Impaired Mitophagy and Protein Acetylation Levels in Fibroblasts from Parkinson's Disease Patients

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. While most PD cases are idiopathic, the known genetic causes of PD are useful to understand common disease mechanisms. Recent data suggests that autophagy is regulated by protein acetylation mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities. The changes in histone acetylation reported to be involved in PD pathogenesis have prompted this investigation of protein acetylation and HAT and HDAC activities in both idiopathic PD and G2019S leucine-rich repeat kinase 2 (LRRK2) cell cultures. Fibroblasts from PD patients (with or without the G2019S LRRK2 mutation) and control subjects were used to assess the different phenotypes between idiopathic and genetic PD. G2019S LRRK2 mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria. This reduction of mitophagy is accompanied by more reactive oxygen species (ROS). In parallel, the acetylation protein levels of idiopathic and genetic individuals are different due to an upregulation in class I and II HDACs. Despite this upregulation, the total HDAC activity is decreased in idiopathic PD and the total HAT activity does not significantly vary. Mitophagy upregulation is beneficial for reducing the ROS-induced harm in genetic PD. The defective mitophagy in idiopathic PD is inherent to the decrease in class III HDACs. Thus, there is an imbalance between total HATs and HDACs activities in idiopathic PD, which increases cell death. The inhibition of HATs in idiopathic PD cells displays a cytoprotective effect

Sexual Size Dimorphism and Body Condition in the Australasian Gannet

Funding: The research was financially supported by the Holsworth Wildlife Research Endowment. Acknowledgments We thank the Victorian Marine Science Consortium, Sea All Dolphin Swim, Parks Victoria, and the Point Danger Management Committee for logistical support. We are grateful for the assistance of the many field volunteers involved in the study.Peer reviewedPublisher PD

Interventions in health organisations to reduce the impact of adverse events in second and third victims

Background Adverse events (AE) are also the cause of suffering in health professionals involved. This study was designed to identify and analyse organization-level strategies adopted in both primary care and hospitals in Spain to address the impact of serious AE on second and third victims. Methods A cross-sectional study was conducted in healthcare organizations assessing: safety culture; health organization crisis management plans for serious AE; actions planned to ensure transparency in communication with patients (and relatives) who experience an AE; support for second victims; and protective measures to safeguard the institution’s reputation (the third victim). Results A total of 406 managers and patient safety coordinators replied to the survey. Deficient provision of support for second victims was acknowledged by 71 and 61 % of the participants from hospitals and primary care respectively; these respondents reported there was no support protocol for second victims in place in their organizations. Regarding third victim initiatives, 35 % of hospital and 43 % of primary care professionals indicated no crisis management plan for serious AE existed in their organization, and in the case of primary care, there was no crisis committee in 34 % of cases. The degree of implementation of second and third victim support interventions was perceived to be greater in hospitals (mean 14.1, SD 3.5) than in primary care (mean 11.8, SD 3.1) (p?<?0.001). Conclusions Many Spanish health organizations do not have a second and third victim support or a crisis management plan in place to respond to serious AEs

The aftermath of adverse events in spanish primary care and hospital health professionals

