Cognitive-Behavioral Therapy Augmentation of SSRI Reduces Cortisol Levels in Older Adults with Generalized Anxiety Disorder: A Randomized Clinical Trial

Objectives: Elevated cortisol in stress and aging, such as has been seen in late-life anxiety disorders, is postulated to accelerate cognitive and physiological decline in this large and increasing population. Selective serotonin-reuptake inhibitors (SSRIs) and cognitive behavior therapy (CBT) are both effective treatments for Generalized Anxiety Disorder (GAD) in older adults. On the other hand, there is very little research examining the effect of combining these therapies on peak cortisol levels. For the current analyses, we examined the effectiveness of CBT augmentation on peak cortisol levels in older adults diagnosed with GAD. Methods: The sample consisted of 42 individuals with late-life GAD who received an acute course of the SSRI escitalopram and then entered a 16-week randomized phase. Twenty-one participants were randomized to receive 16 sessions of CBT in addition to continuing escitalopram and the remaining 21 participants continued on escitalopram without CBT. Generalized Estimating Equations were performed to assess the effectiveness of CBT augmentation on peak cortisol levels (30 minutes after waking). Results: Older adults with GAD who received both escitalopram and CBT demonstrated a significant reduction in peak cortisol levels at post-treatment compared to the group who received escitalopram without CBT augmentation. Conclusions: CBT augmentation of SSRI treatment reduced peak cortisol levels for older adults with GAD. Since persistently high cortisol levels in aging are thought to increase age-related cognitive and medical problems, our findings suggest that there may be a benefit to health and cognition of CBT augmentation for late-life anxiety disorders

Duffer’s Shoal: A Strategic Dream of the Pacific Command Area of Responsibility

This strategic assessment seeks to go beyond a traditional comparative analysis of the military, technological, political, cultural, and economic factors governing the relationships and capabilities of the Asia Pacific environment. To make sense of the intrinsic complexities unique to this region, we endeavor to broaden our view and rely on a tool often overlooked in government studies: imagination. Moreover, we aim to offer a strategic document that is readable, instructive, and provocative. Pulling from a well-referenced piece of military teaching, this assessment borrows a learning concept first employed in 1904 by Major General Sir Ernest Dunlop Swinton in The Defence of Duffer’s Drift. This fictional story describes the plight of young Lieutenant Backsight Forethought as he commands a 50-man platoon tasked to hold a tactically critical piece of land called Duffer’s Drift. The story unfolds in a series of six dreams, where the blunders of the unwitting lieutenant lead to disaster. As the dreams progress, he harnesses the lessons of each of his failures, and by applying these lessons, his platoon ultimately defends Duffer’s Drift.https://press.armywarcollege.edu/monographs/1445/thumbnail.jp

A DNA-binding bromodomain-containing protein interacts with and reduces Rx1-mediated immune response to Potato Virus X

Plant NLR proteins enable the immune system to recognise and respond to pathogen attack. An early consequence of immune activation is transcriptional reprogramming. Some NLRs have been shown to act in the nucleus and interact with transcription factors. The Rx1 NLR protein of potato binds and distorts double-stranded DNA. However, the components of the chromatin localized Rx1-complex are largely unknown. Here we report a physical and functional interaction between Rx1 and NbDBCP, a bromodomain-containing chromatin-interacting protein. NbDBCP accumulates in the nucleolus, interacts with chromatin and redistributes Rx1 to the nucleolus in a subpopulation of imaged cells. Rx1 over-expression reduces NbDBCP interactions with chromatin. NbDBCP is a negative regulator of Rx1-mediated immune responses to potato virus X (PVX) and this activity requires an intact bromodomain. Previously, Rx1 has been shown to regulate the DNA-binding activity of a Golden2-like transcription factor, NbGlk1. Rx1 and NbDBCP act synergistically to reduce NbGlk1 DNA-binding suggesting a mode of action for NbDBCP’s inhibitory effect on immunity. This study provides new mechanistic insight into how a chromatin localised NLR complex co-ordinates immune signalling following pathogen perception

Developing sustainable capacity-building in mental health research: implementation outcomes of training of trainers in systematic reviewing.

Less than 1% of biomedical research papers originate in Africa. Locally relevant mental health research, including synthesis of existing evidence, is essential for developing interventions and strengthening health systems, but institutions may lack the capacity to deliver training on systematic reviewing for publication in international journals. This paper describes the development and implementation of a training-of-trainers (ToT) course on systematic reviewing. The ToT prepared junior faculty ('trainers') from universities in Ethiopia, Malawi, and Zimbabwe to lead a five-day systematic reviewing workshop. Using an evaluation framework based on implementation science outcomes, the feasibility of the ToT was assessed by tracking the number of workshops the trainers subsequently conducted and the number of trainers and trainees who participated; acceptability was assessed through post-workshop surveys on trainee perspectives; impact was evaluated through trainee scores on a 15-item multiple choice test on systematic reviewing concepts; and sustainability was assessed based on whether the workshop was integrated into university curricula. Twelve trainers (86% of those trained) facilitated a total of seven workshops in their home countries (total 103 trainees). The first workshop run in each country was evaluated, and there was a significant improvement in mean knowledge scores between pre- and post-tests among trainees (MD= 3.07, t= 5.90, 95% CI 2.02-4.11). In two of the three countries, there are efforts to integrate the systematic review workshop into university curricula. The cost of the workshop led by the international trainer was $1480 per participant, whereas the trainer-led workshops cost approximately$240 per participant. Overall, ToT is relatively new to research capacity building, although it has been used widely in clinical settings. Our findings suggest ToT is a promising, low-cost way to develop both technical skills of individuals and the pedagogical capacity of universities, and to promote sustainability of research capacity building programs that often have time-limited grant funding

