sel-11 and cdc-42, Two Negative Modulators of LIN-12/Notch Activity in C. elegans

Background: LIN-12/Notch signaling is important for cell-cell interactions during development, and mutations resulting in constitutive LIN-12/Notch signaling can cause cancer. Loss of negative regulators of lin-12/Notch activity has the potential for influencing cell fate decisions during development and the genesis or aggressiveness of cancer. Methodology/Principal Findings: We describe two negative modulators of lin-12 activity in C. elegans. One gene, sel-11, was initially defined as a suppressor of a lin-12 hypomorphic allele; the other gene, cdc-42, is a well-studied Rho GTPase. Here, we show that SEL-11 corresponds to yeast Hrd1p and mammalian Synoviolin. We also show that cdc-42 has the genetic properties consistent with negative regulation of lin-12 activity during vulval precursor cell fate specification. Conclusions/Significance: Our results underscore the multiplicity of negative regulatory mechanisms that impact on lin-12/ Notch activity and suggest novel mechanisms by which constitutive lin-12/Notch activity might be exacerbated in cancer

Effects of Thyroxine Exposure on Osteogenesis in Mouse Calvarial Pre-Osteoblasts

The incidence of craniosynostosis is one in every 1,800-2500 births. The gene-environment model proposes that if a genetic predisposition is coupled with environmental exposures, the effects can be multiplicative resulting in severely abnormal phenotypes. At present, very little is known about the role of gene-environment interactions in modulating craniosynostosis phenotypes, but prior evidence suggests a role for endocrine factors. Here we provide a report of the effects of thyroid hormone exposure on murine calvaria cells. Murine derived calvaria cells were exposed to critical doses of pharmaceutical thyroxine and analyzed after 3 and 7 days of treatment. Endpoint assays were designed to determine the effects of the hormone exposure on markers of osteogenesis and included, proliferation assay, quantitative ALP activity assay, targeted qPCR for mRNA expression of Runx2, Alp, Ocn, and Twist1, genechip array for 28,853 targets, and targeted osteogenic microarray with qPCR confirmations. Exposure to thyroxine stimulated the cells to express ALP in a dose dependent manner. There were no patterns of difference observed for proliferation. Targeted RNA expression data confirmed expression increases for Alp and Ocn at 7 days in culture. The genechip array suggests substantive expression differences for 46 gene targets and the targeted osteogenesis microarray indicated 23 targets with substantive differences. 11 gene targets were chosen for qPCR confirmation because of their known association with bone or craniosynostosis (Col2a1, Dmp1, Fgf1, 2, Igf1, Mmp9, Phex, Tnf, Htra1, Por, and Dcn). We confirmed substantive increases in mRNA for Phex, FGF1, 2, Tnf, Dmp1, Htra1, Por, Igf1 and Mmp9, and substantive decreases for Dcn. It appears thyroid hormone may exert its effects through increasing osteogenesis. Targets isolated suggest a possible interaction for those gene products associated with calvarial suture growth and homeostasis as well as craniosynostosis. © 2013 Cray et al

Responding empathically : a question of heart, not a question of skin

Empathy entails the capacities to resonate with another person’s emotions, understand his/her thoughts and feelings, separate our own thoughts and emotions from those of the observed and responding with the appropriate prosocial and helpful behavior. While there is abundant research on the neurobiological mechanisms of some components of empathy (e.g., emotional contagion), few studies have considered the neurobiological mechanisms underlying the empathic response. The present study explores psychophysiological correlates (skin conductance level and the interbeat interval) as a function of the empathic response while participants watch and respond to actors portraying emotionally laden vignettes. Forty undergraduate psychology students were each presented with 40 emotional vignettes of positive or negative valence and asked to choose among three different empathic responses while their electrodermal and cardiac responses were measured. Overall, the study shows that higher levels of additive empathy are associated with increased cardiac activity (i.e., decreased Interbeat Interval) but not electrodermal activity.BIAL Foundation by the grant ‘‘The Neuropsychophysiological Basis of Empathy: The role of neuroendocrine; autonomic and central nervous system variables (89/08)’’ that supported this research

