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Autism spectrum disorders (ASDs) are perhaps the most severe, intractable and challenging child psychiatric disorders. They are complex, pervasive and highly heterogeneous and depend on multifactorial neurodevelopmental conditions. Although the pathogenesis of autism remains unclear, it revolves around altered neurodevelopmental patterns and their implications for brain function, although these cannot be specifically linked to symptoms. While these affect neuronal migration and connectivity, little is known about the processes that lead to the disruption of specific laminar excitatory and inhibitory cortical circuits, a key feature of ASD. It is evident that ASD has multiple underlying causes and this multigenic condition has been considered to also dependent on epigenetic effects, although the exact nature of the factors that could be involved remains unclear. However, besides the possibility for differential epigenetic markings directly affecting the relative expression levels of individual genes or groups of genes, there are at least three mRNA epitranscriptomic mechanisms, which function cooperatively and could, in association with both genotypes and environmental conditions, alter spatiotemporal proteins expression patterns during brain development, at both quantitative and qualitative levels, in a tissue-specific, and context-dependent manner. As we have already postulated, sudden changes in environmental conditions, such as those conferred by maternal inflammation/immune activation, influence RNA epitranscriptomic mechanisms, with the combination of these processes altering fetal brain development. Herein, we explore the postulate whereby, in ASD pathogenesis, RNA epitranscriptomics might take precedence over epigenetic modifications. RNA epitranscriptomics affects real-time differential expression of receptor and channel proteins isoforms, playing a prominent role in central nervous system (CNS) development and functions, but also RNAi which, in turn, impact the spatiotemporal expression of receptors, channels and regulatory proteins irrespective of isoforms. Slight dysregulations in few early components of brain development, could, depending upon their extent, snowball into a huge variety of pathological cerebral alterations a few years after birth. This may very well explain the enormous genetic, neuropathological and symptomatic heterogeneities that are systematically associated with ASD and psychiatric disorders at large.
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Autism spectrum disorder (ASD) involves alterations in neural connectivity affecting cortical network organization and excitation to inhibition ratio. It is characterized by an early increase in brain volume mediated by abnormal cortical overgrowth patterns and by increases in size, spine density, and neuron population in the amygdala and surrounding nuclei. Neuronal expansion is followed by a rapid decline from adolescence to middle age. Since no known neurobiological mechanism in human postnatal life is capable of generating large excesses of frontocortical neurons, this likely occurs due to a dysregulation of layer formation and layer-specific neuronal migration during key early stages of prenatal cerebral cortex development. This leads to the dysregulation of post-natal synaptic pruning and results in a huge variety of forms and degrees of signal-over-noise discrimination losses, accounting for ASD clinical heterogeneities, including autonomic nervous system abnormalities and comorbidities. We postulate that sudden changes in environmental conditions linked to serotonin/kynurenine supply to the developing fetus, throughout the critical GW7 - GW20 (Gestational Week) developmental window, are likely to promote ASD pathogenesis during fetal brain development. This appears to be driven by discrete alterations in differentiation and patterning mechanisms arising from in utero RNA editing, favoring vulnerability outcomes over plasticity outcomes. This paper attempts to provide a comprehensive model of the pathogenesis and progression of ASD neurodevelopmental disorders.
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Maternal and child malnutrition and anaemia remain the leading factors for health loss in India. Low birth weight (LBW) offspring of women suffering from chronic malnutrition and anaemia often exhibit insulin resistance and infantile stunting and wasting, together with increased risk of developing cardiometabolic disorders in adulthood. The resulting self-perpetuating and highly multifactorial disease burden cannot be remedied through uniform dietary recommendations alone. To inform approaches likely to alleviate this disease burden, we implemented a systems-analytical approach that had already proven its efficacy in multiple published studies. We utilised previously published qualitative and quantitative analytical results of rural and urban field studies addressing maternal and infantile metabolic and nutritional parameters to precisely define the range of pathological phenotypes encountered and their individual biological characteristics. These characteristics were then integrated, via extensive literature searches, into metabolic and physiological mechanisms to identify the maternal and foetal metabolic dysregulations most likely to underpin the 'thin-fat' phenotype in LBW infants and its associated pathological consequences. Our analyses reveal hitherto poorly understood maternal nutrition-dependent mechanisms most likely to promote and sustain the self-perpetuating high disease burden, especially in the Indian population. This work suggests that it most probably is the metabolic consequence of 'ill-nutrition' - the recent and rapid dietary shifts to high salt, high saturated fats and high sugar but low micronutrient diets - over an adaptation to 'thrifty metabolism' which must be addressed in interventions aiming to significantly alleviate the leading risk factors for health deterioration in India.
