Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD.

Primary graft dysfunction (PGD) after lung transplantation causes significant morbidity and mortality. We aimed to determine the role of cytokines and chemokines in PGD. This is a multicenter case-control study of PGD in humans. A Luminex analysis was performed to determine plasma levels of 25 chemokines and cytokines before and at 6, 24, 48 and 72 h following allograft reperfusion in 25 cases (grade 3 PGD) and 25 controls (grade 0 PGD). Biomarker profiles were evaluated using a multivariable logistic regression and generalized estimating equations. PGD cases had higher levels of monocyte chemotactic protein-1 (MCP-1)/chemokine CC motif ligand 2 (CCL2) and interferon (

Renal ischemia-reperfusion injury (IRI) is a common cause of renal dysfunction and renal failure. Histone/protein deacetylases (HDACs) regulate gene accessibility and higher order protein structures and may alter cellular responses to a variety of stresses. We investigated whether use of pan- and class-specific HDAC inhibitors (HDACi) could improve IRI tolerance in the kidney. Using a model of unilateral renal IRI, we investigated early renal function after IRI, and calculated fibrosis after IRI using an automated scoring system. We found that pan-HDAC inhibition using trichostatin (TSA) yielded significant renal functional benefit at 24–96 hours (p < 0.001). Treated mice developed significantly less fibrosis at 30 days (p < 0.0004). Class I HDAC inhibition with MS-275 yielded similar effects. Protection from fibrosis formation was also noted in a cold ischemia transplant model (p < 0.008) with a trend toward improved cold ischemic survival in TSA-treated mice. These effects were not accompanied by induction of typical ischemic tolerance pathways or by priming of heat shock protein expression. In fact, heat shock protein 70 deletion or overexpression did not alter renal ischemia tolerance. Micro-RNA 21, known to be enhanced in vitro in renal tubular cells that survive stress, was enhanced by treatment with HDACi, pointing to possible mechanism.

T-regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these responses involves changes in posttranslational modifications (PTMs) of histones and many nonhistone proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination, and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini-review focuses on recent data concerning the roles that histone/protein deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg-dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform-selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients.

Background MEDI-546 is an investigational human IgG1κ monoclonal antibody directed against subunit 1 of the type I interferon receptor (IFNAR1). An open-label single- and multiple-dose phase 1a clinical trial has been conducted for MEDI-546 in adult systemic sclerosis (SSc) subjects (NCT00930683). Objectives To identify serum markers and pathophysiological pathways modulated by MEDI-546 in SSc subjects. Methods Affymetrix whole genome arrays were used to measure transcript expression in whole blood and skin biopsies of SSc subjects, and a 5 gene type I IFN signature was used to determine the pharmacodynamics effects of MEDI-546. Serum levels of 93 proteins, two collagen synthesis markers, along with 6 novel collagen degradation and tissue damage markers were measured in 47 SSc subjects and 30 healthy controls. These serum markers were then used to assess the down-stream biological effects of MEDI-546 by comparing pre- and post-dose samples. Results Whole blood gene expression study demonstrated down-regulation of type I IFN-inducible transcripts across various time points post-administration of MEDI-546. The most extensive down-stream effects after type I IFN neutralization were seen at day 56, and upstream regulator analysis suggested the suppression of T cell receptor, nuclear factor of activated T cells (NFATC2), and CD40L by MEDI-546 administration. The proteomics study identified 8 proteins with decreased serum levels at day 56 among which 6 are type I IFN-inducible and 4 (CXCL10, CD40L, CXCL11, IL2RA) are associated with T cell activation and movement. Reduction of CXCL10 and CD40L levels were significantly correlated with type I IFN gene signature suppression. Furthermore, our results showed that C3M, a novel serum marker of matrix metalloproteinase-degraded type III collagen, is significantly lower in SSc subjects than normal controls, while the classic type III collagen synthesis marker (PIIINP) is significantly higher in SSc subjects. The ratio of PIIINP/C3M showed trends of correlation with SSc disease index MRTSS and HAQDI. MEDI-546 administration significantly decreased serum PIIINP/C3M ratio, suggesting a suppressive effects of MEDI-546 on collagen accumulation of SSc subjects. Skin microarray data also demonstrated the suppression of multiple collagen transcripts, tissue inhibitor of metalloproteinase, and other extracellular matrix-related transcripts by MEDI-546 administration. The down-regulation of PIIINP/C3M ratio was significantly correlated with the suppression of a T cell-associated composite index defined by serum levels of CXCL10, CD40L, CXCL11, and IL2R. Two SSc subjects with the highest decrease of MRTSS score demonstrated high suppression of both T cell-associated protein index and PIIINP/C3M ratio after MEDI-546 administration. Conclusions Our study demonstrated suppressive effects of MEDI-546 on T cell activation and collagen accumulation through which tissue fibrosis may be alleviated. A T cell-associated protein index and a novel type III collagen turnover marker may serve...

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