The mex-3 3' untranslated region is essential for reproduction during temperature stress.

Organisms must sense temperature and modify their physiology to ensure survival during environmental stress. Elevated temperature leads to reduced fertility in most sexually reproducing organisms. Maternally supplied mRNAs are required for embryogenesis. They encode proteins that govern early events in embryonic patterning. RNA-binding proteins (RBPs) are major effectors of maternal mRNA regulation. MEX-3 is a conserved RBP essential for anterior patterning of Caenorhabditis elegans embryos. We previously demonstrated that the mex-3 3' untranslated region (3'UTR) represses MEX-3 abundance in the germline yet is dispensable for fertility. Here, we show that the 3'UTR becomes essential during thermal stress. Deletion of the 3'UTR causes a highly penetrant temperature sensitive embryonic lethality phenotype distinct from a mex-3 null. Loss of the 3'UTR decreases MEX-3 abundance specifically in maturing oocytes and early embryos experiencing temperature stress, suggesting a mechanism that regulates MEX-3 abundance at the oocyte-to-embryo transition is sensitive to temperature. We propose that a primary role of the mex-3 3'UTR is to buffer MEX-3 expression to ensure viability during fluctuating temperature. We hypothesize that a major role of maternally supplied mRNAs is to ensure robust expression of key cell fate determinants in uncertain conditions.

COVID-19 pandemic and emergency department visits for psychosis: Visit volume, restraint use, medication use, psychiatric hospitalization, and length of stay.

BACKGROUND: Individuals with a schizophrenia spectrum disorder were at heightened risk for interruptions in psychiatric care during the coronavirus-19 (COVID 19) pandemic. There is limited work exploring the pandemic's impact on emergency department (ED) visit volume, use of restraint and parenteral medications, inpatient psychiatric (IP) hospitalization, and ED length of stay (LOS) among this population. METHODS: We retrospectively examined 2134 ED visits with a billing code for psychosis between March 1, 2019-February 28, 2021. We used Poisson regression analysis to compare ED visit volume between the pandemic and pre-pandemic periods. Restraint use, parenteral antipsychotic or benzodiazepine use, IP hospitalization, and ED LOS were compared between the two periods using chi-square tests and independent samples t-tests. RESULTS: Overall volume of psychosis-related ED visits during the pandemic did not differ significantly from the prior year. Rates of restraint use (16.2 % vs 11.6 %, p < .01), parenteral antipsychotic (22.6 % vs 14.9, p < .001), and parenteral benzodiazepine (22.3 % vs 16.3 %, p < .001) use were significantly higher during the pandemic. Fewer patients had an IP hospital disposition during the pandemic than the year prior (57.8 % vs. 61.9 %, p < .05). ED LOS was longer during the pandemic compared to pre-pandemic (28.37 h vs 20.26 h, p < .001). CONCLUSIONS: Although the volume of psychosis-related ED visits remained constant, restraint and parenteral medication use rates were significantly higher during the pandemic. ED LOS increased but fewer ED visits resulted in IP hospitalization. These findings underscore the importance of planning for increased acuity of psychosis ED presentations during public health emergencies.

Demographic predictors of lack of current mental health treatment among university students with a schizophrenia spectrum disorder.

AIM: To identify the demographic predictors of lack of current mental health (MH) treatment among university students with a schizophrenia spectrum disorder (SSD). METHODS: Adult university students with a self-identified diagnosis of an SSD (schizophreniform, schizophrenia, schizoaffective disorder) were identified from the 2019-2020 Healthy Minds Study survey. In this study, pertinent demographic factors included age, race/ethnicity, sex assigned at birth, gender identity, sexual orientation, parental education, financial stress, and employment. Multivariable modelling was used to investigate the demographic predictors of lack of current psychotherapy treatment, no current antipsychotic use, and lack of any MH treatment (defined as concurrent lack of psychotherapy and antipsychotic treatment). RESULTS: Of the 135 included students with a SSD, the median age was 23 years old and 79 (58.5%) were assigned female at birth. Fifty-five participants (40.7%) lacked any current MH treatment. In fully adjusted models, lack of current MH treatment was associated with working more than 20 h per week (OR 2.9 [1.2-7.1], p = 0.02). No current antipsychotic use was associated with Hispanic/Latino race/ethnicity (OR 4.2 (1.2-14.5), p = 0.04). Lack of current psychotherapy treatment was associated with cisgender male identity (OR 5.5 [2.0-15.2], p < 0.01), working greater than 20 hours per week (OR 6.5 [2.2-19.2], p < 0.01), and having one or more structural or attitudinal barriers to care (OR = 4.6 [1.5-13.9], p < 0.01). CONCLUSIONS: The demographic predictors of lack of current MH treatment varied between psychotherapy and antipsychotic use, suggesting university health centres should consider interventions targeting several at-risk populations to increase treatment use among students with a SSD.

