Identification of conserved skeletal enhancers associated with craniosynostosis risk genes.

Craniosynostosis, defined by premature fusion of one or multiple cranial sutures, is a common congenital defect affecting more than 1/2000 infants and results in restricted brain expansion. Single gene mutations account for 15-20% of cases, largely as part of a syndrome, but the majority are nonsyndromic with complex underlying genetics. We hypothesized that the two noncoding genomic regions identified by a GWAS for craniosynostosis contain distal regulatory elements for the risk genes BMPER and BMP2. To identify such regulatory elements, we surveyed conserved noncoding sequences from both risk loci for enhancer activity in transgenic Danio rerio. We identified enhancers from both regions that direct expression to skeletal tissues, consistent with the endogenous expression of bmper and bmp2. For each locus, we also found a skeletal enhancer that also contains a sequence variant associated with craniosynostosis risk. We examined the activity of each enhancer during craniofacial development and found that the BMPER-associated enhancer is active in the restricted region of cartilage closely associated with frontal bone initiation. The same enhancer is active in mouse skeletal tissues, demonstrating evolutionarily conserved activity. Using enhanced yeast one-hybrid assays, we identified transcription factors that bind each enhancer and observed differential binding between alleles, implicating multiple signaling pathways. Our findings help unveil the genetic mechanism of the two craniosynostosis risk loci. More broadly, our combined in vivo approach is applicable to many complex genetic diseases to build a link between association studies and specific genetic mechanisms.

Transient Drude Response Dominates Near-Infrared Pump-Probe Reflectivity in Nodal-Line Semimetals ZrSiS and ZrSiSe.

The ultrafast optical response of nodal-line semimetals ZrSiS and ZrSiSe was studied in the near-infrared using transient reflectivity. The materials exhibit similar responses, characterized by two features, well-resolved in time and energy; the first decays after hundreds of femtoseconds, and the second lasts for nanoseconds. Using Drude-Lorentz fits of the materials' equilibrium reflectance, we show that these are well-represented by a sudden change of the electronic properties (increase of screening or reduction of the plasma frequency) followed by an increase of the Drude scattering rate. This directly connects the transient data to a physical picture in which carriers, after excitation into the conduction band, return to the valence band by sharing excess energy with the phonon bath, resulting in a hot lattice that relaxes through slow diffusive processes. The emerging picture reveals that the sudden electronic reorganization instantaneously modifies the materials' electronic properties on a time scale not compatible with electron-phonon thermalization.

Positive and Negative Themes Found in Sport-Related Films.

Sport participation is an important part of the development of children and adolescents in the United States. The objective of this study was to determine positive and negative themes found in a selected number of sport-related films. A total of 44 sport-related films were independently viewed and analyzed by four reviewers. The most common sports depicted were baseball (27%) and football (25%). The most common positive themes were positive interactions with the coach, positive interactions with family and friends, and positive interactions with teammates (2.04, 1.42, 1.2 mean events per hour). The most common negative themes were taunting/fighting/poor sportsmanship, negative interactions with the coach, and drinking/smoking/drug use (2.13, 1.10, 0.94 mean events per hour). In conclusion, the coviewing of sport films among pediatric athletes and their coaches, athletic trainers, and/or parents in order to focus on "teachable moments" may encourage the acquisition and development of positive themes and the avoidance and de-emphasis of negative themes.

Serum 25-hydroxyvitamin D concentration is inversely associated with mucosal inflammation in patients with ulcerative colitis.

