A reference panel of 64,976 haplotypes for genotype imputation.

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci.

Vascular endothelial growth factor behavior in different stages of tooth germ development.

Background: Scientific studies show a possible influence of intercellular and intracellular proteins (VEGF) on the development of physiological and pathological tissue. VEGF, a key regulator of angiogenesis, it would seem essential to take action during the embryonic development of the dental germ. The purpose of the study is to investigate the importance of the enzymatic activity of VEGF through protein quantification at different stages of tooth germ development.

Direct and high throughput (HT) interactions on the ribosomal surface by iRIA.

Ribosomes function as platforms for binding of other molecules, but technologies for studying this process are lacking. Therefore we developed iRIA (in vitro Ribosomes Interaction Assay). In approach I, Artemia salina ribosomes spotted on solid phase are used for binding picomoles of analytes; in approach II, cellular extracts allow the measurement of ribosome activity in different conditions.

Whole-genome sequence-based analysis of thyroid function.

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335).

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci.

Histone content increases in differentiating embryonic stem cells.

Mouse Embryonic Stem Cells (ESCs) are pluripotent mammalian cells derived from the Inner Cell Mass (ICM) of mouse blastocysts, which give rise to all three embryonic germ layers both in vivo and in vitro. Mouse ESCs have a distinct epigenetic landscape and a more decondensed chromatin compared to differentiated cells. Numerous studies have shown that distinct histone modifications in ESCs serve as hallmarks of pluripotency.

Combined laparoscopic spleen-preserving distal pancreatectomy and islet autotransplantation for benign pancreatic neoplasm.

Aim: To evaluate the safety and feasibility of laparoscopic spleen-preserving distal pancreatectomy (LSPDP) with autologous islet transplantation (AIT) for benign tumors of the pancreatic body-neck.

Methods: Three non-diabetic, female patients (age 37, 44 and 35 years, respectively) were declared candidates for surgery, between May and September 2011, because of pancreatic body/neck cystic lesions. The planned operation was an LSPDP associated with AIT from the normal pancreas distal to the neoplasm.

Genome wide association analysis of a founder population identified TAF3 as a gene for MCHC in humans.

The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5-10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene.

Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations.

Background: Hepcidin is the main regulator of iron homeostasis: inappropriate production of hepcidin results in iron overload or iron deficiency and anaemia.

Aims: To study variation of serum hepcidin concentration in a normal population.

Results: Hepcidin showed age and sex dependent variations that correlated with ferritin but not with serum iron and transferrin saturation.

HMGB1 loves company.

HMGB1, outside of a cell, is a trigger of inflammation and a stimulus for tissue reconstruction; the balance may depend on the complexes it forms with other molecules. HMGB1 is the prime example of a danger signal that originates from the damaged self rather than from invading pathogens. HMGB1 is released by cells that die traumatically and is secreted by cells destined to die and by activated cells of the innate immunity system.

Src family kinases are necessary for cell migration induced by extracellular HMGB1.

HMGB1 is a nuclear protein that signals tissue damage, as it is released by cells dying traumatically or secreted by activated innate immunity cells. Extracellular HMGB1 elicits the migration to the site of tissue damage of several cell types, including inflammatory cells and stem cells. The identity of the signaling pathways activated by extracellular HMGB1 is not known completely: We reported previously that ERK and NF-kappaB pathways are involved, and we report here that Src is also activated.

Effects of vestibular rehabilitation therapy on emotional aspects in chronic vestibular patients.

Objective: A strong relationship exists between vestibular dysfunction and anxiety disorders. The aim of this study was to assess the anxiety and depression levels in patients with chronic dizziness and to assess the effects of vestibular rehabilitation (VR) therapy, on the anxiety and depression levels, without a behavioural or pharmacological therapy.

Method: Two groups of 40 patients, each affected by chronic vestibular deficit, were studied.

Vestibular rehabilitation and 6-month follow-up using objective and subjective measures.

Conclusions: Vestibular rehabilitation improves quality of life by reducing the degree of handicap, improving the ability to perform everyday tasks and providing long-term rehabilitation stability (at 6 months). Recovery of the vestibulo-ocular reflex and the vestibulo-spinal reflex efficiency was proven by the objective results obtained in this study. Vestibular rehabilitation improves both subjective and objective parameters, although no significant correlation between these two indices was found.