Cannabis use among patients presenting to the emergency department for psychosis: Associations with restraint use, medication administration, psychiatric hospitalization, and repeat visits.

Cannabis use is associated with increased severity of psychotic symptoms and the risk of acute agitation and aggressive behavior in inpatient (IP) and outpatient settings. Whether or not cannabis use is associated with increased acuity of psychosis-related ED presentations and risk of repeat ED visits for psychosis is unclear. In this retrospective study of 2,134 ED visits for acute psychosis, we investigated the risk of physical restraint, parenteral medication administration, psychiatric hospitalization, and recurrent ED visits. We examined ED visits between March 1, 2019 and February 28, 2021 based on urinary Tetrahydrocannabinol (THC) screen status (positive vs negative vs no screen). The risk of physical restraint, parenteral antipsychotic, and benzodiazepine administration was significantly greater in ED visits with a positive THC screen compared to those with a negative or no THC screen. We did not find an association between a positive urinary THC screen and IP hospitalization or the risk of recurrent ED presentation for psychosis within 90 days. These findings suggest that positive urinary THC may predict acute agitation or acuity of symptoms in ED settings and underscores the importance of screening for THC during ED presentations for psychosis.

Dismantling Racial Inequities in Early Psychosis Family Psychoeducation.

Families and caregivers play a critical role in the recovery of their loved ones with schizophrenia. Early intervention services, including family psychoeducation, can improve clinical outcomes and reduce stress for caregivers. Despite the benefits of family psychoeducation, Black caregivers engage in treatment at lower rates than do White caregivers. To eliminate disparities in early intervention care, mental health clinicians must understand the system of racism that shapes the Black caregiver experience. This column examines racial disparities in family psychoeducation engagement by contextualizing the Black caregiver experience and encourages culturally appropriate early intervention services to improve psychosis care.

Estimating longitudinal depressive symptoms from smartphone data in a transdiagnostic cohort.

BACKGROUND: Passive measures collected using smartphones have been suggested to represent efficient proxies for depression severity, but the performance of such measures across diagnoses has not been studied. METHODS: We enrolled a cohort of 45 individuals (11 with major depressive disorder, 11 with bipolar disorder, 11 with schizophrenia or schizoaffective disorder, and 12 individuals with no axis I psychiatric disorder). During the 8-week study period, participants were evaluated with a rater-administered Montgomery-Åsberg Depression Rating Scale (MADRS) biweekly, completed self-report PHQ-8 measures weekly on their smartphone, and consented to collection of smartphone-based GPS and accelerometer data in order to learn about their behaviors. We utilized linear mixed models to predict depression severity on the basis of phone-based PHQ-8 and passive measures. RESULTS: Among the 45 individuals, 38 (84%) completed the 8-week study. The average root-mean-squared error (RMSE) in predicting the MADRS score (scale 0-60) was 4.72 using passive data alone, 4.27 using self-report measures alone, and 4.30 using both. CONCLUSIONS: While passive measures did not improve MADRS score prediction in our cross-disorder study, they may capture behavioral phenotypes that cannot be measured objectively, granularly, or over long-term via self-report.

In vivo human brain expression of histone deacetylases in bipolar disorder.

