The two C. elegans class VI myosins, SPE-15/HUM-3 and HUM-8, share similar motor properties, but have distinct developmental and tissue expression patterns.

Myosins of class VI move toward the minus-end of actin filaments and play vital roles in cellular processes such as endocytosis, autophagy, protein secretion, and the regulation of actin filament dynamics. In contrast to the majority of metazoan organisms examined to date which contain a single MYO6 gene, C. elegans, possesses two MYO6 homologues, SPE-15/HUM-3 and HUM-8. Through a combination of in vitro biochemical/biophysical analysis and cellular assays, we confirmed that both SPE-15/HUM-3 and HUM-8 exhibit reverse directionality, velocities, and ATPase activity similar to human MYO6. Our characterization also revealed that unlike SPE-15/HUM-3, HUM-8 is expressed as two distinct splice isoforms, one with an additional unique 14 amino acid insert in the cargo-binding domain. While lipid and adaptor binding sites are conserved in SPE-15/HUM-3 and HUM-8, this conservation does not enable recruitment to endosomes in mammalian cells. Finally, we performed super-resolution confocal imaging on transgenic worms expressing either mNeonGreen SPE-15/HUM-3 or wrmScarlet HUM-8. Our results show a clear distinction in tissue distribution between SPE-15/HUM-3 and HUM-8. While SPE-15/HUM-3 exhibited specific expression in the gonads and neuronal tissue in the head, HUM-8 was exclusively localized in the intestinal epithelium. Overall, these findings align with the established tissue distributions and localizations of human MYO6.

A multiscale characterization of cortical shape asymmetries in early psychosis.

Psychosis has often been linked to abnormal cortical asymmetry, but prior results have been inconsistent. Here, we applied a novel spectral shape analysis to characterize cortical shape asymmetries in patients with early psychosis across different spatial scales. We used the Human Connectome Project for Early Psychosis dataset (aged 16-35), comprising 56 healthy controls (37 males, 19 females) and 112 patients with early psychosis (68 males, 44 females). We quantified shape variations of each hemisphere over different spatial frequencies and applied a general linear model to compare differences between healthy controls and patients with early psychosis. We further used canonical correlation analysis to examine associations between shape asymmetries and clinical symptoms. Cortical shape asymmetries, spanning wavelengths from about 22 to 75 mm, were significantly different between healthy controls and patients with early psychosis (Cohen's d = 0.28-0.51), with patients showing greater asymmetry in cortical shape than controls. A single canonical mode linked the asymmetry measures to symptoms (canonical correlation analysis r = 0.45), such that higher cortical asymmetry was correlated with more severe excitement symptoms and less severe emotional distress. Significant group differences in the asymmetries of traditional morphological measures of cortical thickness, surface area, and gyrification, at either global or regional levels, were not identified. Cortical shape asymmetries are more sensitive than other morphological asymmetries in capturing abnormalities in patients with early psychosis. These abnormalities are expressed at coarse spatial scales and are correlated with specific symptom domains.

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The effect of using group-averaged or individualized brain parcellations when investigating connectome dysfunction in psychosis.

Functional magnetic resonance imaging (fMRI) is widely used to investigate functional coupling (FC) disturbances in a range of clinical disorders. Most analyses performed to date have used group-based parcellations for defining regions of interest (ROIs), in which a single parcellation is applied to each brain. This approach neglects individual differences in brain functional organization and may inaccurately delineate the true borders of functional regions. These inaccuracies could inflate or underestimate group differences in case-control analyses. We investigated how individual differences in brain organization influence group comparisons of FC using psychosis as a case study, drawing on fMRI data in 121 early psychosis patients and 57 controls. We defined FC networks using either a group-based parcellation or an individually tailored variant of the same parcellation. Individualized parcellations yielded more functionally homogeneous ROIs than did group-based parcellations. At the level of individual connections, case-control FC differences were widespread, but the group-based parcellation identified approximately 7.7% more connections as dysfunctional than the individualized parcellation. When considering differences at the level of functional networks, the results from both parcellations converged. Our results suggest that a substantial fraction of dysconnectivity previously observed in psychosis may be driven by the parcellation method, rather than by a pathophysiological process related to psychosis.

Disruptions of Hierarchical Cortical Organization in Early Psychosis and Schizophrenia.

BACKGROUND: The cerebral cortex is organized hierarchically along an axis that spans unimodal sensorimotor to transmodal association areas. This hierarchy is often characterized using low-dimensional embeddings, termed gradients, of interregional functional coupling estimates measured with resting-state functional magnetic resonance imaging. Such analyses may offer insights into the pathophysiology of schizophrenia, which has been frequently linked to dysfunctional interactions between association and sensorimotor areas. METHODS: To examine disruptions of hierarchical cortical function across distinct stages of psychosis, we applied diffusion map embedding to 2 independent functional magnetic resonance imaging datasets: one comprising 114 patients with early psychosis and 48 control participants, and the other comprising 50 patients with established schizophrenia and 121 control participants. Then, we analyzed the primary sensorimotor-to-association and secondary visual-to-sensorimotor gradients of each participant in both datasets. RESULTS: There were no significant differences in regional gradient scores between patients with early psychosis and control participants. Patients with established schizophrenia showed significant differences in the secondary, but not primary, gradient compared with control participants. Gradient differences in schizophrenia were characterized by lower within-network dispersion in the dorsal attention (false discovery rate [FDR]-corrected p [pFDR] < .001), visual (pFDR = .003), frontoparietal (pFDR = .018), and limbic (pFDR = .020) networks and lower between-network dispersion between the visual network and other networks (pFDR < .001). CONCLUSIONS: These findings indicate that differences in cortical hierarchical function occur along the secondary visual-to-sensorimotor axis rather than the primary sensorimotor-to-association axis as previously thought. The absence of differences in early psychosis suggests that visual-sensorimotor abnormalities may emerge as the illness progresses.

Network-Based Spreading of Gray Matter Changes Across Different Stages of Psychosis.

Importance: Psychotic illness is associated with anatomically distributed gray matter reductions that can worsen with illness progression, but the mechanisms underlying the specific spatial patterning of these changes is unknown. Objective: To test the hypothesis that brain network architecture constrains cross-sectional and longitudinal gray matter alterations across different stages of psychotic illness and to identify whether certain brain regions act as putative epicenters from which volume loss spreads. Design, Settings, and Participants: This case-control study included 534 individuals from 4 cohorts, spanning early and late stages of psychotic illness. Early-stage cohorts included patients with antipsychotic-naive first-episode psychosis (n = 59) and a group of patients receiving medications within 3 years of psychosis onset (n = 121). Late-stage cohorts comprised 2 independent samples of people with established schizophrenia (n = 136). Each patient group had a corresponding matched control group (n = 218). A sample of healthy adults (n = 356) was used to derive representative structural and functional brain networks for modeling of network-based spreading processes. Longitudinal illness-related and antipsychotic-related gray matter changes over 3 and 12 months were examined using a triple-blind randomized placebo-control magnetic resonance imaging study of the antipsychotic-naive patients. All data were collected between April 29, 2008, and January 15, 2020, and analyses were performed between March 1, 2021, and January 14, 2023. Main Outcomes and Measures: Coordinated deformation models were used to estimate the extent of gray matter volume (GMV) change in each of 332 parcellated areas by the volume changes observed in areas to which they were structurally or functionally coupled. To identify putative epicenters of volume loss, a network diffusion model was used to simulate the spread of pathology from different seed regions. Correlations between estimated and empirical spatial patterns of GMV alterations were used to quantify model performance. Results: Of 534 included individuals, 354 (66.3%) were men, and the mean (SD) age was 28.4 (7.4) years. In both early and late stages of illness, spatial patterns of cross-sectional volume differences between patients and controls were more accurately estimated by coordinated deformation models constrained by structural, rather than functional, network architecture (r range, >0.46 to <0.57; P < .01). The same model also robustly estimated longitudinal volume changes related to illness (r ≥ 0.52; P < .001) and antipsychotic exposure (r ≥ 0.50; P < .004). Network diffusion modeling consistently identified, across all 4 data sets, the anterior hippocampus as a putative epicenter of pathological spread in psychosis. Epicenters of longitudinal GMV loss were apparent in posterior cortex early in the illness and shifted to the prefrontal cortex with illness progression. Conclusion and Relevance: These findings highlight a central role for white matter fibers as conduits for the spread of pathology across different stages of psychotic illness, mirroring findings reported in neurodegenerative conditions. The structural connectome thus represents a fundamental constraint on brain changes in psychosis, regardless of whether these changes are caused by illness or medication. Moreover, the anterior hippocampus represents a putative epicenter of early brain pathology from which dysfunction may spread to affect connected areas.

The 3D architecture and molecular foundations of de novo centriole assembly via bicentrioles.