Background Adverse events (AEs) cause harm in patients and disturbance for the professionals involved in the event (second victims). This study assessed the impact of AEs in primary care (PC) and hospitals in Spain on second victims. Methods A cross-sectional study was conducted. We carried out a survey based on a random sample of doctors and nurses from PC and hospital settings in Spain. A total of 1087 health professionals responded, 610 from PC and 477 from hospitals. Results A total of 430 health professionals (39.6%) had informed a patient of an error. Reporting to patients was carried out by those with the strongest safety culture (Odds Ratio –OR- 1.1, 95% Confidence Interval –CI- 1.0-1.2), nurses (OR 1.9, 95% CI 1.5-2.3), those under 50 years of age (OR 0.7, 95% CI 0.6-0.9) and primary care staff (OR 0.6, 95% CI 0.5-0.9). A total of 381 (62.5%, 95% CI 59-66%) and 346 (72.5%, IC95% 69-77%) primary care and hospital health professionals, respectively, reported having gone through the second-victim experience, either directly or through a colleague, in the previous 5 years. The emotional responses were: feelings of guilt (521, 58.8%), anxiety (426, 49.6%), re-living the event (360, 42.2%), tiredness (341, 39.4%), insomnia (317, 38.0%) and persistent feelings of insecurity (284, 32.8%). In doctors, the most common responses were: feelings of guilt (OR 0.7 IC95% 0.6-0.8), re-living the event (OR 0.7, IC95% o.6-0.8), and anxiety (OR 0.8, IC95% 0.6-0.9), while nurses showed greater solidarity in terms of supporting the second victim, in both PC (p?=?0.019) and hospital (p?=?0.019) settings. Conclusions Adverse events cause guilt, anxiety, and loss of confidence in health professionals. Most are involved in such events as second victims at least once in their careers. They rarely receive any training or education on coping strategies for this phenomenon

Genetic polymorphisms located in genes related to immune and inflammatory processes are associated with end-stage renal disease: a preliminary study

Background Chronic kidney disease progression has been linked to pro-inflammatory cytokines and markers of inflammation. These markers are also elevated in end-stage renal disease (ESRD), which constitutes a serious public health problem. Objective To investigate whether single nucleotide polymorphisms (SNPs) located in genes related to immune and inflammatory processes, could be associated with ESRD development. Design and methods A retrospective case-control study was carried out on 276 patients with ESRD and 288 control subjects. Forty-eight SNPs were genotyped via SNPlex platform. Logistic regression was used to assess the relationship between each sigle polymorphism and the development of ESRD. Results Four polymorphisms showed association with ESRD: rs1801275 in the interleukin 4 receptor (IL4R) gene (OR: 0.66 (95%CI=0.46-0.95); p=0.025; overdominant model), rs4586 in chemokine (C-C motif) ligand 2 (CCL2) gene (OR: 0.70 (95%CI=0.54-0.90); p=0.005; additive model), rs301640 located in an intergenic binding site for signal transducer and activator of transcription 4 (STAT4) (OR: 1.82 (95%CI=1.17-2.83); p=0.006; additive model) and rs7830 in the nitric oxide synthase 3 (NOS3) gene (OR: 1.31 (95%CI=1.01-1.71); p=0.043; additive model). After adjusting for multiple testing, results lost significance. Conclusion Our preliminary data suggest that four genetic polymorphisms located in genes related to inflammation and immune processes could help to predict the risk of developing ESRD.This work was supported by grants from Instituto de Salud Carlos III (Ref: PI08/0738 and PI11/00245) to SR and Junta de Castilla y Leon (Ref: GRS 234/A/08) to ET. 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Documento de posición sobre las necesidades y niveles óptimos de vitamina D

IntroducciónEn los últimos años se ha producido un notable interés por la vitamina D, no sólo por su importancia crucial en el metabolismo mineral óseo, sino también por los efectos extraóseos, cada vez mejor conocidos. Asi mismo, se ha constatado la existencia de valores séricos bajos de vitamina D, por debajo de lo deseable, en diferentes poblaciones, tanto sanas como enfermas, y se discute cuáles serían los niveles óptimos de vitamina D en sangre. Por todo ello, la Sociedad Española de Investigación Ósea y Metabolismo Mineral (SEIOMM), conjuntamente con todas las Sociedades Científicas implicadas en el estudio del metabolismo óseo, han elaborado el presente documento de posición sobre las necesidades y niveles óptimos de vitamina D

Isoreticular two-dimensional magnetic coordination polymers prepared through pre-synthetic ligand functionalization

