MicroRNAs as new player in rheumatoid arthritis

MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression at the post-transcriptional level. Currently, there are 939 mature human miRNA sequences listed in the Sanger updated miRNA registry. There are approximately 1500 predicted miRNAs in the human genome that may regulate the expression of one third of our genes. By controlling the accumulation of the target protein(s) in cells, these regulatory RNA molecules participate in key functions in many physiological networks and their deregulation has been implicated in the pathogenesis of serious human disorders, such as cancer and infection. The implication of miRNAs in immune-mediated disorders such as rheumatoid arthritis (RA) has recently emerged suggesting that miRNA-based therapeutic approaches may have a promising potential in these diseases. Here, we provide an overview of the state-of-the-art on miRNAs in RA, focusing on both systemic and local features of the pathology

Cytosolic phospholipase A2α gene silencing in monocytes alters development of Th1 responses and reduces autoimmune arthritis

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How Memory Conforms to Brain Development

Nature exhibits countless examples of adaptive networks, whose topology evolves constantly coupled with the activity due to its function. The brain is an illustrative example of a system in which a dynamic complex network develops by the generation and pruning of synaptic contacts between neurons while memories are acquired and consolidated. Here, we consider a recently proposed brain developing model to study how mechanisms responsible for the evolution of brain structure affect and are affected by memory storage processes. Following recent experimental observations, we assume that the basic rules for adding and removing synapses depend on local synaptic currents at the respective neurons in addition to global mechanisms depending on the mean connectivity. In this way a feedback loop between “form” and “function” spontaneously emerges that influences the ability of the system to optimally store and retrieve sensory information in patterns of brain activity or memories. In particular, we report here that, as a consequence of such a feedback-loop, oscillations in the activity of the system among the memorized patterns can occur, depending on parameters, reminding mind dynamical processes. Such oscillations have their origin in the destabilization of memory attractors due to the pruning dynamics, which induces a kind of structural disorder or noise in the system at a long-term scale. This constantly modifies the synaptic disorder induced by the interference among the many patterns of activity memorized in the system. Such new intriguing oscillatory behavior is to be associated only to long-term synaptic mechanisms during the network evolution dynamics, and it does not depend on short-term synaptic processes, as assumed in other studies, that are not present in our model.Financial support from the Spanish Ministry of Science and Technology, and the Agencia Española de Investigación (AEI) under grant FIS2017-84256-P (FEDER funds) and from the Obra Social La Caixa (ID 100010434, with code LCF/BQ/ES15/10360004). This study has been also partially financed by the Consejería de Conocimiento, Investigación y Universidad, Junta de Andalucía and European Regional Development Fund (ERDF), with reference SOMM17/6105/UGR

Complement in the pathogenesis of Alzheimer's disease

The emergence of complement as an important player in normal brain development and pathological remodelling has come as a major surprise to most scientists working in neuroscience and almost all those working in complement. That a system, evolved to protect the host against infection, should have these unanticipated roles has forced a rethink about what complement might be doing in the brain in health and disease, where it is coming from, and whether we can, or indeed should, manipulate complement in the brain to improve function or restore homeostasis. Complement has been implicated in diverse neurological and neuropsychiatric diseases well reviewed elsewhere, from depression through epilepsy to demyelination and dementia, in most complement drives inflammation to exacerbate the disease. Here, I will focus on just one disease, the most common cause of dementia, Alzheimer’s disease. I will briefly review the current understanding of what complement does in the normal brain, noting, in particular, the many gaps in understanding, then describe how complement may influence the genesis and progression of pathology in Alzheimer’s disease. Finally, I will discuss the problems and pitfalls of therapeutic inhibition of complement in the Alzheimer brain

Schizophrenia risk from complex variation of complement component 4

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.This work was supported by R01 HG 006855 (to S.A.M), by the Stanley Center for Psychiatric Research (to S.A.M and B.S.), by R01 MH077139 (to the PGC), and by T32 GM007753 (to A.S. and M.B.)

microRNA target prediction programs predict many false positives

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