The etiology of bipolar disorder (BD) is unknown and the neurobiological underpinnings are not fully understood. Both genetic and environmental factors contribute to the risk of BD, which may be linked through epigenetic mechanisms, including those regulated by histone deacetylase (HDAC) enzymes. This study measures in vivo HDAC expression in individuals with BD for the first time using the HDAC-specific radiotracer [11C]Martinostat. Eleven participants with BD and 11 age- and sex-matched control participants (CON) completed a simultaneous magnetic resonance - positron emission tomography (MR-PET) scan with [11C]Martinostat. Lower [11C]Martinostat uptake was found in the right amygdala of BD compared to CON. We assessed uptake in the dorsolateral prefrontal cortex (DLPFC) to compare previous findings of lower uptake in the DLPFC in schizophrenia and found no group differences in BD. Exploratory whole-brain voxelwise analysis showed lower [11C]Martinostat uptake in the bilateral thalamus, orbitofrontal cortex, right hippocampus, and right amygdala in BD compared to CON. Furthermore, regional [11C]Martinostat uptake was associated with emotion regulation in BD in fronto-limbic areas, which aligns with findings from previous structural, functional, and molecular neuroimaging studies in BD. Regional [11C]Martinostat uptake was associated with attention in BD in fronto-parietal and temporal regions. These findings indicate a potential role of HDACs in BD pathophysiology. In particular, HDAC expression levels may modulate attention and emotion regulation, which represent two core clinical features of BD.

Sterol-Response Pathways Mediate Alkaline Survival in Diverse Fungi.

The ability for cells to maintain homeostasis in the presence of extracellular stress is essential for their survival. Stress adaptations are especially important for microbial pathogens to respond to rapidly changing conditions, such as those encountered during the transition from the environment to the infected host. Many fungal pathogens have acquired the ability to quickly adapt to changes in extracellular pH to promote their survival in the various microenvironments encountered during a host infection. For example, the fungus-specific Rim/Pal alkaline response pathway has been well characterized in many fungal pathogens, including Cryptococcus neoformans However, alternative mechanisms for sensing and responding to host pH have yet to be extensively studied. Recent observations from a genetic screen suggest that the C. neoformans sterol homeostasis pathway is required for growth at elevated pH. This work explores interactions among mechanisms of membrane homeostasis, alkaline pH tolerance, and Rim pathway activation. We find that the sterol homeostasis pathway is necessary for growth in an alkaline environment and that an elevated pH is sufficient to induce Sre1 activation. This pH-mediated activation of the Sre1 transcription factor is linked to the biosynthesis of ergosterol but is not dependent on Rim pathway signaling, suggesting that these two pathways are responding to alkaline pH independently. Furthermore, we discover that C. neoformans is more susceptible to membrane-targeting antifungals under alkaline conditions, highlighting the impact of microenvironmental pH on the treatment of invasive fungal infections. Together, these findings further connect membrane integrity and composition with the fungal pH response and pathogenesis.IMPORTANCE The work described here further elucidates how microorganisms sense and adapt to changes in their environment to establish infections in the human host. Specifically, we uncover a novel mechanism by which an opportunistic human fungal pathogen, Cryptococcus neoformans, responds to increases in extracellular pH in order to survive and thrive within the relatively alkaline environment of the human lung. This mechanism, which is intimately linked with fungal membrane sterol homeostasis, is independent of the previously well-studied alkaline response Rim pathway. Furthermore, this ergosterol-dependent alkaline pH response is present in Candida albicans, indicating that this mechanism spans diverse fungal species. These results are also relevant for novel antimicrobial drug development as we show that currently used ergosterol-targeting antifungals are more active in alkaline environments.

Integrating questionnaire measures for transdiagnostic psychiatric phenotyping using word2vec.

BACKGROUND: Recent initiatives in psychiatry emphasize the utility of characterizing psychiatric symptoms in a multidimensional manner. However, strategies for applying standard self-report scales for multiaxial assessment have not been well-studied, particularly where the aim is to support both categorical and dimensional phenotypes. METHODS: We propose a method for applying natural language processing to derive dimensional measures of psychiatric symptoms from questionnaire data. We utilized nine self-report symptom measures drawn from a large cellular biobanking study that enrolled individuals with mood and psychotic disorders, as well as healthy controls. To summarize questionnaire results we used word embeddings, a technique to represent words as numeric vectors preserving semantic and syntactic meaning. A low-dimensional approximation to the embedding space was used to derive the proposed succinct summary of symptom profiles. To validate our embedding-based disease profiles, these were compared to presence or absence of axis I diagnoses derived from structured clinical interview, and to objective neurocognitive testing. RESULTS: Unsupervised and supervised classification to distinguish presence/absence of axis I disorders using survey-level embeddings remained discriminative, with area under the receiver operating characteristic curve up to 0.85, 95% confidence interval (CI) (0.74,0.91) using Gaussian mixture modeling, and cross-validated area under the receiver operating characteristic curve 0.91, 95% CI (0.88,0.94) using logistic regression. Derived symptom measures and estimated Research Domain Criteria scores also associated significantly with performance on neurocognitive tests. CONCLUSIONS: Our results support the potential utility of deriving dimensional phenotypic measures in psychiatric illness through the use of word embeddings, while illustrating the challenges in identifying truly orthogonal dimensions.

