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Make science more reliable by placing the burden of replicability on the community, not on individual laboratories. Make science more reliable by placing the burden of replicability on the community, not on individual laboratories.

FAPERJ (Funda??o de Amparo ? Pesquisa do Estado do Rio de Janeiro) Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil / Universidade do Estado do Par?. Departamento de Morfologia e Ci?ncias Fisiol?gicas. Bel?m, PA, Brazil / Centro Universit?rio Metropolitano da Amaz?nia. Instituto Euro-Americano de Educa??o, Ci?ncia e Tecnologia. Bel?m, PA, Brazil. University of Groningen. Department of Neuroscience. Section Medical Physiology. Groningen, The Netherlands. Federal University of Rio de Janeiro. Biomedical Sciences Institute. Rio de Janeiro, RJ, Brazil. University of Edinburgh Medical School. Scotland, United Kingdom. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Universidade Federal de S?o Paulo. Programa de P?s-Gradua??o em Psicobiologia. S?o Paulo, SP, Brazil. University of Minnesota. Department of Psychiatry. Minneapolis, MN, USA. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Federal University of Rio de Janeiro. Biomedical Sciences Institute. Rio de Janeiro, RJ, Brazil. Institute of Microbiology of the Czech Academy of Sciences. Czech Republic. University of Illinois at Urbana-Champaign. Carl R Woese Institute for Genomic Biology. Urbana, Illinois, USA. Universidade do Estado do Par?. Departamento de Morfologia e Ci?ncias Fisiol?gicas. Bel?m, PA, Brazil / Centro Universit?rio Metropolitano da Amaz?nia. Instituto Euro-Americano de Educa??o, Ci?ncia e Tecnologia. Bel?m, PA, Brazil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Universidade Federal do Rio Grande do Sul. Instituto de Ci?ncias B?sicas da Sa?de. Departamento de Bioqu?mica. Rio Grande do Sul, RS, Brazil. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Preprint usage is growing rapidly in the life sciences; however, questions remain on the relative quality of preprints when compared to published articles. An objective dimension of quality that is readily measurable is completeness of reporting, as transparency can improve the reader?s ability to independently interpret data and reproduce findings. In this observational study, we compared random samples of articles published in bioRxiv and in PubMed-indexed journals in 2016 using a quality of reporting questionnaire. We found that peer-reviewed articles had, on average, higher quality of reporting than preprints, although this difference was small. We found larger differences favoring PubMed in subjective ratings of how clearly titles and abstracts presented the main findings and how easy it was to locate relevant reporting information. Interestingly, an exploratory analysis showed that preprints with figures and legends embedded within text had reporting scores similar to PubMed articles. These differences cannot be directly attributed to peer review or editorial processes, as manuscripts might already differ before submission due to greater uptake of preprints by particular research communities. Nevertheless, our results show that quality of reporting in preprints in the life sciences is within a similar range as that of peer-reviewed articles, albeit slightly lower on average, supporting the idea that preprints should be considered valid scientific contributions. An ongoing second phase of the project is comparing preprints to their own published versions in order to more directly assess the effects of peer review.

The pressure for every research article to tell a clear story often leads researchers in the life sciences to exclude experiments that 'did not work' when they write up their results. However, this practice can lead to reporting bias if the decisions about which experiments to exclude are taken after data have been collected and analyzed. Here we discuss how to balance clarity and thoroughness when reporting the results of research, and suggest that predefining the criteria for excluding experiments might help researchers to achieve this balance.

Scientists have increasingly recognized that low methodological and analytical rigor combined with publish-or-perish incentives can make the published scientific literature unreliable. As a response to this, large-scale systematic replications of the literature have emerged as a way to assess the problem empirically. The Brazilian Reproducibility Initiative is one such effort, aimed at estimating the reproducibility of Brazilian biomedical research. Its goal is to perform multicenter replications of a quasi-random sample of at least 60 experiments from Brazilian articles published over a 20-year period, using a set of common laboratory methods. In this article, we describe the challenges of managing a multicenter project with collaborating teams across the country, as well as its successes and failures over the first two years. We end with a brief discussion of the Initiative’s current status and its possible future contributions after the project is concluded in 2021.

