Impact of human alpha-synuclein overexpression on the nigrostriatal dopaminergic neurotransmission

Alpha-synuclein is a small 140 amino acid presynaptic protein associated with everal neurodegenerative disorders such as Parkinson’s disease (PD). In idiopathic PD, abnormally misfolded wild-type proteins aggregate in the cytosol of certain neurons, forming what is the main component of Lewy bodies (LBs) - a major PD hallmark. Besides its role in regulating synaptic vesicle functions, alpha-synuclein appears to modulate dopamine (DA), a neurotransmitter particularly important in PD symptoms manifestation. DA can be found sparsely distributed in the brain and is predominantly expressed in midbrain neurons. From the midbrain, two main dopaminergic (DAergic) pathways densely innervate the dorsal portion of the striatum. Degeneration of such DAergic terminals is known to dysregulate DA homeostasis in the striatum. Despite several decades of PD research, the physiological influence of alpha-synuclein on DAergic neurotransmission in the two main areas of the dorsal striatum is still poorly understood. These areas are the dorsomedial striatum (DMS), mainly receiving innervation from the ventral tegmental area, and the dorsolateral striatum (DLS), which receives input from the substantia nigra pars compacta and is more susceptible to neurodegeneration. To clarify how alpha-synuclein may interfere with DAergic neurotransmission in either area, fast-scan cyclic voltammetry experiments were carried out in the DMS and DLS of transgenic mice overexpressing human alpha-synuclein (Tg) at twelve, six and three months of age. Additionally, pharmacological assays, behavioural tasks, and ex vivo immunofluorescence staining were performed to support the electrophysiological ex vivo results. In this thesis, it is hypothesized that due to its intrinsic characteristics, alpha-synuclein preferentially interferes with DA neurotransmission dynamics in the dorsolateral region of the striatum. Data analysis confirmed that overexpression of human alpha-synuclein differentially interfered with normal DA release in the DLS in an age‐dependent manner. At older ages (twelve-month-old Tg mice), decreased evoked DA release and slower DA uptake kinetics were observed. In addition, alterations in dopamine transporter (DAT) distribution, which appeared as increasing amounts of DAT-positive clumps, were found only in the DLS. Moreover, at pre-symptomatic stages (six-month-old) DA neurotransmission appeared to be stabilised before DA disruption. Surprisingly, at younger ages (three-month-old) increased electrically evoked DA release was also recorded in the DLS. Such changes were in line with the motor learning enhancement observed in their behavioural phenotype. In addition, DA uptake appeared to be impaired as evidenced by reduced extracellular DA withdrawal. Further pharmacological experiments demonstrated that such alterations were mediated by DAT. In summary, the present findings indicate that abnormal DAergic neurotransmission and function of DLS can be identified before the onset of structural pathologies in a model of transgenic expression of human alpha-synuclein. Depending on the progression of the pathology, human alpha-synuclein has different impacts on neurotransmission, initially enhancing it but impairing it at later stages. It is here proposed that assessment of DLS function by non-invasive brain imaging and neuropsychological techniques might be relevant in early PD diagnosis and help design appropriate therapeutic intervention

Striatal dopamine neurotransmission is altered in age- and region-specific manner in a Parkinson's disease transgenic mouse

Dopamine (DA) plays a critical role in striatal motor control. The drop in DA level within the dorsal striatum is directly associated with the appearance of motor symptoms in Parkinson's disease (PD). The progression of the disease and inherent disruption of the DA neurotransmission has been closely related to accumulation of the synaptic protein alpha-synuclein. However, it is still unclear how alpha-synuclein affects dopaminergic terminals in different areas of dorsal striatum. Here we demonstrate that the overexpression of human alpha-synuclein (h-alpha-syn) interferes with the striatal DA neurotransmission in an age-dependent manner, preferentially in the dorsolateral striatum (DLS) of PDGF-h-alpha-syn mice. While 3-month-old mice showed an increase at the onset of h-alpha-syn accumulation in the DLS, 12-month-old mice revealed a decrease in electrically-evoked DA release. The enhanced DA release in 3-month-old mice coincided with better performance in a behavioural task. Notably, DA amplitude alterations were also accompanied by a delay in the DA clearance independently from the animal age. Structurally, dopamine transporter (DAT) was found to be redistributed in larger DAT-positive clumps only in the DLS of 3- and 12-month-old mice. Together, our data provide new insight into the vulnerability of DLS and suggest DAT-related dysfunctionalities from the very early stages of h-alpha-syn accumulation