BACKGROUND: Vitamin D exerts anti-inflammatory actions both in vitro and in murine models of colitis. In previous studies, we demonstrated that vitamin D protects against the development of colitis by maintaining the integrity of the intestinal mucosal barrier. OBJECTIVE: We sought to evaluate whether deficient serum 25 hydroxyvitamin D [25(OH)D] concentrations are associated with increased mucosal inflammation, a loss of epithelial junctional proteins, and an increase in mucosal inflammatory cytokines in patients with ulcerative colitis (UC). DESIGN: We prospectively enrolled 230 subjects with UC. Serum 25(OH)D concentrations were compared with the Mayo endoscopic score, the total Mayo score, and histologic activity. Colonic mucosal expression concentrations of vitamin D receptor (VDR), E-cadherin, zonula occluden 1 (ZO-1), occludin, claudin-2, tumor necrosis factor α (TNF-α), and interleukin 8 (IL-8) were compared between dichotomous groups with low or high serum 25(OH)D concentrations. RESULTS: The mean serum 25(OH)D concentration was 21.8 ng/mL. Subjects stratified by concentrations included 12.6% ≥30 ng/mL, 45.6% ≥20 to <30 ng/mL, 37.4% ≥10 to <20 ng/mL, and 4.4% <10 ng/mL. There was an inverse association between serum 25(OH)D concentrations and mucosal inflammation as assessed by the Mayo endoscopy score (P = 0.01), disease activity as indicated by the total Mayo score (P = 0.001), and histologic activity (P = 0.02). A serum 25(OH)D concentration <20 ng/mL was associated with decreased mucosal transcript and protein expression concentrations of VDR, E-cadherin, and occludin as well as decreased protein expression of ZO-1, whereas TNF-α and IL-8 mucosal transcript expression concentrations were increased. CONCLUSIONS: In UC patients, serum 25(OH)D concentration is inversely correlated with mucosal inflammation and disease activity. These results, coupled with the findings that serum 25(OH)D concentrations correlate with the mucosal expression of VDR as well as epithelial junction proteins and inversely with proinflammatory cytokines, suggest that vitamin D deficiency may contribute to UC inflammation by disrupting epithelial barrier function.

Altered myocardial Ca2+ cycling after left ventricular assist device support in the failing human heart.

OBJECTIVES: The objective of the present study was to determine whether improved contractility after left ventricular assist device (LVAD) support reflects altered myocyte calcium cycling and changes in calcium-handling proteins. BACKGROUND: Previous reports demonstrate that LVAD support induces sustained unloading of the heart with regression of pathologic hypertrophy and improvements in contractile performance. METHODS: In the human myocardium of subjects with heart failure (HF), with non-failing hearts (NF), and with LVAD-supported failing hearts (HF-LVAD), intracellular calcium ([Ca(2+)](i)) transients were measured in isolated myocytes at 0.5 Hz, and frequency-dependent force generation was measured in multicellular preparations (trabeculae). Abundance of sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (SERCA), Na(+)/Ca(2+) exchanger (NCX), and phospholamban was assessed by Western analysis. RESULTS: Compared with NF myocytes, HF myocytes exhibited a slowed terminal decay of the Ca(2+) transient (DT(terminal), 376 +/- 18 ms vs. 270 +/- 21 ms, HF vs. NF, p < 0.0008), and HF-LVAD myocytes exhibited a DT(terminal) that was much shorter than that observed in HF myocytes (278 +/- 10 ms, HF vs. HF-LVAD, p < 0.0001). Trabeculae from HF showed a negative force-frequency relationship, compared with a positive relationship in NF, whereas a neutral relationship was observed in HF-LVAD. Although decreased SERCA abundance in HF was not altered by LVAD support, improvements in [Ca(2+)](i) transients and frequency-dependent contractile function were associated with a significant decrease in NCX abundance and activity from HF to HF-LVAD. CONCLUSIONS: Improvement in rate-dependent contractility in LVAD-supported failing human hearts is associated with a faster decay of the myocyte calcium transient. These improvements reflect decreases in NCX abundance and transport capacity without significant changes in SERCA after LVAD support. Our results suggest that reverse remodeling may involve selective, rather than global, normalization of the pathologic patterns associated with the failing heart.

A novel system for rapidly identifying toxic chemicals.

First-responders have a critical need to rapidly identify toxic chemicals during emergencies. However, current systems such as WISER require a large number of inputs before a chemical can be identified. Here we present a novel system which significantly reduces the number of inputs required to identify a toxic chemical.