Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition

Parkinson's disease (PD) is associated with degeneration of nigrostriatal neurons due to intracytoplasmic inclusions composed predominantly of a synaptic protein called α-synuclein. Accumulations of α-synuclein are thought to 'mask' acetylation sites on histone proteins, inhibiting the action of histone acetyltransferase (HAT) enzymes in their equilibrium with histone deacetylases (HDACs), thus deregulating the dynamic control of gene transcription. It is therefore hypothesised that the misbalance in the actions of HATs/HDACs in neurodegeneration can be rectified with the use of HDAC inhibitors, limiting the deregulation of transcription and aiding neuronal homeostasis and neuroprotection in disorders such as PD. Here we quantify histone acetylation in the Substantia Nigra pars compacta (SNpc) in the brains of control, early and late stage PD cases to determine if histone acetylation is a function of disease progression. PD development is associated with Braak-dependent increases in histone acetylation. Concurrently, we show that as expected disease progression is associated with reduced markers of dopaminergic neurons and increased markers of activated microglia. We go on to demonstrate that in vitro, degenerating dopaminergic neurons exhibit histone hypoacetylation whereas activated microglia exhibit histone hyperacetylation. This suggests that the disease-dependent increase in histone acetylation observed in human PD cases is likely a combination of the contributions of both degenerating dopaminergic neurons and infiltrating activated microglia. The HDAC SIRT 2 has become increasingly implicated as a novel target for mediation of neuroprotection in PD: the neuronal and microglial specific effects of its inhibition however remain unclear. We demonstrate that SIRT 2 expression in the SNpc of PD brains remains relatively unchanged from controls and that SIRT 2 inhibition, via AGK2 treatment of neuronal and microglial cultures, results in neuroprotection of dopaminergic neurons and reduced activation of microglial cells. Taken together, here we demonstrate that histone acetylation is disease-dependently altered in PD, likely due the effects of dopaminergic neurodegeneration and microglial infiltration; yet SIRT 2 remains relatively unaltered with disease. Given the stable nature of SIRT 2 expression with disease and the effects of SIRT 2 inhibitor treatment on degenerating dopaminergic neurons and activated microglia detected in vitro, SIRT 2 inhibitors warrant further investigation as potential therapeutics for the treatment of the PD

Molecular gas in nearby powerful radio galaxies

We report the detection of CO(1-0) and CO(2-1) emission from the central region of nearby 3CR radio galaxies (z$<$ 0.03). Out of 21 galaxies, 8 have been detected in, at least, one of the two CO transitions. The total molecular gas content is below 10$^9$ \msun. Their individual CO emission exhibit, for 5 cases, a double-horned line profile that is characteristic of an inclined rotating disk with a central depression at the rising part of its rotation curve. The inferred disk or ring distributions of the molecular gas is consistent with the observed presence of dust disks or rings detected optically in the cores of the galaxies. We reason that if their gas originates from the mergers of two gas-rich disk galaxies, as has been invoked to explain the molecular gas in other radio galaxies, then these galaxies must have merged a long time ago (few Gyr or more) but their remnant elliptical galaxies only recently (last 10$^7$ years or less) become active radio galaxies. Instead, we argue the the cannibalism of gas-rich galaxies provide a simpler explanation for the origin of molecular gas in the elliptical hosts of radio galaxies (Lim et al. 2000). Given the transient nature of their observed disturbances, these galaxies probably become active in radio soon after the accretion event when sufficient molecular gas agglomerates in their nuclei.Comment: 6 pages, including 2 figures,in "QSO Hosts and Their Environments", ed. I. Marquez, in pres

Sources of Relativistic Jets in the Galaxy

Black holes of stellar mass and neutron stars in binary systems are first detected as hard X-ray sources using high-energy space telescopes. Relativistic jets in some of these compact sources are found by means of multiwavelength observations with ground-based telescopes. The X-ray emission probes the inner accretion disk and immediate surroundings of the compact object, whereas the synchrotron emission from the jets is observed in the radio and infrared bands, and in the future could be detected at even shorter wavelengths. Black-hole X-ray binaries with relativistic jets mimic, on a much smaller scale, many of the phenomena seen in quasars and are thus called microquasars. Because of their proximity, their study opens the way for a better understanding of the relativistic jets seen elsewhere in the Universe. From the observation of two-sided moving jets it is inferred that the ejecta in microquasars move with relativistic speeds similar to those believed to be present in quasars. The simultaneous multiwavelength approach to microquasars reveals in short timescales the close connection between instabilities in the accretion disk seen in the X-rays, and the ejection of relativistic clouds of plasma observed as synchrotron emission at longer wavelengths. Besides contributing to a deeper comprehension of accretion disks and jets, microquasars may serve in the future to determine the distances of jet sources using constraints from special relativity, and the spin of black holes using general relativity.Comment: 39 pages, Tex, 8 figures, to appear in vol. 37 (1999) of Annual Reviews of Astronomy and Astrophysic