Renormalization group and isochronous oscillations

We show how the condition of isochronicity can be studied for two dimensional systems in the renormalization group (RG) context. We find a necessary condition for the isochronicity of the Cherkas and another class of cubic systems. Our conditions are satisfied by all the cases studied recently by Bardet et al \cite{bard} and Ghose Choudhury and Guh

Obesity challenges the hepatoprotective function of the integrated stress response to asparaginase exposure in mice

Obesity increases risk for liver toxicity by the anti-leukemic agent asparaginase, but the mechanism is unknown. Asparaginase activates the integrated stress response (ISR) via sensing amino acid depletion by the eukaryotic initiation factor 2 (eIF2) kinase GCN2. The goal of this work was to discern the impact of obesity, alone versus alongside genetic disruption of the ISR, on mechanisms of liver protection during chronic asparaginase exposure in mice. Following diet-induced obesity, biochemical analysis of livers revealed that asparaginase provoked hepatic steatosis that coincided with activation of another eIF2 kinase PKR-like endoplasmic reticulum kinase (PERK), a major ISR transducer to ER stress. Genetic loss of Gcn2 intensified hepatic PERK activation to asparaginase, yet surprisingly, mRNA levels of key ISR gene targets such as Atf5 and Trib3 failed to increase. Instead, mechanistic target of rapamycin complex 1 (mTORC1) signal transduction was unleashed, and this coincided with liver dysfunction reflected by a failure to maintain hydrogen sulfide production or apolipoprotein B100 (ApoB100) expression. In contrast, obese mice lacking hepatic activating transcription factor 4 (Atf4) showed an exaggerated ISR and greater loss of endogenous hydrogen sulfide but normal inhibition of mTORC1 and maintenance of ApoB100 during asparaginase exposure. In both genetic mouse models, expression and phosphorylation of Sestrin2, an ATF4 gene target, was increased by asparaginase, suggesting mTORC1 inhibition during asparaginase exposure is not driven via eIF2-ATF4-Sestrin2. In conclusion, obesity promotes a maladaptive ISR during asparaginase exposure. GCN2 functions to repress mTORC1 activity and maintain ApoB100 protein levels independently of Atf4 expression, whereas hydrogen sulfide production is promoted via GCN2-ATF4 pathway

Canine CNGA3 Gene Mutations Provide Novel Insights Into Human Achromatopsia-Associated Channelopathies and Treatment

Cyclic nucleotide-gated (CNG) ion channels are key mediators underlying signal transduction in retinal and olfactory receptors. Genetic defects in CNGA3 and CNGB3, encoding two structurally related subunits of cone CNG channels, lead to achromatopsia (ACHM). ACHM is a congenital, autosomal recessive retinal disorder that manifests by cone photoreceptor dysfunction, severely reduced visual acuity, impaired or complete color blindness and photophobia. Here, we report the first canine models for CNGA3-associated channelopathy caused by R424W or V644del mutations in the canine CNGA3 ortholog that accurately mimic the clinical and molecular features of human CNGA3-associated ACHM. These two spontaneous mutations exposed CNGA3 residues essential for the preservation of channel function and biogenesis. The CNGA3-R424W results in complete loss of cone function in vivoand channel activity confirmed by in vitro electrophysiology. Structural modeling and molecular dynamics (MD) simulations revealed R424-E306 salt bridge formation and its disruption with the R424W mutant. Reversal of charges in a CNGA3-R424E-E306R double mutant channel rescued cGMP-activated currents uncovering new insights into channel gating. The CNGA3-V644del affects the C-terminal leucine zipper (CLZ) domain destabilizing intersubunit interactions of the coiled-coil complex in the MD simulations; the in vitro experiments showed incompetent trimeric CNGA3 subunit assembly consistent with abnormal biogenesis of in vivochannels. These newly characterized large animal models not only provide a valuable system for studying cone-specific CNG channel function in health and disease, but also represent prime candidates for proof-of-concept studies of CNGA3 gene replacement therapy for ACHM patients

Modelling ruptures of buried high pressure dense phase CO2 pipelines in carbon capture and storage applications - Part I. Validation

Carbon dioxide (CO2) capture and storage presents a short-term option for significantly reducing the amount of CO2 released into the atmosphere and mitigating the effects of climate change. To this end, National Grid initiated the COOLTRANS research programme to consider the pipeline transportation of high pressure dense phase CO2, including the development and application of a mathematical model for predicting the sonic near-field dispersion of pure CO2 following the venting or failure of such a pipeline. Here, the application of this model to the rupture of a buried pipeline is considered and compared to experimental data obtained through the COOLTRANS programme. The rupture experiment was performed on a 230 m length of 152 mm external diameter pipeline with 300 mm soil cover, equivalent to approximately 1/4 scale when compared to the proposed full-scale 600 mm (24-inch) diameter pipelines with 1.2 m soil cover on average proposed in the UK. The experiment was performed in a pre-formed crater based on experimentally formed craters in other experiments. The comparison demonstrates reasonable quantitative and qualitative agreement. Such validated dispersion flow, to be applied to full-scale rupture modelling in Part II, defines novel, robust, thermodynamically accurate multi-phase source conditions, that enable far-field computational fluid dynamics studies and feed into pragmatic quantified risk assessment models