The Effects of a Mindfulness-Based Family Psychoeducation Intervention for the Caregivers of Young Adults with First-Episode Psychosis: A Randomized Controlled Trial.

OBJECTIVE: In this study, we investigated the effects of a mindfulness-based family psychoeducation (MBFPE) program on the mental-health outcomes of both caregivers and young adults with first-episode psychosis with an onset in the past three years through a multi-site randomized controlled trial. We also studied the outcomes of three potential mediating effects of interpersonal mindfulness, expressed emotions, and non-attachment on the program. METHOD: We randomly assigned 65 caregivers of young adults with psychosis to MBFPE (n = 33) or an ordinary family psychoeducation (FPE) program (n = 32); among them, 18 young adults in recovery also participated in the evaluation of outcomes. RESULTS: Intent-to-treat analyses were conducted. No significant time × group interaction effects of MBFPE and FPE programs were found in any of the caregivers' outcomes. However, the young adults with psychosis reported higher levels of recovery after the MBFPE program than after the ordinary FPE program (F = 8.268, p = 0.012, d = 1.484). They also reported a larger reduction in over-involvement of their caregivers (F = 4.846, p = 0.044, d = 1.136), showing that MBFPE had a superior effect to FPE in promoting recovery and reducing over-involvement. CONCLUSIONS: A brief psychoeducation program may not reduce the burden on or improve the mental-health outcome of caregivers of individuals with recent-onset psychosis. However, integrating mindfulness into a conventional family psychoeducation program may reduce the expressed emotions of caregivers, especially over-involvement. Further studies should explore how psychoeducation programs can reduce the impact of psychosis on family through sustainable effects in terms of reducing their burden and expressed emotions, using a rigorous study and adequate sample size.

A Brief Mindfulness-Based Family Psychoeducation Intervention for Chinese Young Adults With First Episode Psychosis: A Study Protocol.

Family psychoeducation (FPE) has been recommended as a major component in the treatment of psychosis. Many previous studies have implemented an intensive program design that often only emphasized improvements in patients' illness outcomes but the benefits for caregivers were limited. There have been calls for a time-limited but cost-effective FPE program to mitigate the looming reality of the suffering of people with psychosis and their families. A Brief Mindfulness-Based Family Psychoeducation for psychosis program is developed to reduce caregivers' burden and promote young adult's recovery. A randomized controlled trial will be conducted to compare this intervention with an ordinary FPE intervention. Both arms will involve six sessions, with a total contact time of 12 h. 300 caregivers of young adults who have experienced first episode psychosis within last 3 years will be recruited. Program effectiveness will be assessed by comparing outcomes measuring the caregivers' burden, mental health symptoms, positive well-being, and the young adult's mental health symptoms during the study and at 9-month post-randomization. The role of expressed emotions, interpersonal mindfulness, and non-attachment in mediating these outcomes will be explored. An additional qualitative approach Photovoice is selected to explore the complex family experiences and the benefits of mindfulness from the caregivers' personal perspectives. Trial Registration: The trial is registered with the United States Clinical Trials Registry (ClinicalTrials.gov): NCT03688009.

Can peptide folding simulations provide predictive information for aggregation propensity?

Nonnative peptide aggregation underlies many diseases and is a major problem in the development of peptide-based therapeutics. Efforts in the past decade have revealed remarkable correlations between aggregation rates or propensities and very simple sequence metrics like hydrophobicity and charge. Here, we investigate the extent to which a molecular picture of peptide folding bears out similar relationships. Using replica exchange molecular dynamics folding simulations, we compute equilibrium conformational ensembles of 142 hexa- and decapeptide systems, of which about half readily form amyloid fibrils and half do not. The simulations are used to compute a variety of ensemble-based properties, and we investigate the extent to which these metrics provide molecular clues about fibril formation. To assess whether multiple metrics together are useful in understanding aggregation, we also develop a number of logistic regression models, some of which predict fibril formers with 70-80% accuracy and identify aggregation-prone regions in larger proteins. Importantly, these models quantify the importance of different molecular properties in aggregation driving forces; notably, they suggest that hydrophobic interactions play a dominant role.

Convergence and Heterogeneity in Peptide Folding with Replica Exchange Molecular Dynamics.