Aversive memories are at the heart of psychiatric disorders such as phobias and post-traumatic stress disorder (PTSD). Here, we present a new behavioral approach in rats that robustly attenuates aversive memories. This method consists of ‘deconditioning’ animals previously trained to associate a tone with a strong footshock by replacing it with a much weaker one during memory retrieval. Our results indicate that deconditioning-update is more effective than traditional extinction in reducing fear responses; moreover, such effects are long lasting and resistant to renewal and spontaneous recovery. Remarkably, this strategy overcame important boundary conditions for memory updating, such as remote or very strong traumatic memories. The same beneficial effect was found in other types of fear-related memories. Deconditioning was mediated by L-type voltage-gated calcium channels and is consistent with computational accounts of mismatch-induced memory updating. Our results suggest that shifting from fear to safety through deconditioning-update is a promising approach to attenuate traumatic memories.

Meta-analytic methods are powerful resources to summarize the existing evidence concerning a given research question and are widely used in many academic fields. Meta-analyzes can also be used to study sources of heterogeneity and bias among results, which should be considered to avoid inaccuracies. Many of these sources can be related to study authorship, as both methodological heterogeneity and researcher bias may lead to deviations in results between different research groups. In this work, we describe a method to objectively attribute study authorship within a given meta-analysis to different research groups by using graph cluster analysis of collaboration networks. We then provide empirical examples of how the research group of origin can impact effect size in distinct types of meta-analyzes, demonstrating how non-independence between within-group results can bias effect size estimates if uncorrected. Finally, we show that multilevel random-effects models using research group as a level of analysis can be a simple tool for correcting for authorship dependence in results.

Meta-analytic methods are powerful resources to summarize the existing evidence concerning a given research question, and are widely used in many academic fields. However, meta-analyses can be vulnerable to various sources of bias, which should be considered to avoid inaccuracies. Many of these sources can be related to study authorship, as both methodological choices and researcher bias may lead to deviations in results between different research groups. In this work, we describe a method to objectively attribute study authorship within a given meta-analysis to different research groups by using graph cluster analysis of collaboration networks. We then provide empirical examples of how the research group of origin can impact effect size in distinct types of meta-analyses, demonstrating how non-independence between within-group results can bias effect size estimates if uncorrected. Finally, we show that multilevel random-effects models using research group as a level of analysis can be a simple tool for correcting biases related to study authorship.

Most efforts to estimate the reproducibility of published findings have focused on specific areas of research, even though science is usually assessed and funded on a regional or national basis. Here we describe a project to assess the reproducibility of findings in biomedical science published by researchers based in Brazil. The Brazilian Reproducibility Initiative is a systematic, multicenter effort to repeat between 60 and 100 experiments: the project will focus on a set of common methods, repeating each experiment in three different laboratories from a countrywide network. The results, due in 2021, will allow us to estimate the level of reproducibility of biomedical science in Brazil, and to investigate what aspects of the published literature might help to predict whether a finding is reproducible.

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory reexposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after reexposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

Neuroscience is frequently used as an argument in various debates on mental health, such as the definition of some behaviors as pathological. To understand how this happens in the Brazilian media, we analyzed neuroscientific facts mentioned in articles about a controversial diagnosis: internet and or/video gaming addiction. Of 85 articles located in web searches of seven major press vehicles, 25% made allusions to neuroscience. The analysis of two frequently mentioned facts (the similarity between cerebral alterations observed in drug and technology addictions and the release of dopamine as a mediator of reward and addiction to video games) showed inconsistencies between media claims and the available empirical evidence. However, similar biases were already observable in the scientific literature itself, suggesting that the theory of a “dependent brain” in behavioral and chemical addictions seems to be favored by both journalists and scientists

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-re-exposure interventions, while those in the hippocampus have performed them after re-exposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory re-exposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after re-exposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory reexposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after reexposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

Prolonged increases in excitation can trigger cell-wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely-moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 h of stimulation with 15-ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin-2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2-expressing mice immediately after the end of stimulation. Lastly, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.