Fludarabine as a cost-effective adjuvant to enhance engraftment of human normal and malignant hematopoiesis in immunodeficient mice

There is still an unmet need for xenotransplantation models that efficiently recapitulate normal and malignant human hematopoiesis. Indeed, there are a number of strategies to generate humanized mice and specific protocols, including techniques to optimize the cytokine environment of recipient mice and drug alternatives or complementary to the standard conditioning regimens, that can be significantly modulated. Unfortunately, the high costs related to the use of sophisticated mouse models may limit the application of these models to studies that require an extensive experimental design. Here, using an affordable and convenient method, we demonstrate that the administration of fludarabine (FludaraTM) promotes the extensive and rapid engraftment of human normal hematopoiesis in immunodeficient mice. Quantification of human CD45+ cells in bone marrow revealed approximately a 102-fold increase in mice conditioned with irradiation plus fludarabine. Engrafted cells in the bone marrow included hematopoietic stem cells, as well as myeloid and lymphoid cells. Moreover, this model proved to be sufficient for robust reconstitution of malignant myeloid hematopoiesis, permitting primary acute myeloid leukemia cells to engraft as early as 8 weeks after the transplant. Overall, these results present a novel and affordable model for engraftment of human normal and malignant hematopoiesis in immunodeficient mice

Performance analysis of cables with attached tuned-inerter-dampers

Cables are structural elements designed to bear tensile forces and experience vibration problems due to their slenderness and low mass. In the field of civil engineering, they are mostly used in bridges where the vibrations are mainly induced by wind, rain, traffic and earthquakes. This paper proposes the use of a tuned-inerter-damper (TID) system, mounted on cables to suppress unwanted vibrations. These are to be attached transversally to the cable, in the vicinity of the support, connected between the deck and the cable. The potential advantage of using a TID system consists in the high apparent mass that can be produced by the inerter. Our analysis showed that the modal damping ratio obtained is much higher than in the case of traditional dampers or tuned mass dampers, leading to an improved overall response. An optimal tuning methodology is also discussed. Numerical results are shown with a cable subjected to both free and forced vibrations and the TID performance is improved when compared with equivalent dampers

Shake table testing of a tuned mass damper inerter (Tmdi)-equipped structure and nonlinear dynamic modeling under harmonic excitations

This paper presents preliminary experimental results from a novel shaking table testing campaign investigating the dynamic response of a two-degree-of-freedom (2DOF) physical specimen with a grounded inerter under harmonic base excitation and contributes a nonlinear dynamic model capturing the behavior of the test specimen. The latter consists of a primary mass connected to the ground through a high damping rubber isolator (HDRI) and a secondary mass connected to the primary mass through a second HDRI. Further, a flywheel-based rack-and-pinion inerter prototype device is used to connect the secondary mass to the ground. The resulting specimen resembles the tuned mass damper inerter (TMDI) configuration with grounded inerter analytically defined and numerically assessed by the authors in a number of previous publications. Physical specimens with three different inerter coefficients are tested on the shake table under sine-sweep excitation with three different amplitudes. Experimental frequency response functions (FRFs) are derived manifesting a softening nonlinear behavior of the specimens and enhanced vibration suppression with increased inerter coefficient. Further, a 2DOF parametric nonlinear model of the specimen is established accounting for non-ideal inerter device behavior and its potential to characterize experimental response time-histories, FRFs, and force-displacement relationships of the HDRIs and of the inerter is verified

National or population level interventions addressing the social determinants of mental health - an umbrella review

Background: Social circumstances in which people live and work impact the population’s mental health. We aimed to synthesise evidence identifying effective interventions and policies that influence the social determinants of mental health at national or scaled population level. We searched five databases (Cochrane Library, Global Health, MEDLINE, EMBASE and PsycINFO) between Jan 1st 2000 and July 23rd 2019 to identify systematic reviews of population-level interventions or policies addressing a recognised social determinant of mental health and collected mental health outcomes. There were no restrictions on country, sub-population or age. A narrative overview of results is provided. Quality assessment was conducted using Assessment of Multiple Systematic Reviews (AMSTAR 2). This study was registered on PROSPERO (CRD42019140198). Results: We identified 20 reviews for inclusion. Most reviews were of low or critically low quality. Primary studies were mostly observational and from higher income settings. Higher quality evidence indicates more generous welfare benefits may reduce socioeconomic inequalities in mental health outcomes. Lower quality evidence suggests unemployment insurance, warm housing interventions, neighbourhood renewal, paid parental leave, gender equality policies, community-based parenting programmes, and less restrictive migration policies are associated with improved mental health outcomes. Low quality evidence suggests restriction of access to lethal means and multi-component suicide prevention programmes are associated with reduced suicide risk. Conclusion: This umbrella review has identified a small and overall low-quality evidence base for population level interventions addressing the social determinants of mental health. There are significant gaps in the evidence base for key policy areas, which limit ability of national policymakers to understand how to effectively improve population mental health

