Daily alcohol intake triggers aberrant synaptic pruning leading to synapse loss and anxiety-like behavior

Alcohol abuse adversely affects the lives of millions of people worldwide. Deficits in synaptic transmission and in microglial function are commonly found in human alcohol abusers and in animal models of alcohol intoxication. Here, we found that a protocol simulating chronic binge drinking in male mice resulted in aberrant synaptic pruning and substantial loss of excitatory synapses in the prefrontal cortex, which resulted in increased anxiety-like behavior. Mechanistically, alcohol intake increased the engulfment capacity of microglia in a manner dependent on the kinase Src, the subsequent activation of the transcription factor NF-κB, and the consequent production of the proinflammatory cytokine TNF. Pharmacological blockade of Src activation or of TNF production in microglia, genetic ablation of Tnf, or conditional ablation of microglia attenuated aberrant synaptic pruning, thereby preventing the neuronal and behavioral effects of the alcohol. Our data suggest that aberrant pruning of excitatory synapses by microglia may disrupt synaptic transmission in response to alcohol abuse.This work was financed by FEDER -Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 -Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER-030647 (PTDC/SAU-TOX/30647/2017) in TS lab. The projects FEDER Portugal (Norte-01-0145-FEDER-000008000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); FCOMP-01-0124-FEDER-021333) and FCT (PTDC/MED-NEU/31318/2017) supported work in JBR lab. CCP and RS hold employment contracts financed by national funds through FCT – Fundação para a Ciência e a Tecnologia, I.P., in the context of the program-contract described in paragraphs 4, 5 and 6 of art. 23 of Law no. 57/2016, of August 29, as amended by Law no. 57/2017 of July 2019. TC is supported by FCT (SFRH/BD/117148/2016). RLA was supported by FCT (PD/BD/114266/2016). AM was supported by FCT (IF/00753/2014). Author contributions: RS, TS, and JBR designed the project. RS, JFH, CCP, TOA, JTM, RLA, TC, CS, and AM performed experiments. RS, TS, and JBR co-supervised the study. RS and JBR wrote the original draft. RS, CCP, TS, and JBR reviewed and edited the manuscript. TS and JBR acquired funding

The temporal dynamics of visual processing in multiple sclerosis

Although the integrity of the visual system is often affected in multiple sclerosis (MS), the potential relationship between the temporal dynamics of visual processing and performance on neuropsychological tests assessing processing speed (PS) remains relatively unexplored. Here, we test if a PS deficit is related to abnormalities within the visual system, rather than impaired higher-level cognitive function. Two groups of participants with MS (1 group with PS deficits and another without) and a healthy control group, matched for age and education, were included. To explore the temporal dynamics of visual processing, we used 2 psychophysical paradigms: attention enhancement/prioritization and rapid serial visual presentation. Visual PS deficits were associated with a decreased capability to detect visual stimuli and a higher limitation in visual temporal-processing capacity. These results suggest that a latent sensorial temporal limitation of the visual system is significantly associated to PS deficits in MS.This work was supported by the Foundation for Science and Technology of Portugal with a doctoral fellowship grant (No. SFRH/BD/455591/2008) to SLC. JA is supported by funding from the Foundation for Science and Technology of Portugal Project Grants PTDC/PSI-PCO/114822/2009 and PTDC/MHC-PCN/3575/2012.info:eu-repo/semantics/publishedVersio

Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetamine

Methamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation, contributing to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders triggered by neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in individuals who abuse Meth), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a process dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production, or suppressing astrocytic calcium mobilization, prevented Meth-elicited microglia reactivity and re-established risk assessment behavior as tested by elevated plus maze (EPM). Overall, our data indicate that glial crosstalk is critical to relay alterations caused by acute Meth exposure.This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT— Fundação para a Ciência e a Tecnologia/Ministério da Ciência (FCT), Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER-030647 (PTDC/ SAU-TOX/30647/2017) in TS lab. FEDER Portugal (Norte-01-0145-FEDER000008000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); FCOMP-01-0124-FEDER-021333). CCP and RS hold employment contracts financed by national funds through FCT –in the context of the program-contract described in paragraphs 4, 5, and 6 of art. 23 of Law no. 57/ 2016, of August 29, as amended by Law no. 57/2017 of July 2019. TC, TOA, AFT, JB, AIS and AM were supported by FCT (SFRH/BD/117148/2016, SFRH/BD/147981/2019, 2020.07188.BD, PD/BD/135450/2017, SFRH/BD/144324/2019, and IF/00753/2014). Work in JBR lab was supported by the FCT project PTDC/ MED-NEU/31318/2017. JFO was also supported by FCT projects PTDC/MED-NEU/31417/2017 and POCI-01- 0145-FEDER-016818; Bial Foundation Grants 207/14 and 037/18, by National funds, through FCT - project UIDB/50026/2020; and by the projects NORTE-01-0145-FEDER000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Funding of i3S Scientific Platforms: Advanced Light Microscopy (ALM), a member of the national infrastructure PPBI-Portuguese Platform of BioImaging (POCI-01–0145-FEDER022122); and Genomics through GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by FCT

Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background: Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients. Methods: Five HLA-A2 patients with inoperable stage III or IV NSCLC were selected to receive two doses of 5 x 107 DC cells administered subcutaneous and intravenously two times at two week intervals. The immunologic response, safety and tolerability to the vaccine were evaluated by the lymphoproliferation assay and clinical and laboratorial evolution, respectively. Results: The dose of the vaccine has shown to be safe and well tolerated. The lymphoproliferation assay showed an improvement in the specific immune response after the immunization, with a significant response after the second dose (p = 0.005). This response was not long lasting and a tendency to reduction two weeks after the second dose of the vaccine was observed. Two patients had a survival almost twice greater than the expected average and were the only ones that expressed HER-2 and CEA together. Conclusion: Despite the small sample size, the results on the immune response, safety and tolerability, combined with the results of other studies, are encouraging to the conduction of a large clinical trial with multiples doses in patients with early lung cancer who underwent surgical treatment.30Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Department of Radiology of the Hospital Estadual Sumare UNICAMPSCOGConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq [401327/05-1

Global Asthma Network survey suggests more national asthma strategies could reduce burden of asthma.

BACKGROUND: Several countries or regions within countries have an effective national asthma strategy resulting in a reduction of the large burden of asthma to individuals and society. There has been no systematic appraisal of the extent of national asthma strategies in the world. METHODS: The Global Asthma Network (GAN) undertook an email survey of 276 Principal Investigators of GAN centres in 120 countries, in 2013-2014. One of the questions was: "Has a national asthma strategy been developed in your country for the next five years? For children? For adults?". RESULTS: Investigators in 112 (93.3%) countries answered this question. Of these, 26 (23.2%) reported having a national asthma strategy for children and 24 (21.4%) for adults; 22 (19.6%) countries had a strategy for both children and adults; 28 (25%) had a strategy for at least one age group. In countries with a high prevalence of current wheeze, strategies were significantly more common than in low prevalence countries (11/13 (85%) and 7/31 (22.6%) respectively, p<0.001). INTERPRETATION: In 25% countries a national asthma strategy was reported. A large reduction in the global burden of asthma could be potentially achieved if more countries had an effective asthma strategy

MOA-2011-BLG-293Lb: A test of pure survey microlensing planet detections

Because of the development of large-format, wide-field cameras, microlensing surveys are now able to monitor millions of stars with sufficient cadence to detect planets. These new discoveries will span the full range of significance levels including planetary signals too small to be distinguished from the noise. At present, we do not understand where the threshold is for detecting planets. MOA-2011-BLG-293Lb is the first planet to be published from the new surveys, and it also has substantial followup observations. This planet is robustly detected in survey+followup data (Delta chi^2 ~ 5400). The planet/host mass ratio is q=5.3+/- 0.2*10^{-3}. The best fit projected separation is s=0.548+/- 0.005 Einstein radii. However, due to the s-->s^{-1} degeneracy, projected separations of s^{-1} are only marginally disfavored at Delta chi^2=3. A Bayesian estimate of the host mass gives M_L = 0.43^{+0.27}_{-0.17} M_Sun, with a sharp upper limit of M_L < 1.2 M_Sun from upper limits on the lens flux. Hence, the planet mass is m_p=2.4^{+1.5}_{-0.9} M_Jup, and the physical projected separation is either r_perp = ~1.0 AU or r_perp = ~3.4 AU. We show that survey data alone predict this solution and are able to characterize the planet, but the Delta chi^2 is much smaller (Delta chi^2~500) than with the followup data. The Delta chi^2 for the survey data alone is smaller than for any other securely detected planet. This event suggests a means to probe the detection threshold, by analyzing a large sample of events like MOA-2011-BLG-293, which have both followup data and high cadence survey data, to provide a guide for the interpretation of pure survey microlensing data.Comment: 29 pages, 6 figures, Replaced 7/3/12 with the version accepted to Ap

Characterizing Low-Mass Binaries From Observation of Long Time-scale Caustic-crossing Gravitational Microlensing Events

Despite astrophysical importance of binary star systems, detections are limited to those located in small ranges of separations, distances, and masses and thus it is necessary to use a variety of observational techniques for a complete view of stellar multiplicity across a broad range of physical parameters. In this paper, we report the detections and measurements of 2 binaries discovered from observations of microlensing events MOA-2011-BLG-090 and OGLE-2011-BLG-0417. Determinations of the binary masses are possible by simultaneously measuring the Einstein radius and the lens parallax. The measured masses of the binary components are 0.43 $M_{\odot}$ and 0.39 $M_{\odot}$ for MOA-2011-BLG-090 and 0.57 $M_{\odot}$ and 0.17 $M_{\odot}$ for OGLE-2011-BLG-0417 and thus both lens components of MOA-2011-BLG-090 and one component of OGLE-2011-BLG-0417 are M dwarfs, demonstrating the usefulness of microlensing in detecting binaries composed of low-mass components. From modeling of the light curves considering full Keplerian motion of the lens, we also measure the orbital parameters of the binaries. The blended light of OGLE-2011-BLG-0417 comes very likely from the lens itself, making it possible to check the microlensing orbital solution by follow-up radial-velocity observation. For both events, the caustic-crossing parts of the light curves, which are critical for determining the physical lens parameters, were resolved by high-cadence survey observations and thus it is expected that the number of microlensing binaries with measured physical parameters will increase in the future.Comment: 8 pages, 5 figures, 4 table