The symptom‐specific efficacy of antidepressant medication vs. cognitive behavioral therapy in the treatment of depression: results from an individual patient data meta‐analysis

A recent individual patient data meta‐analysis showed that antidepressant medication is slightly more efficacious than cognitive behavioral therapy (CBT) in reducing overall depression severity in patients with a DSM‐defined depressive disorder. We used an update of that dataset, based on seventeen randomized clinical trials, to examine the comparative efficacy of antidepressant medication vs. CBT in more detail by focusing on individual depressive symptoms as assessed with the 17‐item Hamilton Rating Scale for Depression. Five symptoms (i.e., “depressed mood” , “feelings of guilt” , “suicidal thoughts” , “psychic anxiety” and “general somatic symptoms”) showed larger improvements in the medication compared to the CBT condition (effect sizes ranging from .13 to .16), whereas no differences were found for the twelve other symptoms. In addition, network estimation techniques revealed that all effects, except that on “depressed mood” , were direct and could not be explained by any of the other direct or indirect treatment effects. Exploratory analyses showed that information about the symptom‐specific efficacy could help in identifying those patients who, based on their pre‐treatment symptomatology, are likely to benefit more from antidepressant medication than from CBT (effect size of .30) versus those for whom both treatments are likely to be equally efficacious. Overall, our symptom‐oriented approach results in a more thorough evaluation of the efficacy of antidepressant medication over CBT and shows potential in “precision psychiatry” .     

Human Pluripotent Stem Cell-Derived Multipotent Vascular Progenitors of the Mesothelium Lineage Have Utility in Tissue Engineering and Repair

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Climate and Land Cover Analysis Suggest No Strong Ecological Barriers to Gene Flow in a Natural Baboon Hybrid Zone

International Journal of Primatology - Admixture between diverging taxa has made, and continues to make, an important contribution to primate diversity and evolution. However, although naturally...     

Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4

Waardenburg syndrome (WS) is an auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. Depending on additional symptoms, WS is classified into four subtypes, WS1-WS4. Absence of additional features characterizes WS2. The association of facial dysmorphic features defines WS1 and WS3, whereas the association with Hirschsprung disease (aganglionic megacolon) characterizes WS4, also called "Waardenburg-Hirschsprung disease." Mutations within the genes MITF and SNAI2 have been identified in WS2, whereas mutations of EDN3, EDNRB, and SOX10 have been observed in patients with WS4. However, not all cases are explained at the molecular level, which raises the possibility that other genes are involved or that some mutations within the known genes are not detected by commonly used genotyping methods. We used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescent in situ hybridization to search for SOX10 heterozygous deletions. We describe the first characterization of SOX10 deletions in patients presenting with WS4. We also found SOX10 deletions in WS2 cases, making SOX10 a new gene of WS2. Interestingly, neurological phenotypes reminiscent of that observed in WS4 (PCWH syndrome [peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease]) were observed in some WS2-affected patients with SOX10 deletions. This study further characterizes the molecular complexity and the close relationship that links the different subtypes of WS.     

Binding thermodynamics of substituted diaminopyrimidine renin inhibitors

Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could be useful for the treatment of hypertension. High-throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized, and structural data were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as to improve affinity and adjust pharmacokinetic parameters. Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both thermodynamic and structural perspectives. The addition of a methoxypropyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven, whereas binding of initial inhibitors with S2 extensions was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy.     

Photoacoustic characterization of protein dynamics following CO photodetachment from fully reduced bovine cytochrome c oxidase

We report a protein conformational change following carbon monoxide photodetachment from fully reduced bovine cytochrome c oxidase that is hypothesized to be associated with changes in ligand mobility through a dioxygen access channel in the protein. Although not resolved by earlier photoacoustic or optical studies on this adduct, utilization of slightly lower temperatures revealed a process with a kinetic lifetime of about 70 ns at 10 degrees C. We measure an enthalpy change of about 8 kcal/mol in 0.050 M HEPES buffer that becomes less endothermic (DeltaH approximately 2 kcal/mol) at higher ionic strength. The volume contraction of about -0.7 mL/mol associated with the process almost doubles in higher ionic strength buffer systems. Measurements of samples in phosphate buffer systems are similar and appear to display the same subtle ionic strength dependence. Both the isolation of this photoacoustic signal component and the possible dependence on ionic strength of the thermodynamic parameters derived from its analysis appear analogous to and consistent with prior photoacoustic results monitoring CO photodetachment from the camphor complex of cytochrome P-450. Accordingly, we consider a similar model in which a conformational change results in movement of an exposed charged group or groups towards the interior of the protein, out of contact with solvent, as in the closing of a salt bridge.     

Dynamics of bioluminescence by Armillaria gallica, A. mellea and A. tabescens

Although fungal bioluminescence is well documented, the ecological significance is poorly understood. We examined bioluminescence by three sympatric species of Armillaria wood decay fungi, differing in parasitic ability. Luminescence by mycelia of four genets of A. gallica, A. mellea and A. tabescens was examined in response to environmental illumination or mechanical disturbance. Luminescence dynamics were assessed in a time series of measurements every 2 min for 72 h for mycelia growing on malt agar or on Cornus florida root wood. Luminescence by the necrotrophic species A. gallica was enhanced by environmental illumination and mechanical disturbance of mycelia. In contrast luminescence by the more parasitic A. mellea and A. tabescens was quenched by prolonged exposure to environmental illumination and less responsive to mechanical disturbance. With environmental illumination absent, all mycelia representing six genets of each Armillaria species were constitutively luminescent. The temporal dynamics of luminescence by all mycelia were complex with no evidence of the previously reported diurnal periodicity. Differences among Armillaria spp. in bioluminescence expression might reflect differences in ecological context as well.