Physical parameters and emission mechanism in Gamma-Ray Bursts

Detailed information on the physical parameters in the sources of cosmological Gamma-Ray Bursts (GRBs) is obtained from few plausible assumptions consistent with observations. Model-independent requirements posed by these assumptions on the emission mechanism in GRBs are formulated. It is found that the observed radiation in sub-MeV energy range is generated by the synchrotron emission mechanism, though about ten per cent of the total GRB energy should be converted via the inverse Compton process into ultra-hard spectral domain (above 100 GeV). We estimate the magnetic field strength in the emitting region, the Lorentz factor of accelerated electrons, and the typical energy of IC photons. We show that there is a "line-of-death" relation for GRBs and derive from this relation the lower limits on both GRB duration and GRB variability timescale. The upper limit on the Lorentz factor of GRB fireballs is also found. We demonstrate that steady-state electron distribution consistent with the Compton losses may produce different spectral indices, e.g., 3/4 as opposed to the figure 1/2 widely discussed in the literature. It is suggested that the changes in the decline rate observed in the lightcurves of several GRB afterglows may be due to the time evolution of spectral break, which appears in the synchrotron emission generated by steady-state self-consistent electron distribution.Comment: Journal reference added, introduction extended, minor changes in notation

A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy

Members of the AAA+ superfamily of ATPases are involved in the unfolding of proteins and disassembly of protein complexes and aggregates. ATAD1 encoding the ATPase family, AAA+ domain containing 1-protein Thorase plays an important role in the function and integrity of mitochondria and peroxisomes. Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2. Using whole-exome sequencing, we identified a homozygous frameshift mutation in the last exon of ATAD1 [c.1070_1071delAT; p.(His357Argfs*15)] in three siblings who presented with a severe, lethal encephalopathy associated with stiffness and arthrogryposis. Biochemical and cellular analyses show that the C-terminal end of Thorase mutant gained a novel function that strongly impacts its oligomeric state, reduces stability or expression of a set of Golgi, peroxisomal and mitochondrial proteins and affects disassembly of GluA2 and Thorase oligomer complexes. Atad1−/− neurons expressing Thorase mutantHis357Argfs*15 display reduced amount of GluA2 at the cell surface suggesting that the Thorase mutant may inhibit the recycling back and/or reinsertion of AMPA receptors to the plasma membrane. Taken together, our molecular and functional analyses identify an activating ATAD1 mutation as a new cause of severe encephalopathy and congenital stiffness

Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei

As part of the Seattle Structural Genomics Center for Infectious Disease, we seek to enhance structural genomics with ligand-bound structure data which can serve as a blueprint for structure-based drug design. We have adapted fragment-based screening methods to our structural genomics pipeline to generate multiple ligand-bound structures of high priority drug targets from pathogenic organisms. In this study, we report fragment screening methods and structure determination results for 2C-methyl-D-erythritol-2,4-cyclo-diphosphate (MECP) synthase from Burkholderia pseudomallei, the gram-negative bacterium which causes melioidosis. Screening by nuclear magnetic resonance spectroscopy as well as crystal soaking followed by X-ray diffraction led to the identification of several small molecules which bind this enzyme in a critical metabolic pathway. A series of complex structures obtained with screening hits reveal distinct binding pockets and a range of small molecules which form complexes with the target. Additional soaks with these compounds further demonstrate a subset of fragments to only bind the protein when present in specific combinations. This ensemble of fragment-bound complexes illuminates several characteristics of MECP synthase, including a previously unknown binding surface external to the catalytic active site. These ligand-bound structures now serve to guide medicinal chemists and structural biologists in rational design of novel inhibitors for this enzyme

Efficacy of AZM therapy in patients with gingival overgrowth induced by Cyclosporine A: a systematic review