Chitin: A "Hidden Figure" in the Fungal Cell Wall.

Chitin and chitosan are two related polysaccharides that provide important structural stability to fungal cell walls. Often embedded deeply within the cell wall structure, these molecules anchor other components at the cell surface. Chitin-directed organization of the cell wall layers allows the fungal cell to effectively monitor and interact with the external environment. For fungal pathogens, this interaction includes maintaining cellular strategies to avoid excessive detection by the host innate immune system. In turn, mammalian and plant hosts have developed their own strategies to process fungal chitin, resulting in chitin fragments of varying molecular size. The size-dependent differences in the immune activation behaviors of variably sized chitin molecules help to explain how chitin and related chitooligomers can both inhibit and activate host immunity. Moreover, chitin and chitosan have recently been exploited for many biomedical applications, including targeted drug delivery and vaccine development.

Efficacy and Tolerability of Adjunctive Intravenous Sodium Nitroprusside Treatment for Outpatients With Schizophrenia: A Randomized Clinical Trial.

Importance: Antipsychotic medications for the treatment of schizophrenia have limitations, and new treatments are needed. A prior pilot investigation suggested that adjunctive sodium nitroprusside (SNP) administered intravenously had rapid efficacy in the treatment of patients with schizophrenia. Objective: To determine the efficacy and tolerability of intravenous SNP infused at a rate of 0.5 µg/kg/min for 4 hours in patients with schizophrenia with some degree of treatment resistance. Design, Setting, and Participants: Multicenter, randomized, double-blind acute treatment study using a sequential parallel comparison design conducted in two 2-week phases at 4 academic medical centers beginning May 20, 2015, and ending March 31, 2017. Participants were adults 18 to 65 years of age with a diagnosis of schizophrenia as confirmed by the Structured Clinical Interview for DSM-IV, taking antipsychotic medication for at least 8 weeks, and had at least 1 failed trial of an antipsychotic medication within the past year. A total of 90 participants consented, 60 participants enrolled, and 52 participants were included in the analyses. A modified intent-to-treat analysis was used. Interventions: Participants were randomized in a 1:1:1 ratio to 1 of 3 treatment sequences: SNP and SNP, placebo and SNP, and placebo and placebo. The SNP and SNP group received SNP in phase 1 and SNP in phase 2 for the purpose of blinding, but the data from phase 2 were not included in the results. The placebo and SNP group received placebo in phase 1 and SNP in phase 2. If there was no response to placebo in phase 1, data from phase 2 were included in the analyses. The placebo and placebo group received placebo in both phases; if there was no response to placebo in phase 1, data from phase 2 were included in the analyses. Main Outcomes and Measures: Effectiveness of SNP compared with placebo in improving Positive and Negative Syndrome Scale (PANSS) total, positive, and negative scores across each 2-week phase. Results: Fifty-two participants (12 women and 40 men) were included in the study. In the SNP and SNP group, the mean (SD) age was 47.1 (10.5) years. In the placebo and SNP group, the mean (SD) age was 45.9 (12.3) years. In the placebo and placebo group, the mean (SD) age was 40.4 (11.0) years. There were no significant differences between the SNP and placebo groups at baseline or in change from baseline for PANSS-total (weighted ß = -1.04; z = -0.59; P = .57), PANSS-positive (weighted ß = -0.62; z = -0.93; P = .35), or PANSS-negative (weighted ß = -0.12; z = -0.19; P = .85) scores. No significant differences in safety or tolerability measures were identified. Conclusions and Relevance: Although intravenous SNP is well tolerated, it was not an efficacious adjunctive treatment of positive or negative symptoms of psychosis among outpatients with schizophrenia with prior history of treatment resistance. Trial Registration: ClinicalTrials.gov identifier: NCT02164981.

Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.

Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.

Risk tolerance measured by probability discounting among individuals with primary mood and psychotic disorders.

OBJECTIVE: Change in risk tolerance is a feature of multiple psychiatric disorders and may contribute to adverse outcomes. We used a probability discounting (PD) task to measure risk-taking behavior among individuals with bipolar disorder (BPAD), major depressive disorder (MDD), schizoaffective disorder (SCAD), and schizophrenia (SCZ). METHOD: A PD task was administered to 117 patients and 88 healthy controls (HCs), along with a cognitive battery using the Cambridge Neuropsychological Test Automated Battery, and relevant symptomatology scales. We examined differences in PD rates between diagnostic groups, and compared with HCs, while controlling for potential confounding factors including measures of cognitive functioning. RESULTS: Individuals with a diagnosis of BPAD or SCAD/SCZ prefer smaller, more guaranteed rewards rather than larger, less likely rewards as compared with healthy controls (p = .002 and p = .034, respectively). There was no effect of performance on cognitive tasks, antipsychotic treatment, or symptomatology on the rate of probability discounting. CONCLUSION: This study supports the transdiagnostic measurement of risk-taking behaviors, even when such behaviors are not the primary area of psychopathology. Quantifying risk-taking may enable targeted therapeutic strategies across disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia.

BACKGROUND: Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [11C]Martinostat positron emission tomography (PET). METHODS: In a case-control study, relative [11C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered. RESULTS: Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls. CONCLUSIONS: These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans. FUNDING: National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program.

Identifying a novel connection between the fungal plasma membrane and pH-sensing.

The mechanisms by which micro-organisms sense and internalize extracellular pH signals are not completely understood. One example of a known external pH-sensing process is the fungal-specific Rim/Pal signal transduction pathway. Fungi, such as the opportunistic pathogen Cryptococcus neoformans, use Rim signaling to sense and respond to changes in environmental pH. Mutations in this pathway result in strains that are attenuated for survival at alkaline pH, and often for survival within the host. Here, we used an insertional mutagenesis screen to identify novel genes required for C. neoformans growth at host pH. We discovered altered alkaline pH growth in several strains with specific defects in plasma membrane composition and maintenance of phospholipid assembly. Among these, loss of function of the Cdc50 lipid flippase regulatory subunit affected the temporal dynamics of Rim pathway activation. We defined distinct and overlapping cellular processes regulated by Rim101 and Cdc50 through analysis of the transcriptome in these mutant strains. We further explored how pH-induced membrane changes affect membrane-bound pH-sensing proteins, specifically the C-terminal domain of the Rra1 protein, an upstream Rim pathway activator and pH sensor. These results suggest both broadly applicable and phylum-specific molecular interactions that drive microbial environmental sensing.

Impairment in delay discounting in schizophrenia and schizoaffective disorder but not primary mood disorders.

A measure of planning and impulse control, the delay-discounting (DD) task estimates the extent to which an individual decreases the perceived value of a reward as the reward is delayed. We examined cross-disorder performance between healthy controls (n = 88), individuals with bipolar disorder (n = 23), major depressive disorder (n = 43), and primary psychotic disorders (schizophrenia and schizoaffective disorder; n = 51) on the DD task (using a $10 delayed larger reward), as well as the interaction of DD scores with other symptom domains (cognition, psychosis, and affect). We found that individuals with schizophrenia and schizoaffective disorder display significantly greater rates of discounting compared to healthy controls, while individuals with a primary mood disorder do not differ from healthy controls after adjustment for IQ. Further, impairment in working memory is associated with higher discounting rates among individuals with schizophrenia and schizoaffective disorder, but cognitive dysfunction alone does not account for the extent of impairment in DD. Taken together, these results suggest an impaired ability to plan for the future and make adaptive decisions that are specific to individuals with psychotic disorders, and likely related to adverse functional outcomes. More generally, this work demonstrates the presence of variation in impulsivity across major psychiatric illnesses, supporting the use of a trans-diagnostic perspective.