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Anemia , Desnutrição , Adulto , Anemia/epidemiologia , Feminino , Humanos , Índia/epidemiologia , Recém-Nascido de Baixo Peso , Recém-Nascido , Desnutrição/complicações , FenótipoRESUMO
Dysbiosis secondary to environmental factors, including dietary patterns, antibiotics use, pollution exposure, and other lifestyle factors, has been associated to many non-infective chronic inflammatory diseases. Autism spectrum disorder (ASD) is related to maternal inflammation, although there is no conclusive evidence that affected individuals suffer from systemic low-grade inflammation as in many psychological and psychiatric diseases. However, neuro-inflammation and neuro-immune abnormalities are observed within ASD-affected individuals. Rebalancing human gut microbiota to treat disease has been widely investigated with inconclusive and contradictory findings. These observations strongly suggest that the forms of dysbiosis encountered in ASD-affected individuals could also originate from autonomic nervous system (ANS) functioning abnormalities, a common neuro-anatomical alteration underlying ASD. According to this hypothesis, overactivation of the sympathetic branch of the ANS, due to the fact of an ASD-specific parasympathetic activity deficit, induces deregulation of the gut-brain axis, attenuating intestinal immune and osmotic homeostasis. This sets-up a dysbiotic state, that gives rise to immune and osmotic dysregulation, maintaining dysbiosis in a vicious cycle. Here, we explore the mechanisms whereby ANS imbalances could lead to alterations in intestinal microbiome-host interactions that may contribute to the severity of ASD by maintaining the brain-gut axis pathways in a dysregulated state.
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Transtorno do Espectro Autista/microbiologia , Eixo Encéfalo-Intestino , Disbiose , Microbioma Gastrointestinal , Sistema Nervoso Autônomo/fisiopatologia , HumanosRESUMO
The limitations of the currently available treatments for chronic neuropathic pain highlight the need for safer and more effective alternatives. The authors carried out a focused review using a systems biology approach to integrate the complex mechanisms of nociception and neuropathic pain, and to decipher the effects of nitrous oxide (N2O) on those pathways, beyond the known effect of N2O on N-methyl-D-aspartate receptors. This review identified a number of potential mechanisms by which N2O could impact the processes involved in peripheral and central sensitization. In the ascending pathway, the effects of N2O include activating TWIK-related K+ channel 1 potassium channels on first-order neurons, blocking voltage-dependent calcium channels to attenuate neuronal excitability, attenuating postsynaptic glutamatergic receptor activation, and possibly blocking voltage-dependent sodium channels. In the descending pathway, N2O induces the release of endogenous opioid ligands and stimulates norepinephrine release. In addition, N2O may mediate epigenetic changes by inhibiting methionine synthase, a key enzyme involved in DNA and RNA methylation. This could explain why this short-acting analgesic has shown long-lasting anti-pain sensitization effects in animal models of chronic pain. These new hypotheses support the rationale for investigating N2O, either alone or in combination with other analgesics, for the management of chronic neuropathic pain.
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Neuralgia/tratamento farmacológico , Óxido Nitroso/uso terapêutico , Biologia de Sistemas , Animais , Doença Crônica , HumanosRESUMO
Autism Spectrum Disorder (ASD) affects approximately 1 child in 54, with a 35-fold increase since 1960. Selected studies suggest that part of the recent increase in prevalence is likely attributable to an improved awareness and recognition, and changes in clinical practice or service availability. However, this is not sufficient to explain this epidemiological phenomenon. Research points to a possible link between ASD and intestinal microbiota because many children with ASD display gastro-intestinal problems. Current large-scale datasets of ASD are limited in their ability to provide mechanistic insight into ASD because they are predominantly cross-sectional studies that do not allow evaluation of perspective associations between early life microbiota composition/function and later ASD diagnoses. Here we describe GEMMA (Genome, Environment, Microbiome and Metabolome in Autism), a prospective study supported by the European Commission, that follows at-risk infants from birth to identify potential biomarker predictors of ASD development followed by validation on large multi-omics datasets. The project includes clinical (observational and interventional trials) and pre-clinical studies in humanized murine models (fecal transfer from ASD probands) and in vitro colon models. This will support the progress of a microbiome-wide association study (of human participants) to identify prognostic microbiome signatures and metabolic pathways underlying mechanisms for ASD progression and severity and potential treatment response.