Proposals to increase research reproducibility frequently call for focusing on effect sizes instead of p values, as well as for increasing the statistical power of experiments. However, it is unclear to what extent these two concepts are indeed taken into account in basic biomedical science. To study this in a real-case scenario, we performed a systematic review of effect sizes and statistical power in studies on learning of rodent fear conditioning, a widely used behavioral task to evaluate memory. Our search criteria yielded 410 experiments comparing control and treated groups in 122 articles. Interventions had a mean effect size of 29.5%, and amnesia caused by memory-impairing interventions was nearly always partial. Mean statistical power to detect the average effect size observed in well-powered experiments with significant differences (37.2%) was 65%, and was lower among studies with non-significant results. Only one article reported a sample size calculation, and our estimated sample size to achieve 80% power considering typical effect sizes and variances (15 animals per group) was reached in only 12.2% of experiments. Actual effect sizes correlated with effect size inferences made by readers on the basis of textual descriptions of results only when findings were non-significant, and neither effect size nor power correlated with study quality indicators, number of citations or impact factor of the publishing journal. In summary, effect sizes and statistical power have a wide distribution in the rodent fear conditioning literature, but do not seem to have a large influence on how results are described or cited. Failure to take these concepts into consideration might limit attempts to improve reproducibility in this field of science.

Memory extinction involves the formation of a new associative memory that inhibits a previously conditioned association. Nonetheless, it could also depend on weakening of the original memory trace if extinction is assumed to have multiple components. The phosphatase calcineurin (CaN) has been described as being involved in extinction but not in the initial consolidation of fear learning. With this in mind, we set to study whether CaN could have different roles in distinct components of extinction. Systemic treatment with the CaN inhibitors cyclosporin A (CsA) or FK-506, as well as i.c.v. administration of CsA, blocked within-session, but not between-session extinction or initial learning of contextual fear conditioning. Similar effects were found in multiple-session extinction of contextual fear conditioning and in auditory fear conditioning, indicating that CaN is involved in different types of short-term extinction. Meanwhile, inhibition of protein synthesis by cycloheximide (CHX) treatment did not affect within-session extinction, but disrupted fear acquisition and slightly impaired between-session extinction. Our results point to a dissociation of within- and between-session extinction of fear conditioning, with the former being more dependent on CaN activity and the latter on protein synthesis. Moreover, the modulation of within-session extinction did not affect between-session extinction, suggesting that these components are at least partially independent.

The search for biomarkers has been one of the leading endeavours in biological psychiatry; nevertheless, in spite of hundreds of publications, hardly any marker has proved useful in clinical practice. To study how biomarker research has progressed over the years, we performed a systematic review of the literature to evaluate (a) the most studied peripheral molecular markers in major psychiatric disorders, (b) the main experimental design features of studies in which they are proposed as biomarkers and (c) whether their patterns of variation are similar across disorders. An automated search revealed that, out of the six molecules most commonly present as keywords in articles studying plasmatic markers of schizophrenia, major depressive disorder or bipolar disorder, five (BDNF, TNF-alpha, IL-6, C-reactive protein and cortisol) were the same across the three diagnoses. An analysis of the literature on these molecules showed that, whilst 66% of original articles compared their levels between patients and controls, only 35% were longitudinal studies, and only 10% presented an evaluation of diagnostic efficacy, a pattern that has not changed significantly over two decades. Interestingly, these molecules varied similarly across the three disorders, suggesting them to be nonspecific systemic consequences of psychiatric illness rather than diagnostic markers. On the basis of this, we discuss how research fragmentation between diagnoses and publication practices rewarding positive findings may be directing the biomarker literature to nonspecific targets, and what steps could be taken to increase clinical translation in the field.

G protein-coupled receptor oligomerization is a concept which is changing the understanding of classical pharmacology. Both, oligomerization and functional interaction between adenosine A 2A, dopamine D 2 and metabotropic glutamate type 5 receptors have been demonstrated in the striatum. However, the transcriptional consequences of receptors co-activation are still unexplored. We aim here to determine the changes in gene expression of striatal primary cultured neurons upon isolated or simultaneous receptor activation. Interestingly, we found that 95 genes of the total analyzed (15,866 transcripts and variants) changed their expression in response to simultaneous stimulation of all three receptors. Among these genes, we focused on the β-synuclein (β-Syn) gene ( SCNB) . Quantitative PCR verified the magnitude and direction of change in expression of SCNB . Since β-Syn belongs to the homologous synuclein family and may be considered a natural regulator of α-synuclein (α-Syn), it has been proposed that β-Syn might act protectively against α-Syn neuropathology.

G protein-coupled receptors are known to form homo-and heteromers at the plasma membrane, but the molecular properties of these oligomers are relatively unknown. Here, we show a method that allows the diffusion of G protein-coupled receptors oligomers in the plasma membrane to be monitored in single cells by combining Bimolecular Fluorescence Complementation and Fluorescence Correlation Spectroscopy. With this approach we have measured, for the first time, the membrane diffusional characteristics of adenosine A(1) and A(2A) receptor homo-and heterodimers in Chinese Hamster Ovary cells. Interestingly, both homodimers display similar diffusion co-efficients (D) when expressed in living cells (D=5.0 and 4.8x10(-9) cm(2)/s, respectively) but the heterodimer formed by these receptors exhibit a significantly faster plasma membrane diffusion co-efficent (D=5.6x10(-9) cm(2)/s) when compared to the adenosine A(1) receptor tagged with the full-length yellow fluorescent protein (D=4.0x10(-9) cm(2)/s). Overall, these results demonstrate differences in plasma membrane diffusion between adenosine receptor homo-and heterodimers, providing new insights into the molecular plasticity of G protein-coupled receptor oligomerization.

Despite some caveats, G protein-coupled receptor oligomerization is a phenomenon that is becoming largely accepted. Within these oligomers, however, stoichiometry remains to be elucidated. Here, by using bimolecular fluorescence complementation, we visualized adenosine A2A receptor homodimers in living cells, showing no apparent difference in the subcellular distribution when compared to the YFP-labelled adenosine A2A receptor protomer. Interestingly, the combination of bimolecular fluorescence complementation and bioluminescence resonance energy transfer techniques allowed us to detect the occurrence of adenosine A2A receptors oligomers containing more than two protomers. These results provide new insights into the molecular composition of G protein-coupled receptor oligomers.Structured summaryMINT-6700472:A2A (uniprotkb:P29274), A2A (uniprotkb:P29274) and A2A (uniprotkb:P29274) physically interact (MI:0218) by bioluminescence resonance energy transfer (MI:0012)MINT-6699330:A2A (uniprotkb:P29274) and A2A (uniprotkb:P29274) physically interact (MI:0218) by bimolecular fluorescence complementation (MI:0809)MINT-6699346:A2A (uniprotkb:P29274) and A2A (uniprotkb:P29274) physically interact (MI:0218) by bioluminescence resonance energy transfer (MI:0012)

The search for biological causes of mental disorders has up to now met with limited success, leading to growing dissatisfaction with diagnostic classifications. However, it is questionable whether most clinical syndromes should be expected to correspond to specific microscale brain alterations, as multiple low-level causes could lead to similar symptoms in different individuals. In order to evaluate the potential multifactoriality of alterations related to psychiatric illness, we performed a parametric exploration of published computational models of schizophrenia. By varying multiple parameters simultaneously, such as receptor conductances, connectivity patterns, and background excitation, we generated 5625 different versions of an attractor-based network model of schizophrenia symptoms. Among networks presenting activity within valid ranges, 154 parameter combinations out of 3002 (5.1%) presented a phenotype reminiscent of schizophrenia symptoms as defined in the original publication. We repeated this analysis in a model of schizophrenia-related deficits in spatial working memory, building 3125 different networks, and found that 41 (4.9%) out of 834 networks with valid activity presented schizophrenia-like alterations. In isolation, none of the parameters in either model showed adequate sensitivity or specificity to identify schizophrenia-like networks. Thus, in computational models of schizophrenia, even simple network phenotypes related to the disorder can be produced by a myriad of causes at the molecular and circuit levels. This suggests that unified explanations for either the full syndrome or its behavioral and network endophenotypes are unlikely to be expected at the genetic and molecular levels.