Perceptual Other-Race Training Reduces Implicit Racial Bias

Background: Implicit racial bias denotes socio-cognitive attitudes towards other-race groups that are exempt from conscious awareness. In parallel, other-race faces are more difficult to differentiate relative to own-race faces – the ‘‘Other-Race Effect.’ ’ To examine the relationship between these two biases, we trained Caucasian subjects to better individuate other-race faces and measured implicit racial bias for those faces both before and after training. Methodology/Principal Findings: Two groups of Caucasian subjects were exposed equally to the same African American faces in a training protocol run over 5 sessions. In the individuation condition, subjects learned to discriminate between African American faces. In the categorization condition, subjects learned to categorize faces as African American or not. For both conditions, both pre- and post-training we measured the Other-Race Effect using old-new recognition and implicit racial biases using a novel implicit social measure – the ‘‘Affective Lexical Priming Score’ ’ (ALPS). Subjects in the individuation condition, but not in the categorization condition, showed improved discrimination of African American faces with training. Concomitantly, subjects in the individuation condition, but not the categorization condition, showed a reduction in their ALPS. Critically, for the individuation condition only, the degree to which an individual subject’s ALPS decreased was significantly correlated with the degree of improvement that subject showed in their ability to differentiate African American faces

A novel human skin chamber model to study wound infection ex vivo

Wound infections with multi-drug resistant bacteria increase morbidity and mortality and have considerable socioeconomic impact. They can lead to impaired wound healing, resulting in rising treatment costs. The aim of this study was to investigate an ex vivo human wound infection model. Human full-thickness skin from the operating room (OR) was placed into the Bo-Drum® and cultivated for 7 days in an air–liquid interphase. On day 8, the skin was inoculated with either (1) Pseudomonas aeruginosa, (2) Staphylococcus aureus (105 CFU, n = 3) or (3) carrier control. 1, 3 and 7 days after inoculation colony forming units in the tissue/media were determined and cytokine expression was quantified. A reliable and reproducible wound infection could be established for 7 days. At this timepoint, 1.8 × 108 CFU/g tissue of P. aeruginosa and 2 × 107 CFU/g tissue of S. aureus were detected. Immunohistochemical analysis demonstrated bacterial infection and epidermolysis in infected skin. RT-PCR analysis exhibited a significant induction of proinflammatory cytokines after infection. The BO-drum® is a robust, easy-to-use, sterilizable and reusable ex vivo full-skin culture system. For investigation of wound infection, treatment and healing, the BO-drum® presents a convenient model and may help to standardize wound research

N-acetylcysteine reduces oxidative stress in sickle cell patients

Oxidative stress is of importance in the pathophysiology of sickle cell disease (SCD). In this open label randomized pilot study the effects of oral N-acetylcysteine (NAC) on phosphatidylserine (PS) expression as marker of cellular oxidative damage (primary end point), and markers of hemolysis, coagulation and endothelial activation and NAC tolerability (secondary end points) were studied. Eleven consecutive patients (ten homozygous [HbSS] sickle cell patients, one HbSβ0-thalassemia patient) were randomly assigned to treatment with either 1,200 or 2,400 mg NAC daily during 6 weeks. The data indicate an increment in whole blood glutathione levels and a decrease in erythrocyte outer membrane phosphatidylserine exposure, plasma levels of advanced glycation end-products (AGEs) and cell-free hemoglobin after 6 weeks of NAC treatment in both dose groups. One patient did not tolerate the 2,400 mg dose and continued with the 1,200 mg dose. During the study period, none of the patients experienced painful crises or other significant SCD or NAC related complications. These data indicate that N-acetylcysteine treatment of sickle cell patients may reduce SCD related oxidative stress