GR and HMGB1 interact only within chromatin and influence each other's residence time.

Most nuclear proteins reside on a specific chromatin site only for seconds or less. The hit-and-run model of transcriptional control maintains that transcription complexes are assembled in a stochastic fashion from freely diffusible proteins; this contrasts to models involving stepwise assembly of stable holo complexes. However, the chances of forming a productive complex improve if the binding of one factor promotes the binding of its interactors.

High mobility group box 1 protein, a cue for stem cell recruitment.

High mobility group box 1 (HMGB1) is a non-histone protein required to maintain chromatin architecture. Recent observations demonstrated that HMGB1 can also act as a cytokine to regulate different biological processes such as inflammation, cell migration and metastasis. We showed previously that HMGB1 can be released passively by cells that die in a traumatic and unprogrammed way, and can serve a signal of tissue damage.

Up-regulation of CD1d expression restores the immunoregulatory function of NKT cells and prevents autoimmune diabetes in nonobese diabetic mice.

The immunoregulatory function of NKT cells is crucial for prevention of autoimmunity. The prototypical NKT cell Ag alpha-galactosylceramide is not present in mammalian cells, and little is known about the mechanism responsible for NKT cell recruitment and activation. Up-regulation of CD1d, the NKT cell restriction molecule, expressed on mononuclear cells infiltrating the target organ, could represent the physiological trigger for NKT cells to self-contain T cell immunity and to prevent autoimmune disease.

Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation.

High mobility group box 1 (HMGB1) is an abundant chromatin protein that acts as a cytokine when released in the extracellular milieu by necrotic and inflammatory cells. Here, we show that extracellular HMGB1 and its receptor for advanced glycation end products (RAGE) induce both migration and proliferation of vessel-associated stem cells (mesoangioblasts), and thus may play a role in muscle tissue regeneration. In vitro, HMGB1 induces migration and proliferation of both adult and embryonic mesoangioblasts, and disrupts the barrier function of endothelial monolayers.

Cellular mechanisms of striatum-dependent behavioral plasticity and drug addiction.

The striatum has long been known to be involved in the control of motor behavior, since disruption of dopamine-mediated function in this brain structure is directly linked to Parkinson's disease and other disorders of movement. However, it is now accepted that both dorsal and ventral striatal nuclei are also essential for a variety of cognitive processes, which depend on reward-based stimulus-response learning. Since the neuroanatomical and neurochemical organization of dorsal and ventral striatum is only partially overlapping, it is likely that both common and nucleus-specific cellular and molecular events contribute to synaptic plasticity, learning and memory processes mediated by these cerebral structures.

Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory.

Extracellular signal-regulated kinases (ERK1 and 2) are synaptic signaling components necessary for several forms of learning. In mice lacking ERK1, we observe a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens. At the cellular level, we find that ablation of ERK1 results in a stimulus-dependent increase of ERK2 signaling, likely due to its enhanced interaction with the upstream kinase MEK.

Protease nexin-1-urokinase complexes are internalized and degraded through a mechanism that requires both urokinase receptor and alpha 2-macroglobulin receptor.

After binding to its receptor (uPAR), active cell-surface urokinase (uPA) is not internalized while the complex formed by uPA with plasminogen activator inhibitor type 1 (PAI-1) is internalized and degraded. Internalization and degradation require binding to uPAR and subsequently an interaction with the alpha 2-macroglobulin receptor (alpha 2-MR). To analyze the generality of this mechanism, we studied the internalization of uPA by recombinant protease nexin-1 (rPN-1), an inhibitor of thrombin, uPA, and plasmin.

A Saporin-6 cDNA containing a precursor sequence coding for a carboxyl-terminal extension.

Saporin-6 is a single-chain ribosome inactivating protein (RIP) from the seeds and the leaves of Saponaria officinalis (Caryophyllaceae). Here we have identified the COOH-terminal end of mature Saporin-6 and, by cDNA sequencing, the predicted carboxyl-terminal sequence of a leaf Saporin-6 primary translation product. Our data indicate that the characterized cDNA codes for a precursor containing a 22 amino acid carboxyl-terminal extension, not present in mature Saporin-6, that shows similarity to carboxyl-terminal propeptides of vacuolar proteins, suggesting that it may be involved in protein trafficking.