<p>Abstract</p> <p>Background</p> <p>In daily clinical practice of a dental department it's common to find gingival overgrowth (GO) in periodontal patients under treatment with Cyclosporine A (CsA). The pathogenesis of GO and the mechanism of action of Azithromycin (AZM) are unclear. A systematic review was conducted in order to evaluate the efficacy of Azithromycin in patients with gingival overgrowth induced by assumption of Cyclosporine A.</p> <p>Methods</p> <p>A bibliographic search was performed using the online databases MEDLINE, EMBASE and Cochrane Central of Register Controlled Trials (CENTRAL) in the time period between 1966 and September 2008.</p> <p>Results</p> <p>The literature search retrieved 24 articles; only 5 were Randomised Controlled Trials (RCTs), published in English, fulfilled the inclusion criteria. A great heterogeneity between proposed treatments and outcomes was found, and this did not allow to conduct a quantitative meta-analysis. The systematic review revealed that a 5-day course of Azithromycin with Scaling and Root Planing reduces the degree of gingival overgrowth, while a 7-day course of metronidazole is only effective on concomitant bacterial over-infection.</p> <p>Conclusion</p> <p>Few RCTs on the efficacy of systemic antibiotic therapy in case of GO were found in the literature review. A systemic antibiotic therapy without plaque and calculus removal is not able to reduce gingival overgrowth. The great heterogeneity of diagnostic data and outcomes is due to the lack of precise diagnostic methods and protocols about GO. Future studies need to improve both diagnostic methods and tools and adequate classification aimed to determine a correct prognosis and an appropriate therapy for gingival overgrowth.</p

(How) do medical students regulate their emotions?

BACKGROUND: Medical training can be a challenging and emotionally intense period for medical students. However the emotions experienced by medical students in the face of challenging situations and the emotion regulation strategies they use remains relatively unexplored. The aim of the present study was to explore the emotions elicited by memorable incidents reported by medical students and the associated emotion regulation strategies. METHODS: Peer interviewing was used to collect medical students’ memorable incidents. Medical students at both preclinical and clinical stage of medical school were eligible to participate. In total 104 medical students provided memorable incidents. Only 54 narratives included references to emotions and emotion regulation and thus were further analyzed. RESULTS: The narratives of 47 clinical and 7 preclinical students were further analyzed for their references to emotions and emotion regulation strategies. Forty seven out of 54 incidents described a negative incident associated with negative emotions. The most frequently mentioned emotion was shock and surprise followed by feelings of embarrassment, sadness, anger and tension or anxiety. The most frequent reaction was inaction often associated with emotion regulation strategies such as distraction, focusing on a task, suppression of emotions and reappraisal. When students witnessed mistreatment or disrespect exhibited towards patients, the regulation strategy used involved focusing and comforting the patient. CONCLUSIONS: The present study sheds light on the strategies medical students use to deal with intense negative emotions. The vast majority reported inaction in the face of a challenging situation and the use of more subtle strategies to deal with the emotional impact of the incident. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12909-016-0832-9) contains supplementary material, which is available to authorized users

Relativistic Dynamics and Extreme Mass Ratio Inspirals

It is now well-established that a dark, compact object (DCO), very likely a massive black hole (MBH) of around four million solar masses is lurking at the centre of the Milky Way. While a consensus is emerging about the origin and growth of supermassive black holes (with masses larger than a billion solar masses), MBHs with smaller masses, such as the one in our galactic centre, remain understudied and enigmatic. The key to understanding these holes - how some of them grow by orders of magnitude in mass - lies in understanding the dynamics of the stars in the galactic neighbourhood. Stars interact with the central MBH primarily through their gradual inspiral due to the emission of gravitational radiation. Also stars produce gases which will subsequently be accreted by the MBH through collisions and disruptions brought about by the strong central tidal field. Such processes can contribute significantly to the mass of the MBH and progress in understanding them requires theoretical work in preparation for future gravitational radiation millihertz missions and X-ray observatories. In particular, a unique probe of these regions is the gravitational radiation that is emitted by some compact stars very close to the black holes and which could be surveyed by a millihertz gravitational wave interferometer scrutinizing the range of masses fundamental to understanding the origin and growth of supermassive black holes. By extracting the information carried by the gravitational radiation, we can determine the mass and spin of the central MBH with unprecedented precision and we can determine how the holes "eat" stars that happen to be near them.Comment: Update from the first version, 151 pages, accepted for publication @ Living Reviews in Relativit

The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia

BACKGROUND: A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors. PRESENTATION OF THE HYPOTHESIS: Based on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia. TESTING THE HYPOTHESIS: Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis suggests glial cells as the locus of the genes-environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments