Phylogenetically informed logic relationships improve detection of biological network organization

Background: A "phylogenetic profile" refers to the presence or absence of a gene across a set of organisms, and it has been proven valuable for understanding gene functional relationships and network organization. Despite this success, few studies have attempted to search beyond just pairwise relationships among genes. Here we search for logic relationships involving three genes, and explore its potential application in gene network analyses. Results: Taking advantage of a phylogenetic matrix constructed from the large orthologs database Roundup, we invented a method to create balanced profiles for individual triplets of genes that guarantee equal weight on the different phylogenetic scenarios of coevolution between genes. When we applied this idea to LAPP, the method to search for logic triplets of genes, the balanced profiles resulted in significant performance improvement and the discovery of hundreds of thousands more putative triplets than unadjusted profiles. We found that logic triplets detected biological network organization and identified key proteins and their functions, ranging from neighbouring proteins in local pathways, to well separated proteins in the whole pathway, and to the interactions among different pathways at the system level. Finally, our case study suggested that the directionality in a logic relationship and the profile of a triplet could disclose the connectivity between the triplet and surrounding networks. Conclusion: Balanced profiles are superior to the raw profiles employed by traditional methods of phylogenetic profiling in searching for high order gene sets. Gene triplets can provide valuable information in detection of biological network organization and identification of key genes at different levels of cellular interaction

Efficient Physical Embedding of Topologically Complex Information Processing Networks in Brains and Computer Circuits

Nervous systems are information processing networks that evolved by natural selection, whereas very large scale integrated (VLSI) computer circuits have evolved by commercially driven technology development. Here we follow historic intuition that all physical information processing systems will share key organizational properties, such as modularity, that generally confer adaptivity of function. It has long been observed that modular VLSI circuits demonstrate an isometric scaling relationship between the number of processing elements and the number of connections, known as Rent's rule, which is related to the dimensionality of the circuit's interconnect topology and its logical capacity. We show that human brain structural networks, and the nervous system of the nematode C. elegans, also obey Rent's rule, and exhibit some degree of hierarchical modularity. We further show that the estimated Rent exponent of human brain networks, derived from MRI data, can explain the allometric scaling relations between gray and white matter volumes across a wide range of mammalian species, again suggesting that these principles of nervous system design are highly conserved. For each of these fractal modular networks, the dimensionality of the interconnect topology was greater than the 2 or 3 Euclidean dimensions of the space in which it was embedded. This relatively high complexity entailed extra cost in physical wiring: although all networks were economically or cost-efficiently wired they did not strictly minimize wiring costs. Artificial and biological information processing systems both may evolve to optimize a trade-off between physical cost and topological complexity, resulting in the emergence of homologous principles of economical, fractal and modular design across many different kinds of nervous and computational networks

Law and Human Nature: The Social-Adaptive Function of the Normative Behavior

The objective of this article is to offer a critical (re)interpretation of genesis and evolution, object and purpose, as well as useful qualified methods for interpreting, justifying and applying modern practical law, all with the intention of putting philosophic thought and contemporary formal theory of reason at the service of hermeutics and juridical argumentation. Law is no more—no less—than an social-adaptive strategy, evermore complex, but always noticeably deficient, used to articulate argumentatively—in fact, not always with justice—through the virtue of prudence, elementary relational social ties through which men construct approved styles of interaction and social structure, i.e., to organize and ethically improve political and social life in such a way as to permit that no free citizen—rich or poor—should fear the arbitrary interference of other social actors in his life plan

The social neuroscience of mentalizing: challenges and recommendations

Our ability to understand and think about the mental states of other people is referred to as “mentalizing” or “theory of mind”. It features prominently in all social behavior, is essential for maintaining relationships, and shows pronounced individual differences. Here we review new approaches to study the underlying psychological mechanisms and discuss how they could best be investigated using modern tools from social neuroscience. We list key desiderata for the field, such as validity, specificity, and reproducibility, and link them to specific recommendations for the future. We also discuss new computational modeling approaches, and the application to psychopathology

The social neuroscience of mentalizing: challenges and recommendations

Our ability to understand and think about the mental states of other people is referred to as “mentalizing” or “theory of mind”. It features prominently in all social behavior, is essential for maintaining relationships, and shows pronounced individual differences. Here we review new approaches to study the underlying psychological mechanisms and discuss how they could best be investigated using modern tools from social neuroscience. We list key desiderata for the field, such as validity, specificity, and reproducibility, and link them to specific recommendations for the future. We also discuss new computational modeling approaches, and the application to psychopathology