Eclampsia is defined as the occurrence of seizures and/or coma resulting from hypertensive encephalopathy on a background of preeclampsia (1). Eclampsia appears to be caused by a failure of the brain’s autoregulatory response to increases in blood pressure, leading to an increase in cerebral perfusion pressure with overperfusion injury similar to that observed in hypertensive encephalopathy (2)(3). Brain edema and hemorrhage ensue, as observed in imaging studies (4)(5), and there is evidence to suggest that these alterations can cause ischemia to brain cells. These events lead to neurologic symptoms (6), including seizures as well as cortical blindness, aphasia, limb weakness, psychosis, coma, and cerebrovascular accidents. Studies have analyzed various diagnostic methods, such as transcranial Doppler measurements, as a way to evaluate neurologic involvement in preeclampsia (3)(7). To date, however, there is no reliable laboratory marker to identify patients at risk for eclampsia or its related complications. S100B is a 21-kDa protein physiologically produced and released primarily by astrocytes in the central nervous system (CNS), where it exerts neurotrophic and gliotrophic actions (8). Because ∼95% of S100B is located in the CNS, the results of several studies have suggested that an increase in S100B in blood and cerebrospinal fluid could be a potential marker of neural injury, indicating reactive gliosis, astrocytic death, and/or blood–brain barrier dysfunction. Accordingly, increased S100B concentrations in cerebrospinal fluid and/or blood have been reported in several pathologic conditions causing acute and chronic brain injury, such as head trauma (9), stroke (10), schizophrenia (11), and human T-lymphotropic virus type 1-associated myelopathy (12). Some studies have also evaluated S100B as a marker of recent seizures. Although S100B has been shown to be increased in both cerebrospinal fluid and brain tissue of patients with temporal lobe epilepsy (13)(14), studies in which …

When 5-lipoxygenase (5-LO) is inhibited, roughly half of the CNS effect of the prototypic endocannabinoid anandamide (AEA) is lost. Therefore, we decided to investigate whether inhibiting this enzyme would influence physiological functions classically described as being under control of the endocannabinoid system. Although 5-LO inhibition by MK-886 reduced lipoxin A4 levels in the brain, no effect was found in the elevated plus maze (EPM), even at the highest possible doses, via i.p. (10 mg/kg,) or i.c.v. (500 pmol/2 µl) routes. Accordingly, no alterations in anxiety-like behavior in the EPM test were observed in 5-LO KO mice. Interestingly, aged mice, which show reduced circulating lipoxin A4 levels, were sensitive to MK-886, displaying an anxiogenic-like state in response to treatment. Moreover, exogenous lipoxin A4 induced an anxiolytic-like profile in the EPM test. Our findings are in line with other reports showing no difference between FLAP KO or 5-LO KO and their control strains in adult mice, but increased anxiety-like behavior in aged mice. We also show for the first time that lipoxin A4 affects mouse behavior. In conclusion, we propose an age-dependent relevancy of endogenous 5-LO derivatives in the modulation of anxiety-like behavior, in addition to a potential for exogenous lipoxin A4 in producing an anxiolytic-like state.