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The production and implementation of methodologies allowing the construction of coherent, precise and trustworthy predictive biological models has become an inescapable necessity. The financial stakes -attached to this reality are very high indeed, be it in the public or the private domains (health, research, pharma and foodstuffs industries, environment, etc.). Modelling biological systems is widely presented as a problem in computational sciences. While certainly very true for low complexity, practically continuous systems, this view cannot be upheld in the case of discontinuous, hyper-complex systems such as living entities. In these domains, modelling becomes a problem in biology assisted by computational sciences and certainly not the obverse. The following article will attempt to demonstrate why it is so, using concrete examples.
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Biologia Computacional/métodos , Modelos Biológicos , Biologia/normas , Biologia/tendências , Biologia Computacional/normas , Saúde , Humanos , Valor Preditivo dos Testes , Pesquisa/normas , Pesquisa/tendênciasRESUMO
It is becoming generally accepted that the current diagnostic system often guarantees, rather than diminishes, disease heterogeneity. In effects, syndrome-dominated conceptual thinking has become a barrier to understanding the biological causes of complex, multifactorial diseases characterized by clinical and therapeutic heterogeneity. Furthermore, not only is the flood of currently available medical and biological information highly heterogeneous, it is also often conflicting. Together with the entire absence of functional models of pathogenesis and pathological evolution of complex diseases, this leads to a situation where illness activity cannot be coherently approached and where therapeutic developments become highly problematic. Acquisition of the necessary knowledge can be obtained, in parts, using in silico models produced through analytical approaches and processes collectively known as `Systems Biology'. However, without analytical approaches that specifically incorporate the facts that all that is called `information' is not necessarily useful nor utilisable and that all information should be considered as a priori suspect, modelling attempts will fail because of the much too numerous conflicting and, although correct in molecular terms, physiologically invalid reports. In the present essay, we suggest means whereby this body of problems could be functionally attacked and describe new analytical approaches that have demonstrated their efficacy in alleviating these difficulties.
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Biologia de Sistemas/métodos , Animais , Simulação por Computador , HumanosRESUMO
To understand the cellular mechanisms of malignant transformation induced by constitutive activation of the ras oncogene (Ha-ras), we used a subtractive hybridization method (VGID) together with an integrative analytical procedure based upon literature databases in the form of extensive interaction graphs. We found 166 over- and under-expressed genes which, in the human MCF7-ras breast epithelial cell line, are involved in the different aspects of tumoral transformation such as defined signaling pathways, cellular growth, protection against apoptosis, extracellular matrix and cytoskeleton remodeling. Integrative analysis led to the construction of a physiological model defining cross-talk and signaling pathway alterations which explicitly suggested mechanisms directly involved in tumor progression. The model further suggested points and means of intervention which could induce cell death in Ha-ras-transformed cells specifically. These hypotheses were directly tested in vitro and found to be largely correct, hence indicating that these new analytical and technological approaches allow the discovery of pathology-associated cellular mechanisms and physiologically defined targets leading to phenotype-specific pharmacological interventions.
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Neoplasias da Mama/genética , Transformação Celular Neoplásica , Biologia Computacional/métodos , Hibridização de Ácido Nucleico/métodos , Proteína Oncogênica p21(ras)/metabolismo , Algoritmos , Mama/citologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Morte Celular , Linhagem Celular Transformada , Células Epiteliais/citologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Teóricos , Análise de Sequência com Séries de Oligonucleotídeos , Reprodutibilidade dos Testes , Transcrição Gênica , Células Tumorais CultivadasRESUMO
Natural outbreaks of multidrug-resistant microorganisms can cause widespread devastation, and several can be used or engineered as agents of bioterrorism. From a biosecurity standpoint, the capacity to detect and then efficiently control, within hours, the spread and the potential pathological effects of an emergent outbreak, for which there may be no effective antibiotics or vaccines, become key challenges that must be met. We turned to phage engineering as a potentially highly flexible and effective means to both detect and eradicate threats originating from emergent (uncharacterized) bacterial strains. To this end, we developed technologies allowing us to (1) concurrently modify multiple regions within the coding sequence of a gene while conserving intact the remainder of the gene, (2) reversibly interrupt the lytic cycle of an obligate virulent phage (T4) within its host, (3) carry out efficient insertion, by homologous recombination, of any number of engineered genes into the deactivated genomes of a T4 wild-type phage population, and (4) reactivate the lytic cycle, leading to the production of engineered infective virulent recombinant progeny. This allows the production of very large, genetically engineered lytic phage banks containing, in an E. coli host, a very wide spectrum of variants for any chosen phage-associated function, including phage host-range. Screening of such a bank should allow the rapid isolation of recombinant T4 particles capable of detecting (ie, diagnosing), infecting, and destroying hosts belonging to gram-negative bacterial species far removed from the original E. coli host.