Evaluation of Alt a 1 as specific marker of exposure to fungal allergenic sources and clinical relevance of a manganese-dependent superoxide dismutase and a serine protease as new Alternaria alternata allergens

Allergic diseases are considered to be one of the epidemics of the century, affecting approximately one-third of the general population. Classically, among the allergenic sources able to induce IgE-mediated reactions, fungi have been one of the less favored areas of study. It has been demonstrated that sensitization to fungal aeroallergens, particularly from Alternaria alternata, represents an unequivocal risk factor for the development, persistence and severity of asthma. Thus, the better understanding and management of fungal allergy, namely by improvements in the actual assessment and diagnostic approaches are needed. Regarding the assessment of fungal exposure, actual methodologies are generally laborious and time-consuming making difficult to establish or exclude a fungal contamination and potential associations with allergic disease. In terms of diagnosis, the main difficulty arises from the high number of patients that are apparently sensitized to multiple fungi in which the identification of primary cause of sensitization is complex. Because A. alternata is one of the most abundant and potent source of airborne allergens, the panel of allergenic components produced by this fungal specie, seems to be a very relevant target of study. Among the several allergens described in this mold, Alt a 1 has been demonstrated to be the most important, sensitizing approximately 80% of A. alternata allergic patients. For this reason, Alt a 1 has been used as the diagnostic marker of genuine sensitization to A. alternata. However, given the complex A. alternata sensitization data, which shows a significant level of polysensitization, due to co-sensitization and/or cross-reactivity to several other phylogenetically related and non-related molds, other allergenic A. alternata components should be studied to explain the whole broad range of reported clinical observations. In the last years, componentresolved diagnosis (CRD) has been shown to be a valuable tool to elucidate clinical observations and to differentiate between cases of co-sensitization and cross-reactivity. Nevertheless, the actual available panel of A. alternata allergens appears to not be enough for achieving an accurate diagnosis and prognosis of sensitization to this mold. Considering the above mentioned facts, the major aims of this work were, on one hand to develop an approach to specifically detect Alternaria and related species by using the A. alternata major allergen, Alt a 1, as a specie-specific molecular marker. And, on other hand, to characterize two new cross-reactive A. alternata allergens belonging to the manganesedependent superoxide dismutase (MnSOD) and serine protease (SP) protein families and to study their role in A. alternata sensitization. The strategies used to accomplish both aims made use of phylogenetic relationships among fungal species that share A. alternata allergen homologues. First, investigating conservation of the genes encoding for Alt a 1 and its homologues which allowed the design of a set of primers in the conserved immunologically relevant Alt a 1 coding sequence region. This primer set, together with a pair of primers to amplify the complete Alt a 1 encoding gene, was applied in a polymerase chain reaction (PCR)-based system. This approach yielded two rapid, sensitive and specific methodologies with high potential to be applied both for the detection of Alt a 1 and Alt a 1 homologues and for specific identification of the existence of contamination by the very close taxonomically related species A. alternata and A. tenuissima. The investigation of conservation of the genes encoding for A. alternata protein homologues, was also employed to design primers in the invariant region of fungal MnSOD and SP nucleotide sequences available in public databases. The aforementioned primers along with rapid amplification of cDNA ends (RACE) and sequencing assays allowed for the isolation of the full-length cDNA encoding for A. alternata MnSOD and SP. Both proteins were then produced as recombinant proteins in E. coli and evaluated for IgE immunoreactivity using a comprehensive panel of sera from patients clinically labeled as to be sensitized to A. alternata. Immunoblotting analysis showed that IgE antibodies from A. alternata-sensitized patients bound to recombinant A. alternata MnSOD and SP with prevalence of 11.5% (n=61) and 10.2% (n=59), respectively. These results were reported to the World Health Organization and International Union of Immunological Societies (WHO/IUIS) Allergen Nomenclature Sub- Committee, and both proteins, respectively named Alt a 14 and Alt a 15, are currently included in the official A. alternata allergen list. By performing immunoblotting inhibition assays it was demonstrated that Alt a 14 and Alt a 15 are able to mediate IgE cross-reactivity with similar homologues allergens from other important allergenic fungal species, such as A. fumigatus and C. lunata, respectively. Furthermore, evidence of reactivity of Alt a 14 to IgE of Allergic Bronchopulmonary Aspergillosis (ABPA)-diagnosed patients was found, thus indicating that sensitization to this A. alternata allergen could play important implications in the development of ABPA. On the other hand, sensitization to Alt a 15 was shown to be restricted to apparently poly-sensitized patients