Although different hypotheses have been formulated to explain schizophrenia pathogenesis, the links between them are weak. The observation that five psychotic patients on chronic warfarin therapy for deep-vein thrombosis showed long-term remission of psychotic symptoms made us suspect that abnormalities in the coagulation pathway, specifically low tissue plasminogen activator (tPA) activity, could be one of the missing links. Our hypothesis is supported by a high prevalence of conditions affecting tPA activity in drug-naive schizophrenia, such as antiphospholipid antibodies, elevated cytokine levels, hyperinsulinemia and hyperhomocysteinemia. We recently screened a group of schizophrenia patients and controls for conditions affecting tPA activity. Free-protein S deficiency was highly prevalent among patients, but not found in controls. Free-protein S and functional protein C are natural anticoagulants that form complexes that inhibit tPA inhibitors. All participants had normal protein C levels, suggesting that protein S could have a role in schizophrenia, independent of protein C. Chronic patients and those studied during acute episodes had between three and six conditions affecting tPA and/or protein S activity, while patients in remission had up to two, which led us to postulate that multiple conditions affecting tPA and/or protein S activity could contribute to the full expression of schizophrenia phenotype. This paper describes the physiological roles of tPA and protein S, reviewing how their activity influences pathogenesis and comorbidity of schizophrenia. Next, it analyzes how activity of tPA and protein S is influenced by biochemical abnormalities found in schizophrenia. Last, it suggests future directions for research, such as studies on animal models and on therapeutic approaches for schizophrenia aiming at increasing tPA and protein S activity.

Conselho Nacional de Desenvolvimento Científico e Tecnológico, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, e Fundação de Apoio à Pesquisa do Estado do Rio Grande do Norte. Journal impact factors have become an important criterion to judge the quality of scientific publications over the years, influencing the evaluation of institutions and individual researchers worldwide. However, they are also subject to a number of criticisms. Here we point out that the calculation of a journal’s impact factor is mainly based on the date of publication of its articles in print form, despite the fact that most journals now make their articles available online before that date. We analyze 61 neuroscience journals and show that delays between online and print publication of articles increased steadily over the last decade. Importantly, such a practice varies widely among journals, as some of them have no delays, while for others this period is longer than a year. Using a modified impact factor based on online rather than print publication dates, we demonstrate that online-to-print delays can artificially raise a journal’s impact factor, and that this inflation is greater for longer publication lags. We also show that correcting the effect of publication delay on impact factors changes journal rankings based on this metric. We thus suggest that indexing of articles in citation databases and calculation of citation metrics should be based on the date of an article’s online appearance, rather than on that of its publication in print.

Scientific activity in Brazil has experienced an accelerated growth in the past decades, with an increase in productivity that greatly surpasses the international average. This growth has occurred mostly at the expense of centers of excellence in public universities, which account for the vast majority of the country's scientific output. The aim of this study was to evaluate the production of the Department of Biochemistry of a large public university in southern Brazil (Universidade Federal do Rio Grande do Sul), as well as to identify internal and external policies that have influenced this growing production profile. We have performed a historical analysis of the scientific output of this Department of Biochemistry, which accounts for a considerable share of the indexed scientific production at this university. By focusing on the temporal course of its growth and drawing correlations between scientific output and important events in the history of the Department of Biochemistry and of the Brazilian science policies, we concluded that internal factors (as the creation of a postgraduation program, collaboration among researchers, experienced abroad researchers, qualification of faculty members) and external factors (as investments in the postgraduate education, the establishment of national scientific policies, such as financial stimuli for productive researchers and evaluation systems) influence scientific productivity in Brazil.A atividade científica no Brasil apresentou um crescimento acelerado nas últimas décadas, com um aumento na produtividade que ultrapassou os valores médios internacionais. Este crescimento tem ocorrido através dos centros de excelência em pesquisa nas Universidades Públicas, as quais são responsáveis pela maior parte da produção científica do país. O presente estudo tem como objetivo avaliar a produção do Departamento de Bioquímica de uma grande universidade pública do sul do Brasil (Universidade Federal do Rio Grande do Sul - UFRGS), bem como identificar os fatores internos e externos que influenciaram este perfil crescente de produção. Foi realizada uma análise histórica da produção científica do Departamento, a qual representa uma parte considerável da produção científica da Universidade. Ao enfocar a evolução temporal do seu crescimento e o estudo das correlações entre a produção científica e eventos importantes na história do Departamento de Bioquímica e das políticas científicas brasileiras, podemos concluir que os fatores internos (como a criação de um programa de pós-graduação, a colaboração entre pesquisadores, a experiência no exterior por parte dos pesquisadores, a qualificação dos docentes) e fatores externos (como os investimentos na formação de pós-graduandos, o estabelecimento de políticas nacionais científicas, tais como estímulos financeiros para os pesquisadores produtivos e sistemas de avaliação) influenciam a produção científica no Brasil.

