Efficient computation of contributional diversity metrics from microbiome data with FuncDiv.

MOTIVATION: Microbiome datasets with taxa linked to the functions (e.g. genes) they encode are becoming more common as metagenomics sequencing approaches improve. However, these data are challenging to analyze due to their complexity. Summary metrics, such as the alpha and beta diversity of taxa contributing to each function (i.e. contributional diversity), represent one approach to investigate these data, but currently there are no straightforward methods for doing so. RESULTS: We addressed this gap by developing FuncDiv, which efficiently performs these computations. Contributional diversity metrics can provide novel insights that would be impossible to identify without jointly considering taxa and functions. AVAILABILITY AND IMPLEMENTATION: FuncDiv is distributed under a GNU Affero General Public License v3.0 and is available at https://github.com/gavinmdouglas/FuncDiv. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Child Opportunity Index and Pediatric Intensive Care Outcomes: A Multicenter Retrospective Study in the United States.

OBJECTIVES: To evaluate for associations between a child's neighborhood, as categorized by Child Opportunity Index (COI 2.0), and 1) PICU mortality, 2) severity of illness at PICU admission, and 3) PICU length of stay (LOS). DESIGN: Retrospective cohort study. SETTING: Fifteen PICUs in the United States. PATIENTS: Children younger than 18 years admitted from 2019 to 2020, excluding those after cardiac procedures. Nationally-normed COI category (very low, low, moderate, high, very high) was determined for each admission by census tract, and clinical features were obtained from the Virtual Pediatric Systems LLC (Los Angeles, CA) data from each site. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 33,901 index PICU admissions during the time period, median patient age was 4.9 years and PICU mortality was 2.1%. There was a higher percentage of admissions from the very low COI category (27.3%) than other COI categories (17.2-19.5%, p < 0.0001). Patient admissions from the high and very high COI categories had a lower median Pediatric Index of Mortality 3 risk of mortality (0.70) than those from the very low, low, and moderate COI groups (0.71) ( p < 0.001). PICU mortality was lowest in the very high (1.7%) and high (1.9%) COI groups and highest in the moderate group (2.5%), followed by very low (2.3%) and low (2.2%) ( p = 0.001 across categories). Median PICU LOS was between 1.37 and 1.50 days in all COI categories. Multivariable regression revealed adjusted odds of PICU mortality of 1.30 (95% CI, 0.94-1.79; p = 0.11) for children from a very low versus very high COI neighborhood, with an odds ratio [OR] of 0.996 (95% CI, 0.993-1.00; p = 0.05) for mortality for COI as an ordinal value from 0 to 100. Children without insurance coverage had an OR for mortality of 3.58 (95% CI, 2.46-5.20; p < 0.0001) as compared with those with commercial insurance. CONCLUSIONS: Children admitted to a cohort of U.S. PICUs were often from very low COI neighborhoods. Children from very high COI neighborhoods had the lowest risk of mortality and observed mortality; however, odds of mortality were not statistically different by COI category in a multivariable model. Children without insurance coverage had significantly higher odds of PICU mortality regardless of neighborhood.

Air pollution mortality benefits of sustained COVID-19 mobility restrictions in Australian cities.

OBJECTIVES: Emissions from road traffic, power generation and industry were substantially reduced during pandemic lockdown periods globally. Thus, we analysed reductions in traffic-related air pollution in Australian capital cities during March-April 2020 and then modelled the mortality benefits that could be realised if similar reductions were sustained by structural policy interventions. STUDY DESIGN: Satellite, air pollution monitor and land use observations were used to estimate ground-level nitrogen dioxide (NO2) concentrations in all Australian capital cities during: (a) a typical year with no prolonged air pollution events; (b) a hypothetical sustained reduction in NO2 equivalent to the COVID-19 lockdowns. METHODS: We use the WHO recommended NO2 exposure-response coefficient for mortality (1.023, 95 % CI: 1.008-1.037, per 10 µg/m3 annual average) to assess gains in life expectancy and population-wide years of life from reduced exposure to traffic-related air pollution. RESULTS: We attribute 1.1 % of deaths to anthropogenic NO2 exposures in Australian cities, corresponding to a total of 13,340 years of life lost annually. Although COVID-19-related reductions in NO2 varied widely between Australian cities during April 2020, equivalent and sustained reductions in NO2 emissions could reduce NO2-attributable deaths by 27 %, resulting in 3348 years of life gained annually. CONCLUSIONS: COVID-19 mobility restrictions reduced NO2 emissions and population-wide exposures in Australian cities. When sustained to the same extent by policy interventions that reduce fossil fuel consumption by favouring the uptake of electric vehicles, active travel and public transport, the health, mortality and economic benefits will be measurable in Australian cities.