and to justify some cases of sensitization to A. alternata in which there is no evidence of Alt a 1 sensitization. A homologue to Alt a 14, together with a manitol desidrogenase (MtDH), of the edible mushroom A. bisporus were identified to induce an anaphylactic shock reaction in a patient who presented a previous history of respiratory allergic symptoms associated to mold aeroallergens. These results were useful in proving that although minor allergens, A. alternata cross-reacting proteins may be the primary cause of strong allergic reactions to various other allergenic sources, such as mushrooms. Overall, in this work we successfully developed a specific and sensitive PCR method based on the amplification of regions of the gene encoding for the allergenic Alt a 1 and Alt a 1 homologues which it is intended to be applied for environmental monitoring as well as for quality and biosecurity control of food stuffs. Moreover, cloning and characterization of Alt a 14 and Alt a 15 as minor allergens of A. alternata that can trigger cross-reactive IgE response with other important and prevalent allergenic fungal species were also accomplished. The availability of these allergens as recombinant molecules suitable for application in a molecule-based diagnostic approach to fungal allergy can improve the diagnostic process prognosis of clinical manifestations and potential cross-reactivities. Furthermore, this can guide to a more effective specific immunotherapy using a single or a few allergenic molecules. Hence, this work provided valuable findings that can contribute to improving the accuracy of assessment of allergen exposure, diagnosis and management of IgE-mediated fungal diseases.As doenças alérgicas são consideradas uma das epidemias do século XXI, afectando aproximadamente um terço da população em geral. De entre as fontes alergénicas ambientais capazes de induzir reacções de hipersensibilidade de tipo I, os fungos têm sido uma das áreas de estudo menos favorecidas. No entanto, a sensibilização a aero-alergénios de origem fúngica tem sido apontada por vários autores como um factor de risco indiscutível para o desenvolvimento, persistência e severidade de doença alérgica respiratória, nomeadamente da asma. Estes dados sugerem que a realização de estudos visando progressos, nomeadamente, nos métodos de detecção de exposição ambiental, assim como nas metodologias de diagnóstico, são necessários e cruciais para a melhor compreensão, diagnóstico e tratamento das doenças alérgicas provocadas por espécies fúngicas. Os métodos de avaliação de contaminação ambiental por fungos de importância alergológica, tradicionalmente usados em estudos epidemiológicos e aerobiológicos, têm como base a detecção e identificação de espécies por observação microscópica de características morfológicas e contagem de esporos. Na sua generalidade, a execução destes métodos é bastante demorada, complexa e requer a presença de pessoal treinado com elevados conhecimentos na área da micologia. Desta forma, a definição ou exclusão de contaminação ambiental por uma determinada espécie fúngica e a associação de exposição com um padrão de sintomatologia alérgica tem sido bastante problemática. Em termos de diagnóstico, a principal dificuldade atual resulta do grande número de doentes que estão aparentemente sensibilizados a mais do que uma espécie fúngica. Nestes casos clínicos, o diagnóstico da causa primária de sensibilização é bastante complexo. Vários estudos epidemiológicos realizados, fundamentalmente na Europa, têm descrito Alternaria alternata como a fonte de aero-alergénios de origem fúngica mais importante e com maior alergenicidade. Tais relatos sugerem que o estudo do painel de alergénios produzidos por esta espécie pode ser um alvo de estudo que pode contribuir para o avanço significativo na área de conhecimento das alergias a fungos. Entre as várias proteínas alergénicas descritas até ao momento, Alt a 1, constitui o alergénio de A. alternata mais importante, sendo responsável pela sensibilização de, pelo menos, 80% dos doentes diagnosticados como alérgicos a Alternaria. Devido a esta elevada prevalência de sensibilização, este componente alergénico tem sido correntemente utilizado como um marcador de sensibilização genuína a A. alternata, sendo referido por muitos autores como um marcador de sensibilização à família das Pleosporaceae. Nos últimos anos, o diagnóstico molecular tem sido apresentado como uma ferramenta com resultados bastante promissores para definir o perfil de sensibilização individual de cada doente alérgico e sua associação com as manifestações clínicas observadas, assim como para discriminar entre casos de cosensibilização e reatividade cruzada. Nestes estudos, a sensibilização a Alt a 1 e aos outros alergénios descritos, parece não ser suficiente para justificar todo o espectro de sintomas clínicos observado em doentes sensibilizados a A. alternata. Tendo por base estes conhecimentos, estabeleceram-se como objectivos principais deste trabalho: por um lado, desenvolver uma tecnologia por detecção específica de A. alternata e espécies taxonomicamente relacionadas, utilizando Alt a 1 como um marcador molecular espécie-específico. E por outro lado, ampliar o painel alergénico de A. alternata, por caracterização de uma superóxido dismutase dependente de manganês (MnSOD) e uma protease de serina (SP) como dois novos alergénios de A alternata e estudar o seu papel no diagnóstico e prognóstico das doenças alérgicas causadas por fungos. As estratégias usadas