Chemical functionalization is a powerful approach to tailor the physical and chemical properties of two-dimensional materials, increase their processability and stability, tune their functionalities and, even, create new 2D materials. This is typically achieved through post-synthetic functionalization by anchoring molecules on the surface of an exfoliated 2D crystal, but it inevitably alters the long-range structural order of the material. Here we present a pre-synthetic approach that allows the isolation of crystalline, robust, and magnetic functionalized monolayers of coordination polymers. A series of five isoreticular layered magnetic coordination polymers based on Fe(II) centres and different benzimidazole derivatives (bearing a Cl, H, CH3, Br or NH2 side group) were first prepared. On mechanical exfoliation, 2D materials are obtained that retain their long-range structural order and exhibit good mechanical and magnetic properties. This combination, together with the possibility to functionalize their surface at will, makes them good candidates to explore magnetism in the 2D limit and to fabricate mechanical resonators for selective gas sensing

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Oxidative Stress Mediates Physiological Costs of Begging in Magpie (Pica pica) Nestlings

[Background] Theoretical models predict that a cost is necessary to guarantee honesty in begging displays given by offspring to solicit food from their parents. There is evidence for begging costs in the form of a reduced growth rate and immunocompetence. Moreover, begging implies vigorous physical activity and attentiveness, which should increase metabolism and thus the releasing of pro-oxidant substances. Consequently, we predict that soliciting offspring incur a cost in terms of oxidative stress, and growth rate and immune response (processes that generate pro-oxidants substances) are reduced in order to maintain oxidative balance. [Methodology/Principal Findings] We test whether magpie (Pica pica) nestlings incur a cost in terms of oxidative stress when experimentally forced to beg intensively, and whether oxidative balance is maintained by reducing growth rate and immune response. Our results show that begging provokes oxidative stress, and that nestlings begging for longer bouts reduce growth and immune response, thereby maintaining their oxidative status. [Conclusions/Significance] These findings help explaining the physiological link between begging and its associated growth and immunocompetence costs, which seems to be mediated by oxidative stress. Our study is a unique example of the complex relationships between the intensity of a communicative display (begging), oxidative stress, and life-history traits directly linked to viability.GM-R was supported by the Spanish Government (Ministerio de Ciencia y Tecnología, “Juan de la Cierva” program), and TR was supported by the Consejo Superior de Investigaciones Científicas (CSIC; Proyectos Intramurales Especiales)

Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures

Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes. Secretion of these exosomes requires neutral sphingomyelinase 2 and sphingolipid synthesis. Our results reveal a homeostatic response counteracting lysosomal dysfunction via secretion of atypical exosomes eliminating lysosomal waste and define exosomal APP-CTFs and BMP as candidate biomarkers for endolysosomal dysfunction associated with neurodegenerative disorders.Fan Wang for the kind gift of the Pi3kc3flox/flox mice. We thank Basant Abdulrahman and Hermann Schaetzl for providing the gene-edited Atg5 KO N2a cells. We are also grateful to Zhenyu Yue, Ralph Nixon, and Jean Gruenberg for the kind gift of anti-Atg14L, Cathepsin D, and BMP antibodies, respectively. We thank Thomas Südhof for sharing Cre recombinase lentiviruses. We thank the OCS Microscopy Core of New York University Langone Medical Center for the support of the EM work and Rocio Perez-Gonzalez and Efrat Levy of New York University for their support during optimization of the brain exosome isolation technique. We thank Elizabeta Micevska for the maintenance and genotyping of the animal colony and Bowen Zhou for the preliminary lipidomic analysis of conditional Pi3kc3 cKO mice. We also thank Rebecca Williams and Catherine Marquer for critically reading the manuscript. This work was supported by grants from the Fundação para a Ciência e Tecnologia (PD/BD/105915/2014 to A.M.M.); the National Institute of Health (R01 NS056049 to G.D.P., transferred to Ron Liem, Columbia University; T32-MH015174 to Rene Hen (Z.M.L.)). Z.M.L. and R.B.C. received pilot grants from ADRC grant P50 AG008702 to S.A.S.info:eu-repo/semantics/publishedVersio