ambiguity and uncertainty that appear to reflect extant attitudinal predispositions toward technology, objectivity, culture, value- and theory-ladeness, and the need for self-examination. This paper reports on those findings specifically related to the theme of uncertainty as relevant to teaching about cultural diversity. Its focus is to identify how and where the theme of certainty arose in the teaching and learning of cultural diversity, what were the attitudes toward this theme and topic, and how these attitudes and responses reflect and inform this area of medical pedagogy. METHODS: A semi-structured interview was undertaken with 61 stakeholders (including policymakers, diversity teachers, students and users). The data were analysed and themes identified. RESULTS: There were diverse views about what the term cultural diversity means and what should constitute the cultural diversity curriculum. There was a need to provide certainty in teaching cultural diversity with diversity teachers feeling under considerable pressure to provide information. Students discomfort with uncertainty was felt to drive cultural diversity teaching towards factual emphasis rather than reflection or taking a patient centred approach. CONCLUSION: Students and faculty may feel that cultural diversity teaching is more about how to avoid professional, medico-legal pitfalls, rather than improving the patient experience or the patient-physician relationship. There may be pressure to imbue cultural diversity issues with levels of objectivity and certainty representative of other aspects of the medical curriculum (e.g.--biochemistry). This may reflect a particular selection bias for students with a technocentric orientation. Inadvertently, medical education may enhance this bias through training effects, and accommodate disregard for subjectivity, over-reliance upon technology and thereby foster incorrect assumptions of objective certainty. We opine that it is important to teach students that technology cannot guarantee certainty, and that dealing with subjectivity, diversity, ambiguity and uncertainty is inseparable from the personal dimension of medicine as moral enterprise. Uncertainty is inherent in cultural diversity so this part of the curriculum provides an opportunity to address the issue as it relates to patient care

MAGIC observations and multiwavelength properties of the quasar 3C279 in 2007 and 2009

3C 279, the first quasar discovered to emit VHE gamma-rays by the MAGIC telescope in 2006, was reobserved by MAGIC in January 2007 during a major optical flare and from December 2008 to April 2009 following an alert from the Fermi space telescope on an exceptionally high gamma -ray state. The January 2007 observations resulted in a detection on January 16 with significance 5.2 sigma, corresponding to a F(&gt; 150 GeV) (3.8 \pm 0.8) \cdot 10^-11 ph cm^-2 s^-1 while the overall data sample does not show significant signal. The December 2008 - April 2009 observations did not detect the source. We study the multiwavelength behavior of the source at the epochs of MAGIC observations, collecting quasi-simultaneous data at optical and X-ray frequencies and for 2009 also gamma-ray data from Fermi. We study the light curves and spectral energy distribution of the source. The spectral energy distributions of three observing epochs (including the February 2006, which has been previously published in Albert et al. 2008a) are modeled with one-zone inverse Compton models and the emission on January 16, 2007 also with two zone model and with a lepto-hadronic model. We find that the VHE gamma-ray emission detected in 2006 and 2007 challenges standard one-zone model, based on relativistic electrons in a jet scattering broad line region photons, while the other studied models fit the observed spectral energy distribution more satisfactorily

A search for Very High Energy gamma-ray emission from Scorpius X-1 with the MAGIC telescopes

The acceleration of particles up to GeV or higher energies in microquasars has been the subject of considerable theoretical and observational efforts in the past few years. Sco X-1 is a microquasar from which evidence of highly energetic particles in the jet has been found when it is in the so-called Horizontal Branch (HB), a state when the radio and hard X-ray fluxes are higher and a powerful relativistic jet is present. Here we present the first very high energy gamma-ray observations of Sco X-1 obtained with the MAGIC telescopes. An analysis of the whole dataset does not yield a significant signal, with 95% CL flux upper limits above 300 GeV at the level of 2.4x10^{-12} ph/cm^2/s. Simultaneous RXTE observations were conducted to search for TeV emission during particular X-ray states of the source. A selection of the gamma-ray data obtained during the HB based on the X-ray colors did not yield a signal either, with an upper limit of 3.4x10^{-12} ph/cm^2/s. These upper limits place a constraint on the maximum TeV luminosity to non-thermal X-ray luminosity of L_{VHE}/L_{ntX}<0.02, that can be related to a maximum TeV luminosity to jet power ratio of L_{VHE}/L_{j}<10^{-3}. Our upper limits indicate that the underlying high-energy emission physics in Sco X-1 must be inherently different from that of the hitherto detected gamma-ray binaries.Comment: 5 pages, 2 figures, 2 tables. Version as published in ApJ

PG 1553+113: five years of observations with MAGIC

We present the results of five years (2005-2009) of MAGIC observations of the BL Lac object PG 1553+113 at very high energies (VHEs, E > 100 GeV). Power law fits of the individual years are compatible with a steady mean photon index \Gamma = 4.27 $\pm$ 0.14. In the last three years of data, the flux level above 150 GeV shows a clear variability (probability of constant flux < 0.001%). The flux variations are modest, lying in the range from 4% to 11% of the Crab Nebula flux. Simultaneous optical data also show only modest variability that seems to be correlated with VHE gamma ray variability. We also performed a temporal analysis of (all available) simultaneous Fermi/LAT data of PG 1553+113 above 1 GeV, which reveals hints of variability in the 2008-2009 sample. Finally, we present a combination of the mean spectrum measured at very high energies with archival data available for other wavelengths. The mean spectral energy distribution can be modeled with a one-zone Synchrotron Self Compton (SSC) model, which gives the main physical parameters governing the VHE emission in the blazar jet.Comment: 11 pages, 6 figures, accepted for publication in Ap