para a concretização destes objectivos tiveram como princípio base o estudo das relações filogenéticas das espécies fúngicas que partilham proteínas homólogas aos alergénios de A. alternata. Assim, primeiramente, o estudo de conservação dos genes de expressão de Alt a 1 e homólogos possibilitou o desenho de um par de primers para o reconhecimento da região conservada e imunologicamente relevante, ou seja, da zona que codifica para os epítopos alergénicos da molécula de Alt a 1. Foram então realizados ensaios de PCR utilizando este par de primers e um segundo par de oligonucleótidos que permite a amplificação do gene completo de Alt a 1. Desta forma, foram desenvolvidas e optimizadas duas metodologias específicas, sensíveis e rápidas: a primeira com potencial para a detecção de Alt a 1 e homólogos, independentemente da fonte alergénica que o produz e uma segunda que permitiu detetar de forma restringida as espécies filogeneticamente próximas, A. alternata e A. tenuissima. O estudo de homologia e conservação de genes que codificam para proteínas homólogas às de A. alternata, foi também aplicado no desenho de primers degenerados para a região não variável das sequências nucleotídicas codificantes de MnSODs e SPs de origem fúngica disponíveis nas bases de dados. Os cDNA completos que codificam estas proteínas foram isolados pela realização de ensaios RACE-PCR; as respectivas moléculas recombinantes foram produzidas em Escherichia coli e purificadas a partir dos corpos de inclusão. A capacidade de reconhecimento de IgE existente em soros de uma população representativa de doentes sensibilizados a A. alternata foi analisada mediante immunoblotting. Desta análise verificaram-se prevalências de sensibilização às MnSOD e SP de A. alternata recombinantes de 11.5% (n=61) e 10.2% (n=59), respetivamente. Estes resultados foram comunicados ao World Health Organization and International Union of Immunological Societies (WHO/IUIS) Allergen Nomenclature Sub-Committee e ambas proteínas foram registadas por esta entidade como alergénios clinicamente relevantes de A. alternata, oficialmente designados de Alt a 14 e Alt a 15. Pela realização de ensaios de inibição por ELISA pôde constatar-se que os alergénios recombinantes produzidos apresentavam características imunoquímicas de reatividade para a IgE, similares às respetivas moléculas nativas existentes num extracto crude de A. alternata. Adicionalmente, Alt a 14 e Alt a 15 demonstraram um alto potencial para mediar reações de reatividade cruzada entre A. alternata e outras espécies fúngicas de importância alergológica, nomeadamente Aspergillus fumigatus e Curvularia lunata. A associação de dados clínicos com as evidências de immunorreatividade e reatividade cruzada permitiu demonstrar que a sensibilização a Alt a 14 parece ser um indicador de desenvolvimento de aspergilose broncopulmonar alérgica (ABPA). Em relação a Alt a 15, a sensibilização a esta proteína alergénica pareceu ser restrita a doentes aparentemente sensibilizados a múltiplos fungos. Além disso, esta molécula parece justificar a sensibilização a A. alternata em alguns casos nos quais a sensibilização ao marcador de sensibilização genuína a Alternaria (Alt a 1) não foi verificada. Neste trabalho de investigação foi ainda apresentado um caso clínico de um doente com história clínica prévia de sintomas respiratórios associados a alergia diagnosticada a fungos ambientais, entre os quais a A. alternata, que recentemente sofreu um choque anafilático após a ingestão de cogumelos. Os resultados obtidos pela análise da reatividade da IgE sérica da doente identificaram uma MnSOD (homóloga da Alt a 14) e uma manitol desidrogenase (MtDH) existentes num extrato da espécie de cogumelo comestível Agaricus bisporus, como as moléculas responsáveis pelo desencadeamento da reação sistémica observada. Estas demonstrações sustentam a teoria de que uma anterior sensibilização a alergénios fúngicos ambientais de reatividade cruzada, tais como os que são apresentados neste trabalho, em particular Alt a 14, pode suscitar o desenvolvimento de reações sistémicas a alimentos que partilham alergénios homólogos aos sensibilizantes primários. Em suma, neste trabalho doutoral, foi desenvolvida uma técnica de PCR específica e bastante sensível para aplicação no controlo de contaminação por espécies fúngicas produtoras de Alt a 1. Além disso, dois novos alergénios de A. alternata, Alt a 14 e Alt a 15, foram caracterizados como alergénios minor capazes de mediar fenómenos de reatividade cruzada com várias espécies fúngicas, resultando em quadros clínicos de resposta alérgica complexos. A disponibilidade destes alergénios como moléculas recombinantes com aptidão para serem aplicadas em diagnóstico molecular pode constituir uma mais valia para melhorar a precisão do diagnóstico das doenças alérgicas provocadas por fungos, através da definição de perfis de sensibilização individuais. Pelas evidências clínicas demonstradas ao longo deste trabalho pode também concluir-se que a correta identificação de sensibilização a Alt a 14 e Alt a 15, pode orientar o alergologista e o doente para a tomada de medidas de prevenção de potenciais quadros clínicos que podem ocorrer, nomeadamente, em consequência de reatividade cruzada. Este trabalho fornece ferramentas e informações úteis e valiosas que podem contribuir para um avanço significativo na avaliação de exposição a alergénios de origem fúngica, assim como no diagnóstico, prognóstico e tratamento das doenças alérgicas provocadas por espécies fúngicas