Replica exchange molecular dynamics (REMD) techniques have emerged as standard tools for simulating peptides and small proteins, in part, to evaluate the accuracy of modern classical force fields for polypeptides. However, it often remains a challenge to unambiguously discriminate force field flaws from simulations that do not reach equilibrium convergence. Here, we examine closely the convergence behavior of REMD runs for 14 test alpha and beta peptide systems, using an AMBER force field with a generalized Born/surface area implicit solvation model. Somewhat surprisingly, we find that convergence times can be quite large compared to the time scales reached in many earlier REMD efforts, with some short peptides requiring up to 60 ns of run time (per replica). Moreover, we detect a high degree of run-to-run heterogeneity, finding that REMD runs of the same peptide seeded with different initial velocities can exhibit a range of fast- and slow-folding behavior. By increasing the number of swap attempts per REMD cycle, we are able to reduce heterogeneity by diminishing the presence of slower-folding trajectories. Finally, we notice that convergence often can be signaled by a spike in the population of the most populated configurational cluster - a metric that is independent of the native structure. These results suggest that the systematic application of long runs, multiple trials, and convergence indicators may be important in future folding studies and in force field development efforts.

Rotational on-off switching of a hybrid membrane sensor kinase Tar-ArcB in Escherichia coli.

Signal transduction in biological systems typically involves receptor proteins that possess an extracytosolic sensory domain connected to a cytosolic catalytic domain. Relatively little is known about the mechanism by which the signal is transmitted from the sensory site to the catalytic site. At least in the case of Tar (methyl-accepting chemotaxis protein for sensing aspartate) of Escherichia coli, vertical piston-like displacements of one transmembrane segment relative to the other within the monomer induced by ligand binding has been shown to modulate the catalytic activity of the cytosolic domain. The ArcB sensor kinase of E. coli is a transmembrane protein without a significant periplasmic domain. Here, we explore how the signal is conveyed to the catalytic site by analyzing the property of various Tar-ArcB hybrids. Our results suggest that, in contrast to the piston-like displacement that operates in Tar, the catalytic activity of ArcB is set by altering the orientation of the cytosolic domain of one monomer relative to the other in the homodimer. Thus, ArcB represents a distinct family of membrane receptor proteins whose catalytic activity is determined by rotational movements of the cytosolic domain.

Genome-wide profiling of promoter recognition by the two-component response regulator CpxR-P in Escherichia coli.

In Escherichia coli, the two-component Cpx system comprising the CpxA sensor kinase and the CpxR response regulator modulates gene expression in response to a variety of stresses including membrane-protein damage, starvation, and high osmolarity. To date, the few known CpxR-P target operons were mostly identified by genetic screens. To facilitate the discovery of all target operons, we derived a 15-bp weighted matrix for CpxR-P recognition that takes into account the relative base frequency at each nucleotide position. This matrix essentially consists of two tandem 5'-GTAAA-3' motifs separated by a 5-bp linker. All of the 15-bp stretches on both strands of the E. coli MG1655 genome were then scored for their degree of matching with the matrix and classified in statistical deviation groups. The effectiveness of this screening is indicated by the identification of eight new target operons (ung, ompC, psd, mviA, aroK, rpoErseABC, secA, and aer) among eleven candidates tested. Moreover, the matrix score correlates with the likelihood that a site is a true target and with the relative site affinity for CpxR-P in vitro. Our data indicate that some 100 operons are under direct CpxR-P control and that the signal transduction pathway interacts with several other control circuits in manners hitherto unanticipated.

Transport of L-Lactate, D-Lactate, and glycolate by the LldP and GlcA membrane carriers of Escherichia coli.

To examine the substrate specificity of the membrane transport carriers LldP (L-lactate permease) and GlcA (glycolate permease) of Escherichia coli, a mutant strain lacking their structural genes and blocked in the metabolism of the tested substrates was constructed and transformed with a plasmid bearing either the lldP or the glcA gene. Each transformant acquired the ability to accumulate L-lactate, D-lactate, and glycolate against a high concentration gradient. Substrate accumulation was inhibited by carbonyl cyanide m-chlorophenylhydrazone, a hydrophobic proton conductor that dissipates proton motive force. Competition of (14)C-L-lactate transport by nonradioactive L-lactate, D-lactate, and glycolate in LldP synthesizing cells and competition of (14)C-glycolate transport by the same three substrates in GlcA synthesizing cells showed that both carriers effectively transported all three substrates with a K(i) value ranging from 10 to 20 microM. D-Lactate does not appear to have a permease of its own. Utilization of the compound depends mainly on LldP.