Centrioles are structurally conserved organelles, composing both centrosomes and cilia. In animal cycling cells, centrioles often form through a highly characterized process termed canonical duplication. However, a large diversity of eukaryotes assemble centrioles de novo through uncharacterized pathways. This unexplored diversity is key to understanding centriole assembly mechanisms and how they evolved to assist specific cellular functions. Here, we show that, during spermatogenesis of the bryophyte Physcomitrium patens, centrioles are born as a co-axially oriented centriole pair united by a cartwheel. Interestingly, we observe that these centrioles are twisted in opposite orientations. Microtubules emanate from the bicentrioles, which localize to the spindle poles during cell division. After their separation, the two resulting sister centrioles mature asymmetrically, elongating specific microtubule triplets and a naked cartwheel. Subsequently, two motile cilia are assembled that appear to alternate between different motility patterns. We further show that centriolar components SAS6, Bld10, and POC1, which are conserved across eukaryotes, are expressed during spermatogenesis and required for this de novo biogenesis pathway. Our work supports a scenario where centriole biogenesis, while driven by conserved molecular modules, is more diverse than previously thought.

A Pilot Study of the Efficacy of the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders in Treating Posttraumatic Psychopathology: A Randomized Controlled Trial.

The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) is an intervention that targets common mechanisms that maintain symptoms across multiple disorders. The UP has been shown to be effective across many disorders, including generalized anxiety disorder, major depressive episode (MDE), and panic disorder, that commonly codevelop following trauma exposure. The present study represented the first randomized controlled trial of the UP in the treatment of trauma-related psychopathology, including posttraumatic stress disorder (PTSD), depression, and anxiety symptoms. Adults (N = 43) who developed posttraumatic psychopathology that included PTSD, MDE, or an anxiety disorder after sustaining a severe injury were randomly assigned to receive 10-14 weekly, 60-min sessions of UP (n = 22) or usual care (n = 21). The primary treatment outcome was PTSD symptom severity, with secondary outcomes of depression and anxiety symptom severity and loss of diagnosis for any trauma-related psychiatric disorder. Assessments were conducted at intake, posttreatment, and 6-month follow-up. Posttreatment, participants who received the UP showed significantly larger reductions in PTSD, Hedges' g = 1.27; anxiety, Hedges' g = 1.20; and depression symptom severity, Hedges' g = 1.40, compared to those receiving usual care. These treatment effects were maintained at 6-month follow-up for PTSD, anxiety, and depressive symptom severity. Statistically significant posttreatment loss of PTSD, MDE, and agoraphobia diagnoses was observed for participants who received the UP but not usual care. This study provides preliminary evidence that the UP may be an effective non-trauma-focused treatment for PTSD and other trauma-related psychopathology.

A chemotactic model of trunk neural crest cell migration.

Trunk neural crest cells follow a common ventral migratory pathway but are distributed into two distinct locations to form discrete sympathetic and dorsal root ganglia along the vertebrate axis. Although fluorescent cell labeling and time-lapse studies have recorded complex trunk neural crest cell migratory behaviors, the signals that underlie this dynamic patterning remain unclear. The absence of molecular information has led to a number of mechanistic hypotheses for trunk neural crest cell migration. Here, we review recent data in support of three distinct mechanisms of trunk neural crest cell migration and develop and simulate a computational model based on chemotactic signaling. We show that by integrating the timing and spatial location of multiple chemotactic signals, trunk neural crest cells may be accurately positioned into two distinct targets that correspond to the sympathetic and dorsal root ganglia. In doing so, we honor the contributions of Wilhelm His to his identification of the neural crest and extend the observations of His and others to better understand a complex question in neural crest cell biology.

A Randomized Controlled Trial of Postoperative Thoracic Epidural Analgesia Versus Intravenous Patient-controlled Analgesia After Major Hepatopancreatobiliary Surgery.

OBJECTIVES: The primary objective of this randomized trial was to compare thoracic epidural analgesia (TEA) to intravenous patient-controlled analgesia (IV-PCA) for pain control over the first 48 hours after hepatopancreatobiliary (HPB) surgery. Secondary endpoints were patient-reported outcomes, total narcotic utilization, and complications. BACKGROUND: Although adequate postoperative pain control is critical to patient and surgeon success, the optimal analgesia regimen in HPB surgery remains controversial. METHODS: Using a 2.5:1 randomization strategy, 140 patients were randomized to TEA (N = 106) or intravenous patient-controlled analgesia (N = 34). Patient-reported pain was measured on a Likert scale (0-10) at standard time intervals. Cumulative pain area under the curve was determined using the trapezoidal method. RESULTS: Between the study groups key demographic, comorbidity, clinical, and operative variables were equivalently distributed. The median area under the curve of the postoperative time 0- to 48-hour pain scores was lower in the TEA group (78.6 vs 105.2 pain-hours, P = 0.032) with a 35% reduction in patients experiencing ≥7/10 pain (43% vs 62%, P = 0.07). Patient-reported outcomes and total opiate use further supported the benefit of TEA on patient experience. Anesthesia-related events requiring change in analgesic therapy were comparable (12.2% vs 2.9%, respectively, P = 0.187). Grade 3 or higher surgical complications (6.6% vs 9.4%), median length of stay (6 days vs 6 days), readmission (1.9% vs 3.1%), and return to the operating room (0.9% vs 3.1%) were similar (all P > 0.05). There were no mortalities in either group. CONCLUSIONS: In major HPB surgery, TEA provides a superior patient experience through improved pain control and less narcotic use, without increased length of stay or complications.