Evolutionary processes from the perspective of flowering time diversity.

Although it is well appreciated that genetic studies of flowering time regulation have led to fundamental advances in the fields of molecular and developmental biology, the ways in which genetic studies of flowering time diversity have enriched the field of evolutionary biology have received less attention despite often being equally profound. Because flowering time is a complex, environmentally responsive trait that has critical impacts on plant fitness, crop yield, and reproductive isolation, research into the genetic architecture and molecular basis of its evolution continues to yield novel insights into our understanding of domestication, adaptation, and speciation. For instance, recent studies of flowering time variation have reconstructed how, when, and where polygenic evolution of phenotypic plasticity proceeded from standing variation and de novo mutations; shown how antagonistic pleiotropy and temporally varying selection maintain polymorphisms in natural populations; and provided important case studies of how assortative mating can evolve and facilitate speciation with gene flow. In addition, functional studies have built detailed regulatory networks for this trait in diverse taxa, leading to new knowledge about how and why developmental pathways are rewired and elaborated through evolutionary time

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies

Preserved Consciousness in the Absence of a Cerebral Cortex, the Legal and Ethical Implications of Redefining Consciousness and Its Neural Correlates: A Case for a Subcortical System Generating Affective Consciousness

Historically, the scientific and medical communities have taken a corticocentric view on consciousness, emphasizing the need for a cortex in producing the conscious experience. The preserved consciousness observed in hydranencephalic children and decorticated rats suggests that some form of consciousness may be produced by a subcortical network. The brainstem, a phylogenetically ancient and conserved brain structure, could serve as the major integrative machinery to produce this form of consciousness, which is called affective consciousness—the evolutionary antecedent to the reflective consciousness that allows humans to reflect on their experiences. The functional convergence of the brainstem with the amygdala, motor system, and other subcortical structures provides the necessary architecture to support an affective state of consciousness by which instinctual-emotional goal-directed behavior is produced. This subcortical system operates by what Merker (2007) calls the selection triangle—an interface between bodily actions (action selection), the world (target selection), and personal motivation—to produce action through integration. By this model, it is possible that consciousness may persist in the absence of a cortex, such as in the persistent vegetative state. Because of this, it is necessary to establish that multiple forms of consciousness exist and to distinguish between affective and reflective consciousness, because such a distinction would have tremendous ethical implications in the conventional medical treatment of those with disorders of consciousness