Adaptation, reliability and validity of a Brief Multicomponent AIDS Phobia Scale (MAPS) in Colombian adolescents

La fobia al sida consiste en un miedo persistente, anormal e injustificado a contraer el VIH. Uno de los instrumentos disponibles para evaluar la fobia al sida es la Multicomponent AIDS Phobia Scale (MAPS). El objetivo de este estudio fue adaptar y validar la MAPS en adolescentes colombianos. Participaron 859 estudiantes entre 14-19 años respondiendo a la MAPS y otros autoinformes para analizar su validez (conocimientos sobre las ITS, actitud hacia el VIH y ansiedad por la salud). El análisis factorial confirmó la estructura bifactorial (F1: miedo a la infección y F2: miedo a otros), de acuerdo con la versión original. Se obtuvo evidencias de fiabilidad y validez consistentes con la teoría. La aplicación de la MAPS es idónea para evaluar miedo al VIH/sida y estudiar su relación con factores de riesgo sexual (uso de condón, múltiples parejas sexuales) a nivel investigador y comunitario en Colombia. También puede ser útil para evaluar el impacto de campañas sociales para reducir el estigma hacia el VIH y programas de prevención dirigidos a promover una sexualidad saludable en adolescentes mediante la transmisión de conocimientos adecuados y actitudes más tolerantes hacia las personas que viven con VIH.The AIDS phobia is a persistent, abnormal and unjustified fear of contracting HIV. The objective of this study was to adapt and validate MAPS in Colombian adolescents. Participants included 856 students aged 14-19 years who responded to the MAPS and other self-reports to analyze its validity (including knowledge about STIs, attitude towards HIV and health anxiety). Factor analysis confirmed the bifactorial structure (F1: fear of infection and F2: fear of others), according to the original version. Evidence of reliability and validity was obtained consistently with the theory. The application of MAPS is appropriate for assessing fear of HIV/AIDS and to study its relationship with sexual risk factors (e.g. condom use, multiple sexual partners) at research and community levels in Colombia. It also can be useful for assessing the impact of social campaigns to reduce stigma towards HIV and prevention programs aimed at promoting healthy sexuality in adolescents through the transmission of adequate knowledge and more favorable attitudes toward people living with HI

Optically triggered infrared photodetector

We demonstrate a new class of semiconductor device: the optically triggered infrared photodetector (OTIP). This photodetector is based on a new physical principle that allows the detection of infrared light to be switched ON and OFF by means of an external light. Our experimental device, fabricated using InAs/AlGaAs quantum-dot technology, demonstrates normal incidence infrared detection in the 2−6 μm range. The detection is optically triggered by a 590 nm light-emitting diode. Furthermore, the detection gain is achieved in our device without an increase of the noise level. The novel characteristics of OTIPs open up new possibilities for third generation infrared imaging system

Optically triggered infrared photodetector

We present and demonstrate experimentally a new kind of semiconductor device: the Optically Triggered Infrared Photodetector. This IR photodetector exhibits the following distinctive features: (1) It can be optically commuted ON and OFF by means of an external light bias, and (2) it does not require electrical power supply. The operation principle of the OTIP is as follows. External high-energy (higher than the semiconductor bandgap) light produces photocurrent in the device. Part of this current is lost as recombination through an intermediate band (IB) [1] within the bandgap of the semiconductor. The addition of IR light reduces such recombination and can be, therefore, measured as an increase in current. This new detector concept can be implemented by including quantum dots (QDs) in-between a p-n junction [2]. We demonstrate the operation of the OTIP in an InAs/AlGaAs QD-based device. Our experimental device shows response to normally incident light in the 2?6 ?m range when externally biased by a 590-nm light emitting diode (LED). It also exhibits IR detection driven by a continuous range of photon energies above the bandgap of the device. Furthermore, we demonstrate an increase in detection gain with increasing light-bias intensity. For high intensities the photo-detection seems to saturate. In our experiments, the increase in detection gain did not come with an increase in the measurement noise; hence, it can be understood as an increase in the detectivity. The novel features of the OTIP opens up possibilities for new device applications, for instance, in optical communications

Expansion of Signal Transduction Pathways in Fungi by Extensive Genome Duplication

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Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication