A synoptic characterization of the dust transport and associated thermal anomalies in the Mediterranean basin

Presentación realizada para las XXXII Jornadas Científicas de la Asociación Meteorológica Española y 13º Encuentro Hispano-Luso de Meteorología celebrados en Alcobendas (Madrid), del 28 al 30 de mayo de 2012

Hippocampal neuroplasticity and inflammation: relevance for multiple sclerosis

Cognitive impairment is very frequent during multiple sclerosis (MS), involving approximately 40–70% of the patients, with a profound impact on patient's life. It is now established that among the various central nervous system (CNS) structures involved during the course of MS, the hippocampus is particularly sensitive to the detrimental effects of neuroinflammation. Different studies demonstrated hippocampal involvement during MS, in association with depression and cognitive impairment, such as verbal and visuo-spatial memory deficits, even during the earlier phases of the disease. These cognitive alterations could represent the visible consequences of a hidden synaptic impairment. Indeed, neuronal and immune functions are intertwined and the immune system is able to modulate the efficacy of synaptic transmission and the induction of the main forms of synaptic plasticity, such as long term potentiation (LTP). Hippocampal synaptic plasticity has been studied during the last decades as the physiological basis of human learning and memory and its disruption can be associated with behavioral and cognitive abnormalities. The aim of the present work is to review the available evidence about the presence of hippocampal synaptic plasticity alterations in experimental models of MS, specifically during the course of experimental autoimmune encephalomyelitis (EAE) and to discuss their relevance with regard to human MS. Indeed, the failure of synapses to express plasticity during neuroinflammation could potentially lead to a progressive failure of the brain plastic reserve, possibly contributing to disability progression and cognitive impairment during MS

The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression

Mutations in the gene autoimmune regulator (AIRE) cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. AIRE is expressed in thymic medullary epithelial cells, where it promotes the expression of tissue-restricted antigens. By the combined use of biochemical and biophysical methods, we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger (AIRE–PHD1) and preferentially binds to non-methylated H3K4 (H3K4me0). Accordingly, in vivo AIRE binds to and activates promoters containing low levels of H3K4me3 in human embryonic kidney 293 cells. We conclude that AIRE–PHD1 is an important member of a newly identified class of PHD fingers that specifically recognize H3K4me0, thus providing a new link between the status of histone modifications and the regulation of tissue-restricted antigen expression in thymus

An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation

To characterize molecular changes during cell type transitions, the authors develop a method to simultaneously measure protein expression and thermal stability changes. They apply this approach to study differences between human pluripotent stem cells, their progenies, parental and allogeneic cells. Detailed characterization of cell type transitions is essential for cell biology in general and particularly for the development of stem cell-based therapies in regenerative medicine. To systematically study such transitions, we introduce a method that simultaneously measures protein expression and thermal stability changes in cells and provide the web-based visualization tool ProteoTracker. We apply our method to study differences between human pluripotent stem cells and several cell types including their parental cell line and differentiated progeny. We detect alterations of protein properties in numerous cellular pathways and components including ribosome biogenesis and demonstrate that modulation of ribosome maturation through SBDS protein can be helpful for manipulating cell stemness in vitro. Using our integrative proteomics approach and the web-based tool, we uncover a molecular basis for the uncoupling of robust transcription from parsimonious translation in stem cells and propose a method for maintaining pluripotency in vitro

Diagnostic value of kappa free light chain index in patients with primary progressive multiple sclerosis – a multicentre study

BackgroundKappa free light chains (κ-FLC) in the cerebrospinal fluid (CSF) are an emerging biomarker in multiple sclerosis (MS).ObjectiveTo investigate whether κ-FLC index has similar diagnostic value in patients with primary progressive multiple sclerosis (PPMS) compared to oligoclonal bands (OCB).MethodsPatients with PPMS were recruited through 11 MS centres across 7 countries. κ-FLC were measured by immunonephelometry/-turbidimetry. OCB were determined by isoelectric focusing and immunofixation.ResultsA total of 174 patients (mean age of 52±11 years, 51% males) were included. κ-FLC index using a cut-off of 6.1 was positive in 161 (93%) and OCB in 153 (88%) patients.Conclusionκ-FLC index shows similar diagnostic sensitivity than OCB in PPMS

The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation

Plant homeodomain (PHD) fingers are often present in chromatin-binding proteins and have been shown to bind histone H3 N-terminal tails. Mutations in the autoimmune regulator (AIRE) protein, which harbours two PHD fingers, cause a rare monogenic disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE activates the expression of tissue-specific antigens by directly binding through its first PHD finger (AIRE-PHD1) to histone H3 tails non-methylated at K4 (H3K4me0). Here, we present the solution structure of AIRE-PHD1 in complex with H3K4me0 peptide and show that AIRE-PHD1 is a highly specialized non-modified histone H3 tail reader, as post-translational modifications of the first 10 histone H3 residues reduce binding affinity. In particular, H3R2 dimethylation abrogates AIRE-PHD1 binding in vitro and reduces the in vivo activation of AIRE target genes in HEK293 cells. The observed antagonism by R2 methylation on AIRE-PHD1 binding is unique among the H3K4me0 histone readers and represents the first case of epigenetic negative cross-talk between non-methylated H3K4 and methylated H3R2. Collectively, our results point to a very specific histone code responsible for non-modified H3 tail recognition by AIRE-PHD1 and describe at atomic level one crucial step in the molecular mechanism responsible for antigen expression in the thymus

Synaptic Dysfunction in Multiple Sclerosis: A Red Thread from Inflammation to Network Disconnection

Multiple sclerosis (MS) has been clinically considered a chronic inflammatory disease of the white matter; however, in the last decade growing evidence supported an important role of gray matter pathology as a major contributor of MS-related disability and the involvement of synaptic structures assumed a key role in the pathophysiology of the disease. Synaptic contacts are considered central units in the information flow, involved in synaptic transmission and plasticity, critical processes for the shaping and functioning of brain networks. During the course of MS, the immune system and its diffusible mediators interact with synaptic structures leading to changes in their structure and function, influencing brain network dynamics. The purpose of this review is to provide an overview of the existing literature on synaptic involvement during experimental and human MS, in order to understand the mechanisms by which synaptic failure eventually leads to brain networks alterations and contributes to disabling MS symptoms and disease progression

Neuroinflammation and Alzheimer’s Disease: A Machine Learning Approach to CSF Proteomics

In Alzheimer’s disease (AD), the contribution of pathophysiological mechanisms other than amyloidosis and tauopathy is now widely recognized, although not clearly quantifiable by means of fluid biomarkers. We aimed to identify quantifiable protein biomarkers reflecting neuroinflammation in AD using multiplex proximity extension assay (PEA) testing. Cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment due to AD (AD-MCI) and from controls, i.e., patients with other neurological diseases (OND), were analyzed with the Olink Inflammation PEA biomarker panel. A machine-learning approach was then used to identify biomarkers discriminating AD-MCI (n: 34) from OND (n: 25). On univariate analysis, SIRT2, HGF, MMP-10, and CXCL5 showed high discriminatory performance (AUC 0.809, p = 5.2 × 10−4, AUC 0.802, p = 6.4 × 10−4, AUC 0.793, p = 3.2 × 10−3, AUC 0.761, p = 2.3 × 10−3, respectively), with higher CSF levels in AD-MCI patients as compared to controls. These same proteins were the best contributors to the penalized logistic regression model discriminating AD-MCI from controls (AUC of the model 0.906, p = 2.97 × 10−7). The biological processes regulated by these proteins include astrocyte and microglia activation, amyloid, and tau misfolding modulation, and blood-brain barrier dysfunction. Using a high-throughput multiplex CSF analysis coupled with a machine-learning statistical approach, we identified novel biomarkers reflecting neuroinflammation in AD. Studies confirming these results by means of different assays are needed to validate PEA as a multiplex technique for CSF analysis and biomarker discovery in the field of neurological diseases

Biocompatibility and Connectivity of Semiconductor Nanostructures for Cardiac Tissue Engineering Applications

Nano- or microdevices, enabling simultaneous, long-term, multisite, cellular recording and stimulation from many excitable cells, are expected to make a strategic turn in basic and applied cardiology (particularly tissue engineering) and neuroscience. We propose an innovative approach aiming to elicit bioelectrical information from the cell membrane using an integrated circuit (IC) bearing a coating of nanowires on the chip surface. Nanowires grow directly on the backend of the ICs, thus allowing on-site amplification of bioelectric signals with uniform and controlled morphology and growth of the NWs on templates. To implement this technology, we evaluated the biocompatibility of silicon and zinc oxide nanowires (NWs), used as a seeding substrate for cells in culture, on two different primary cell lines. Human cardiac stromal cells were used to evaluate the effects of ZnO NWs of different lengths on cell behavior, morphology and growth, while BV-2 microglial-like cells and GH4-C1 neuroendocrine-like cell lines were used to evaluate cell membrane–NW interaction and contact when cultured on Si NWs. As the optimization of the contact between integrated microelectronics circuits and cellular membranes represents a long-standing issue, our technological approach may lay the basis for a new era of devices exploiting the microelectronics’ sensitivity and “smartness” to both improve investigation of biological systems and to develop suitable NW-based systems available for tissue engineering and regenerative medicine