Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model

Recent advances in structural bioinformatics have enabled the prediction of protein-drug off-targets based on their ligand binding sites. Concurrent developments in systems biology allow for prediction of the functional effects of system perturbations using large-scale network models. Integration of these two capabilities provides a framework for evaluating metabolic drug response phenotypes in silico. This combined approach was applied to investigate the hypertensive side effect of the cholesteryl ester transfer protein inhibitor torcetrapib in the context of human renal function. A metabolic kidney model was generated in which to simulate drug treatment. Causal drug off-targets were predicted that have previously been observed to impact renal function in gene-deficient patients and may play a role in the adverse side effects observed in clinical trials. Genetic risk factors for drug treatment were also predicted that correspond to both characterized and unknown renal metabolic disorders as well as cryptic genetic deficiencies that are not expected to exhibit a renal disorder phenotype except under drug treatment. This study represents a novel integration of structural and systems biology and a first step towards computational systems medicine. The methodology introduced herein has important implications for drug development and personalized medicine

Association between methylation of the SLC6A4 promoter region in peripheral blood leukocytes and methylation in amygdala tissue

Objective The aim of this study was to examine the association of depressive symptoms with asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Patients with chronic hepatitis C infection were examined during interferon- (IFN-) treatment, which is often associated with treatment-induced depression. The associations between IFN--induced depressive symptoms with ADMA and SDMA levels were prospectively investigated until 3 months after treatment. Methods Psychiatric and biological assessments were obtained at six different time points: before, during (at 1, 3, 6, and 9 months), and after the end of IFN- treatment. Results During IFN- treatment, 22 (53.7%) patients fulfilled the criteria for a treatment-related depressive disorder at least once during treatment. The increase in ADMA levels from baseline (depression group: 0.63 [0.08] M, no depression group: 0.69 [0.08] M) in response to IFN- treatment was considerably higher in patients with IFN- treatment-induced depressive episodes compared with patients without treatment-induced depressive episodes (3 months after the start of treatment: depression group: 0.72 [0.08] M, no depression group: 0.72 [0.11] M; ADMA: repeated-measure design analysis of variance [time x depression]: F(5,151) = 2.446, p = .036). The increase in SDMA was not associated with treatment-induced depression. Conclusions Depression in response to IFN- treatment is associated with elevated ADMA levels. These findings are relevant to nitric oxide-related biological pathways linking depression to increased cardiovascular disease risk. Future studies are needed to clarify the role of serotonin in these pathways and may lead to preventative treatment strategies