The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation.

OSAN, R. , TORT, A. B. L. , AMARAL, O. B. . A mismatch-based model for memory reconsolidation and extinction in attractor networks. Plos One, v. 6, p. e23113, 2011. Centro de Neurociências, da Universidade de Boston, EUA (RO), Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasil (ABLT e OBA), e Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro, Brasil (OBA). The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation

Environmental enrichment is known to induce plastic changes in the brain, including morphological changes in hippocampal neurons, with increases in synaptic and spine densities. In recent years, the evidence for a role of astrocytes in regulating synaptic transmission and plasticity has increased, and it is likely that morphological and functional changes in astrocytes play an important role in brain plasticity. Our study was designed to evaluate changes in astrocytes induced by environmental enrichment in the CA1 region of the hippocampus, focusing on astrocytic density and on morphological changes in astrocytic processes. After 8 weeks of environmental enrichment starting at weaning, male CF-1 mice presented no significant changes in astrocyte number or in the density of glial fibrillary acidic protein (GFAP) immunoreactivity in the stratum radiatum. However, they did present changes in astrocytic morphology in the same region, as expressed by a significant increase in the ramification of astrocytic processes measured by the Sholl concentric circles method, as well as by an increase in the number and length of primary processes extending in a parallel orientation to CA1 nerve fibers. This led astrocytes to acquire a more stellate morphology, a fact which could be related to the increase in hippocampal synaptic density observed in previous studies. These findings corroborate the idea that structural changes in astrocytic networks are an integral part of plasticity processes occurring in the brain.

The series of disease mongering articles in the April 2006 issue of PLoS Medicine overall seem to define the term as “widening the boundaries of illness” [ 1] by “taking a normal function and implying that there's something wrong with it and that it should be treated” [ 2]. While there is undoubtedly a strong case to be made for this sort of practice by pharmaceutical companies, perhaps we should also question ourselves on what we mean by “disease boundaries.” All of the conditions touched on by the disease mongering series (e.g., bipolar disease, attention deficit hyperactivity disorder, restless legs syndrome, and sexual dysfunctions) share the fact that they represent spectra of symptoms felt by virtually everyone, but which for some people can reach a point at which they become disturbing. However, since the benefit of treating these symptoms is ultimately dependent on their significance in a patient's life, it seems doubtful that anyone but the patient can adequately define the “boundaries” of illness for these conditions. The existence of these large “grey zones” between disease and normality (as well as the difficulty of doctors in dealing with them) might help to explain the increase in “lifestyle drug use” and self-prescription of psychiatric medication [ 3]. While these behaviors undoubtedly carry risks, they might well be an inevitable development in an age where information on anything (including drugs) is so widely available. Moreover, tampering with body chemistry is nothing new (alcohol, coffee, chocolate, and sunlight come to mind as examples), and it is hard to expect people will not do it because of pharmaceutical labels. Therefore, complain as we may, it is unlikely that this trend can be feasibly prevented. Therefore, if we want to prevent disease mongering, perhaps we should start by focusing on our own concept of “disease.” Maybe it is time we start to loosen the grip on our powers to define disease and start working less as diagnosing machines and more as decision facilitators for patients. It seems quite absurd to decide on a “concept” of erectile dysfunction or depression that can define who should be treated. On the contrary, our role should be to inform patients of the benefits and risks of treatment (or nontreatment) for their particular condition. This also means being comfortable with the fact that, no matter which criteria one uses to define disease, there will always be “normal” people who will want treatment as well as “sick” people who will refuse it. And in both cases they are probably entitled to do so, without necessarily receiving a diagnosis of “normal” or “sick.” Moreover, since the trend for self-prescription is not likely to be prevented, and since the pharmaceutical industry will surely try to capitalize on it, perhaps we should also worry about making nonprofit, unbiased scientific information more available to the public. Education on health matters is an important responsibility that traditionally has been overlooked by doctors in most countries. Now, if ever, seems to be the time to change that, because if physicians do not concentrate on it, drug companies will be happy to do it for them. It is obvious that medicine cannot abandon the concept of disease boundaries, since most of our medical knowledge and research is still based on it. Moreover, there are fields in which medical responsibility is sure to remain important in defining these boundaries (e.g., attribution of public funds, research studies, and treatment of children). But after reading so much on disease mongering, it seems to me that if we become a little more flexible in admitting that “disease boundaries” for many conditions are an oxymoron, perhaps the pharmaceutical industry will make less of a fuss in trying to convince people they are ill. My guess is that this would do everybody a favor.