Tetraspanin (TSP-17) protects dopaminergic neurons against 6-OHDA-induced neurodegeneration in C. elegans.

Parkinson's disease (PD), the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA). In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1) and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling.

Developing performance indicators for homeless outreach psychiatric services.

OBJECTIVE: Performance indicators (PIs) aim to improve services by measuring key activities in a way that allows comparison over time, between services and against benchmarks. This paper describes the development and implementation of Homeless Psychiatric Service PIs and explores their potential benefits and limitations. METHOD: We collected descripton of quality service from key stakeholders. We identified eight key parameters, from which PIs were developed and tested over a 12-month period. RESULTS: The use of the PIs led to increased awareness of the practice being measured. PIs were used to stimulate practice changes. They played a positive role in team dynamics and were useful in clarifying team aims and identity. The main challenge to their use was the burden of data collection and analysis. CONCLUSION: Homeless service PIs can assist in determining how well the programs are performing in activities that are relevant to clients and non clinical services for the homeless. With the movement of homeless clients away from inner urban areas, homeless performance measures may aid teams to develop the capacity to work effectively with homeless clients.

Disability after injury: the cumulative burden of physical and mental health.

CONTEXT: Injury is one of the leading contributors to the global burden of disease. The factors that drive long-term disability after injury are poorly understood. OBJECTIVE: The main aim of the study was to model the direct and indirect pathways to long-term disability after injury. Specifically, the relationships between 3 groups of variables and long-term disability were examined over time. These included physical factors (including injury characteristics and premorbid disability), pain severity (including pain at 1 week and 12 months), and psychiatric symptoms (including psychiatric history and posttraumatic stress, depression, and anxiety symptoms at 1 week and 12 months). DESIGN, SETTING, AND PARTICIPANTS: A multisite, longitudinal cohort study of 715 randomly selected injury patients (from April 2004 to February 2006). Participants were assessed just prior to discharge (mean = 7.0 days, SD = 7.8 days) and reassessed at 12 months postinjury. Injury patients who experienced moderate/severe traumatic brain injury and spinal cord injury were excluded from the study. MAIN OUTCOME MEASURE: The World Health Organization Disability Assessment Schedule 2.0 was used to assess disability at 12 months after injury. RESULTS: Disability at 12 months was up to 4 times greater than community norms, across all age groups. The development and maintenance of long-term disability occurred through a complex interaction of physical factors, pain severity across time, and psychiatric symptoms across time. While both physical factors and pain severity contributed significantly to 12-month disability (pain at 1 week: total effect [TE] = 0.2, standard error [SE] < 0.1; pain at 12 months: TE = 0.3, SE < 0.1; injury characteristics: TE = 0.3, SE < 0.1), the total effects of psychiatric symptoms were substantial (psychiatric symptoms 1 week: TE = 0.30, SE < 0.1; psychiatric symptoms 12 months: TE = 0.71, SE < 0.1). Taken together, psychiatric symptoms accounted for the largest proportion of the variance in disability at 12 months. CONCLUSIONS: While the physical and pain consequences of injury contribute significantly to enduring disability after injury, psychiatric symptoms play a greater role. Early interventions targeting psychiatric symptoms may play an important role in improving functional outcomes after injury.

Stepped early psychological intervention for posttraumatic stress disorder, other anxiety disorders, and depression following serious injury.

The best approach for implementing early psychological intervention for anxiety and depressive disorders after a traumatic event has not been established. This study aimed to test the effectiveness of a stepped model of early psychological intervention following traumatic injury. A sample of 683 consecutively admitted injury patients were screened during hospitalization. High-risk patients were followed up at 4-weeks postinjury and assessed for anxiety and depression symptom levels. Patients with elevated symptoms were randomly assigned to receive 4-10 sessions of cognitive-behavioral therapy (n = 24) or usual care (n = 22). Screening in the hospital identified 89% of those who went on to develop any anxiety or affective disorder at 12 months. Relative to usual care, patients receiving early intervention had significantly improved mental health at 12 months. A stepped model can effectively identify and treat injury patients with high psychiatric symptoms within 3 months of the initial trauma.

A 17 T horizontal field cryomagnet with rapid sample change designed for beamline use.

We describe a new 17 T cryomagnet for neutron, x-ray or optical experiments with rapid in situ sample change. Sample temperatures are controllable from below 2 K to 300 K in vacuum. Alternatively a room temperature bore insert can be used for experiments at the field center under atmospheric conditions. Some of the advantages of this system include very low background scattering due to the small amount of material in the beam path, rapid cooldown, and fast field ramping. Access is available in a ±10°-11° cone around the field direction on both sides.

Posttraumatic stress disorder after injury: does admission to intensive care unit increase risk?

BACKGROUND: This study aimed to index the prevalence of posttraumatic stress disorder (PTSD) after injury requiring intensive care unit (ICU) admission to investigate whether an ICU admission after injury increases risk for PTSD and to identify predictors of PTSD after ICU admission. METHODS: A two-group (those admitted to the ICU vs. those not admitted to ICU), prospective, cohort study of 829 randomly selected injury patients from five major trauma hospitals across Australia. We collected information on factors that may increase risk for PTSD including demographic variables (gender, age, income, education, and marital status), preinjury mental health status (prior trauma, psychiatric history, and prior social support), and injury characteristics (mild traumatic brain injury, injury severity, length of hospital admission, discharge destination, pain, and perceived threat). PTSD was measured at 12 months by structured clinical interview. RESULTS: ICU patients were significantly more likely to have PTSD at 12 months than trauma controls (17% vs. 7%). Stepwise logistic regressions showed that an ICU admission significantly contributed to the development of PTSD after controlling for demographic, preinjury mental health status, and injury characteristic variables. CONCLUSIONS: Injury patients are three times more likely to develop later PTSD if they have an ICU admission. Given we controlled for many risk variables, it seems that an ICU admission itself may contribute to the development of PTSD. Mental health services such as screening and early intervention may be particularly useful for this population.

The role of post-traumatic stress disorder and depression in predicting disability after injury.

OBJECTIVES: To examine the relationship between psychological response to injury at 1 week and 3 months, and disability at 12 months. DESIGN: Multisite, longitudinal study. PARTICIPANTS AND SETTING: 802 adult patients admitted to trauma services at four Australian hospitals from 13 March 2004 to 21 February 2006 were assessed before discharge and followed up at 3 and 12 months. MAIN OUTCOME MEASURE: Disability, measured with the 12-item version of the World Health Organization Disability Assessment Schedule II. RESULTS: Logistic regression identified the degree to which high levels of depression and post-traumatic stress disorder (PTSD) at 1 week and at 3 months predicted disability at 12 months. After controlling for demographic variables and characteristics of the injury, patients with PTSD or subsyndromal PTSD at 1 week were 2.4 times more likely, and those with depression at 1 week were 1.9 times more likely to have high disability levels at 12 months. PTSD at 3 months was associated with 3.7 times, and depression at 3 months with 3.4 times the risk of high disability at 12 months. CONCLUSIONS: PTSD and depression at 1 week and at 3 months after injury significantly increased the risk of disability at 12 months. Routine assessment of symptoms of depression and PTSD in patients who have been physically injured may facilitate triage to evidence-based treatments, leading to improvement in both physical and psychological outcomes.

A predictive screening index for posttraumatic stress disorder and depression following traumatic injury.

Posttraumatic stress disorder (PTSD) and major depressive episode (MDE) are frequent and disabling consequences of surviving severe injury. The majority of those who develop these problems are not identified or treated. The aim of this study was to develop and validate a screening instrument that identifies, during hospitalization, adults at high risk for developing PTSD and/or MDE. Hospitalized injury patients (n = 527) completed a pool of questions that represented 13 constructs of vulnerability. They were followed up at 12 months and assessed for PTSD and MDE. The resulting database was split into 2 subsamples. A principal-axis factor analysis and then a confirmatory factor analysis were conducted on the 1st subsample, resulting in a 5-factor solution. Two questions were selected from each factor, resulting in a 10-item scale. The final model was cross-validated with the 2nd subsample. Receiver-operating characteristic curves were then created. The resulting Posttraumatic Adjustment Scale had a sensitivity of .82 and a specificity of .84 when predicting PTSD and a sensitivity of .72 and a specificity of .75 in predicting posttraumatic MDE. This 10-item screening index represents a clinically useful instrument to identify trauma survivors at risk for the later development of PTSD and/or MDE.