Cross infection control measures and the treatment of patients at risk of Creutzfeldt Jakob disease in UK general dental practice

AIMS: To determine the suitability of key infection control measures currently employed in UK dental practice for delivery of dental care to patients at risk of prion diseases. MATERIALS AND METHODS: Subjects: Five hundred dental surgeons currently registered with the General Dental Council of the UK. Data collection: Structured postal questionnaire. Analysis: Frequencies, cross-tabulations and chi-squared analysis. RESULTS: The valid response rate to the questionnaire was 69%. 33% of practices had no policy on general disinfection and sterilisation procedures. Only 10 of the 327 responding practices (3%) possessed a vacuum autoclave. 49% of dentists reported using the BDA medical history form but less than 25% asked the specific questions recommended by the BDA to identify patients at risk of iatrogenic or familial CJD. However, 63% of practitioners would refer such patients, if identified, to a secondary care facility. Of the 107 practitioners who were prepared to provide dental treatment, 75 (70%) would do so using routine infection control procedures. CONCLUSIONS: Most of the dental practices surveyed were not actively seeking to identify patients at risk of prion diseases. In many cases, recommended procedures for providing safe dental care for such patients were not in place

U.S. academic libraries: understanding their web presence and their relationship with economic indicators

The final publication is available at Springer via http://dx.doi.org/10.1007/s11192-013-1001-0The main goal of this research is to analyze the web structure and performance of units and services belonging to U.S. academic libraries in order to check their suitability for webometric studies. Our objectives include studying their possible correlation with economic data and assessing their use for complementary evaluation purposes. We conducted a survey of library homepages, institutional repositories, digital collections, and online catalogs (a total of 374 URLs) belonging to the 100 U.S. universities with the highest total expenditures in academic libraries according to data provided by the National Center for Education Statistics. Several data points were taken and analyzed, including web variables (page count, external links, and visits) and economic variables (total expenditures, expenditures on printed and electronic books, and physical visits). The results indicate that the variety of URL syntaxes is wide, diverse and complex, which produces a misrepresentation of academic libraries’ web resources and reduces the accuracy of web analysis. On the other hand, institutional and web data indicators are not highly correlated. Better results are obtained by correlating total library expenditures with URL mentions measured by Google (r = 0.546) and visits measured by Compete (r = 0.573), respectively. Because correlation values obtained are not highly significant, we estimate such correlations will increase if users can avoid linkage problems (due to the complexity of URLs) and gain direct access to log files (for more accurate data about visits).Orduña Malea, E.; Regazzi, JJ. (2014). U.S. academic libraries: understanding their web presence and their relationship with economic indicators. Scientometrics. 98(1):315-336. doi:10.1007/s11192-013-1001-0S315336981Adecannby, J. (2011). 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The optimal succinylcholine dose for intubating emergency patients: retrospective comparative study

Background : Succinylcholine remains the drug of choice for satisfactory rapid-sequence tracheal intubation. It is not clear from the literature why the 1 mg/kg dose of succinylcholine has been traditionally used. The effective dose (ED95) of succinylcholine is less than 0.3 mg/kg. The dose of 1 mg/kg represents 3.5 to 4 times the ED95. Objectives : To compare the effect of the traditionally used 1 mg/kg of succinylcholine with lower doses of 0.6 mg/kg and 0.45 mg/kg on intubation condition regarding the onset time, duration of action, duration of abdominal fasciculation, and the intubation grading. Methods : This retrospective comparative study was carried into three groups of ASA III & IV (American Society of Anesthesiologist's Physical Status III and IV) non-prepared emergency patients who were intubated at emergency department of Hamad General Hospital, Doha, Qatar during January 1st 2007 to August 31, 2010. The Institutional Research Board (IRB) approval was obtained. This study was limited to 88 patients who received fentanyl 1 µg/kg followed by etomidate 0.3 mg/kg intravenously as induction agents and succinylcholine as a muscle relaxant agent in doses of 0.45 mg/kg, 0.6 mg/kg, or 1 mg/kg. Results : Increasing the succinylcholine dosage shortened the onset time, prolonged the duration of action, and prolonged the duration of abdominal fasciculation significantly (P<.001). Tracheal intubation was 100% successful in the three groups of patients. Conclusion : Succinylcholine dose of 0.45 mg/kg provides an optimal intubation condition in ASA III & IV emergency non-prepared patients. Duration of action of succinylcholine is dose dependent; reducing the dose allows a more rapid return of spontaneous respiration and airway reflexes