There is growing pharmacological evidence from several animal models of seizure disorders that adenosine possesses endogenous anticonvulsant activity. Apart from being released from cells, adenosine can be produced by the degradation of adenine nucleotides by ectoenzymes or soluble nucleotidases. These enzymes constitute an important mechanism in synaptic modulation, as they hydrolyze ATP, an excitatory neurotransmitter, to adenosine, a neuroprotective compound. We recently demonstrated an increase in ectoenzyme activity in rat brain synaptosomes after pentylenetetrazol-kindling in rats resistant to kindling, suggesting a role for ectonucleotidases in the seizure control. The present work investigates the effect of seizures induced by pentylenetetrazol kindling on the enzymes that could be playing a role in ATP, ADP and AMP hydrolysis to adenosine in rat blood serum. Animals received injections of PTZ (30 mg/kg, i.p., dissolved in 0.9% saline) once every 48 h, totaling 10 stimulations and the controls animals were injected with saline. The hydrolysis of ATP, ADP and AMP were significantly increased (42, 40, and 45%, respectively), while phosphodiesterase activity was unchanged. These results suggest once more that an increase in the ATP diphosphohydrolase and 5'-nucleotidase activities and, possibly, in adenosine levels, could represent an important compensatory mechanism in the development of chronic epilepsy. Moreover, the fact that this increase can also be measured in serum could mean that these enzymes might be useful as plasma markers of seizures in epilepsy.

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Purpose: the physiologic role of the cellular prion protein (PrPc) is unknown. Mice devoid of PrPc develop normally and show only minor deficits. However, electrophysiologic and histologic alterations found in these mice suggest a possible:role fur PrPc in seizure threshold and/or epilepsy.Methods: We tested the sensitivity of PrPc knockout mice to seizures induced by single convulsant or repeated subconvulsant (kindling) doses of pentylenetetrazol (PTZ), and to status epilepticus (SE) induced by kainic acid or pilocarpine.Results. in PTZ kindling, seizure severity progressed faster in the PrPc knockout group, in which 92.8% reached stage 5 or death after 4 days of stimulation, as opposed to 38.4% in wildtype animals: After 10 injections, mortality was 85.7% among knockouts and 15.3% among controls. After a single PTZ injection (60 mg/kg), overall mortality due to seizures was 91% in knockout mice, but only 33% among wild-type animals. Pilocarpine-induced SE (320 mg/kg) caused an 86.7% mortality in knockouts, as opposed to 40% in wild-type animals. Finally, after kainic acid injections (10 mg/kg), 70% of the knockouts developed at least one severe seizure, and 50% showed repetitive seizures, whereas no wild-type animal exhibited observable seizures.Conclusions: Animals lacking cellular prion protein expression are more susceptible to seizures induced by various convulsant agents. This is perhaps the most striking alteration yet found in PrPc-null mice, who at first analysis appeared to be completely normal. A possible role for PrPc in chronic and idiopathic (familial), secondary, or cryptogenic epilepsies in humans remains to be investigated. Univ Fed Rio Grande Sul, ICBS, Dept Bioquim, Ctr Memoria, BR-90035003 Porto Alegre, RS, Brazil UNIFESP, EPM, Dept Expt Neurol, São Paulo, Brazil Ludwig Inst Canc Res, São Paulo, Brazil UNIFESP, EPM, Dept Expt Neurol, São Paulo, Brazil Web of Science