Functional role of PGAM5 multimeric assemblies and their polymerization into filaments.

PGAM5 is a mitochondrial protein phosphatase whose genetic ablation in mice results in mitochondria-related disorders, including neurodegeneration. Functions of PGAM5 include regulation of mitophagy, cell death, metabolism and aging. However, mechanisms regulating PGAM5 activation and signaling are poorly understood. Using electron cryo-microscopy, we show that PGAM5 forms dodecamers in solution. We also present a crystal structure of PGAM5 that reveals the determinants of dodecamer formation. Furthermore, we observe PGAM5 dodecamer assembly into filaments both in vitro and in cells. We find that PGAM5 oligomerization into a dodecamer is not only essential for catalytic activation, but this form also plays a structural role on mitochondrial membranes, which is independent of phosphatase activity. Together, these findings suggest that modulation of the oligomerization of PGAM5 may be a regulatory switch of potential therapeutic interest

Perceptions and Practices of Key Worker Stakeholder Groups in Hospital Animal- Assisted Intervention Programs on Occupational Benefits and Perceived Risks

Background: Animal-assisted intervention (AAI) programs, used widely for patient benefit, have increasingly been used for healthcare workers (HCW) to reduce occupational stress. However, there are barriers to these programs which limit their utilization, for both patients and HCW, specifically infectious disease concerns. The aim of the research project is to identify barriers and facilitators to AAI program use for healthcare worker benefit, and determine knowledge, beliefs, and practices regarding infectious disease risk and control policies, in order to understand the contextual parameters of program implementation. Methods: We collected perceptions of key stakeholders involved with hospital AAI programs (HCW and AAI workers) through semi-structured in-depth interviews. We used framework analysis to guide thematic coding, completed independently by three researchers. Results: We interviewed 37 participants in this study. We divided our themes into two topic areas: program use for HCW and perceived infectious disease risk. Use for healthcare workers included perspectives on the benefits for HCW and program barriers and facilitators (specifically collaboration and leadership). Perceived risk included opinions on infection concerns with AAI, thoughts on control measures to reduce this risk, and responsibility for safety during these programs. Conclusions: While significant benefits were reported for HCW, they were limited by administrative barriers and hazard concerns. Facilitators to surmount these barriers are best implemented with collaboration across the hospital and appropriate leadership roles to direct safe program implementation. By addressing these barriers through targeted facilitators in the form of evidence-backed guidelines, AAI programs can be used to benefit both patients and HCW

Mother's and children's ADHD genetic risk, household chaos and children's ADHD symptoms:A gene–environment correlation study

BACKGROUND: Chaotic home environments may contribute to children's attention‐deficit hyperactivity disorder (ADHD) symptoms. However, ADHD genetic risk may also influence household chaos. This study investigated whether children in chaotic households had more ADHD symptoms, if mothers and children with higher ADHD genetic risk lived in more chaotic households, and the joint association of genetic risk and household chaos on the longitudinal course of ADHD symptoms across childhood. METHODS: Participants were mothers and children from the Environmental Risk (E‐Risk) Longitudinal Twin Study, a UK population‐representative birth cohort of 2,232 twins. Children's ADHD symptoms were assessed at ages 5, 7, 10 and 12 years. Household chaos was rated by research workers at ages 7, 10 and 12, and by mother's and twin's self‐report at age 12. Genome‐wide ADHD polygenic risk scores (PRS) were calculated for mothers (n = 880) and twins (n = 1,999); of these, n = 871 mothers and n = 1,925 children had information on children's ADHD and household chaos. RESULTS: Children in more chaotic households had higher ADHD symptoms. Mothers and children with higher ADHD PRS lived in more chaotic households. Children's ADHD PRS was associated with household chaos over and above mother's PRS, suggesting evocative gene–environment correlation. Children in more chaotic households had higher baseline ADHD symptoms and a slower rate of decline in symptoms. However, sensitivity analyses estimated that gene–environment correlation accounted for a large proportion of the association of household chaos on ADHD symptoms. CONCLUSIONS: Children's ADHD genetic risk was independently associated with higher levels of household chaos, emphasising the active role of children in shaping their home environment. Our findings suggest that household chaos partly reflects children's genetic risk for ADHD, calling into question whether household chaos directly influences children's core ADHD symptoms. Our findings highlight the importance of considering parent and child genetic risk in relation to apparent environmental exposures

Polygenic risk and the course of Attention-Deficit/Hyperactivity Disorder from childhood to young adulthood:Findings from a nationally representative cohort

OBJECTIVE: To understand whether genetic risk for attention-deficit/hyperactivity disorder (ADHD) is associated with the course of the disorder across childhood and into young adulthood. METHOD: Participants were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a population-based birth cohort of 2,232 twins. ADHD was assessed at ages 5, 7, 10, and 12 with mother- and teacher-reports and at age 18 with self-report. Polygenic risk scores (PRSs) were created using a genome-wide association study of ADHD case status. Associations with PRS were examined at multiple points in childhood and longitudinally from early childhood to adolescence. We investigated ADHD PRS and course to young adulthood, as reflected by ADHD remission, persistence, and late onset. RESULTS: Participants with higher ADHD PRSs had increased risk for meeting ADHD diagnostic criteria (odds ratios ranging from 1.17 at age 10 to 1.54 at age 12) and for elevated symptoms at ages 5, 7, 10, and 12. Higher PRS was longitudinally associated with more hyperactivity/impulsivity (incidence rate ratio = 1.18) and inattention (incidence rate ratio = 1.14) from age 5 to age 12. In young adulthood, participants with persistent ADHD exhibited the highest PRS (mean PRS = 0.37), followed by participants with remission (mean PRS = 0.21); both groups had higher PRS than controls (mean PRS = −0.03), but did not significantly differ from one another. Participants with late-onset ADHD did not show elevated PRS for ADHD, depression, alcohol dependence, or marijuana use disorder. CONCLUSION: Genetic risk scores derived from case-control genome-wide association studies may have relevance not only for incidence of mental health disorders, but also for understanding the longitudinal course of mental health disorders

Future Seismic Hazards in Southern California - Phase I: Implications of the 1992 Landers Earthquake Sequence

Southern California and its seismologists received a wake-up call on June 28, 1992. The largest earthquake to strike southern California in 40 years occurred near the town of Landers, located 30 km north of the San Andreas fault. It had a magnitude of 7.5 (M7.5). Three and one-half hours later, a M6.5 aftershock struck the Big Bear area 40 km (kilometers) to the west of Landers. An ad hoc working group was rapidly convened in July, 1992, to evaluate how the Landers-Big Bear earthquake sequence might affect future large earthquakes along major faults in southern California. In particular, what are the chances of large earthquakes in the next few years and how do they compare to previous estimates (such as those of the Working Group on California Earthquake Probabilities -- WGCEP, 1988)? Such an evaluation was made for central California after the Lorna Prieta earthquake of 1989 (WGCEP, 1990). The charge to the Landers ad hoc working group included analyzing the seismicity for the last several years in southern California and the new paleoseismic, geologic, and geodetic data recently available for southern California. To inform the public about the potential hazard of plausible earthquakes, the working group was also asked to map the predicted severity of ground shaking for such earthquakes compared to that from the Landers earthquake