What Are the Psychosocial Effects of Pavlik Harness Treatment? A Prospective Study on Perceived Impact on Families and Maternal-Infant Bonding.

BACKGROUND: The Pavlik harness (PH) is the most common treatment for infants with developmental dysplasia of the hip. Although success rates are high when used appropriately, brace treatment may impact family function and parental bonding. The purpose of this study was to prospectively determine how PH treatment affected these psychosocial variables. METHODS: This is a prospective, single-surgeon study at a tertiary-care, urban, academic children's hospital between November 2022 and March 2023. All patients newly treated with a Pavlik were eligible. Caregivers were administered the Postpartum Bonding Questionnaire and the Revised Impact on Family Scale (rIOFS) at the baseline visit and 2- and 6 weeks following treatment initiation. Demographic and treatment-specific information was collected through surveys and retrospective chart review. Descriptive statistics and bivariate analysis were used. RESULTS: A total of 55 caregiver-child dyads were included in the final analysis. Most patients were female (89%) and/or first-born (73%). Forty (73%) hips were diagnosed as having stable dysplasia. rIOFS scores steadily improved from baseline, through 2- and 6 weeks posttreatment initiation. Six-week rIOFS scores were significantly lower than both baseline ( P= 0.002) and 2 weeks ( P =0.018). Average parental bonding scores also improved steadily throughout treatment and did not surpass the threshold of clinical concern at any time. Neither full-time harness use (24 h/d vs. 23 h/d based upon clinical stability) nor age at treatment initiation had a statistically significant effect on parental bonding or family functioning (all P >0.05). Additional demographic variables such as birth order, parental history of anxiety/depression, and relative socioeconomic disadvantage also had no significant effect on psychosocial outcomes. CONCLUSION: PH treatment did not significantly impact maternal-fetal bonding or family dynamics. Relative to other pediatric diseases, PH treatment has an impact on family life greater than that of single-leg spica, but less than that of school-age children with chronic medical illnesses. As PH treatment is a widely used treatment for infantile developmental dysplasia of the hip, this study provides information that clinicians may use to more accurately counsel families and assuage parental concerns. LEVELS OF EVIDENCE: Level IV-prospective uncontrolled cohort study.

Intraoperative Epiphyseal Perfusion Monitoring Does Not Reliably Predict Osteonecrosis Following Treatment of Unstable SCFE.

BACKGROUND: Avascular necrosis (AVN) remains the most dreaded complication of unstable slipped capital femoral epiphysis (SCFE) treatment. Newer closed reduction techniques (with perfusion monitoring) have emerged as a technically straightforward means to address residual SCFE deformity while still minimizing the risk of osteonecrosis. However, limited data exists regarding the reliability of intraoperative epiphyseal perfusion monitoring to predict the development of AVN. The purpose of this study was to evaluate its reliability. METHODS: We retrospectively reviewed all patients with unstable SCFE who underwent closed or open reduction with epiphyseal perfusion monitoring using an intracranial pressure (ICP) probe from 2015 to 2023 at a single institution with a minimum 6-month radiographic follow-up. Demographic, clinical, and radiographic data were recorded, including duration of symptoms, type of reduction, capsulotomy performed, presence of a waveform on ICP monitoring after epiphyseal fixation, and development of AVN on follow-up radiographs. RESULTS: Our cohort included 33 hips (32 patients), of which 60.6% (n=20) were male. The average age was 12.5±1.8 years, with a median follow-up of 15.8 months. Eleven hips were treated with open reduction using the modified Dunn technique (10 hips) or anterior approach (1 hip), and 22 hips were treated with inadvertent (5 hips) or purposeful closed reduction using the Leadbetter technique (17 hips). Overall, 8 of the 33 hips in our series (24.2%) developed AVN, 6 of which (20%) had a pulsatile waveform on intraoperative epiphyseal perfusion monitoring. The overall rate of AVN after closed reductions was 31.8% (7 of 22 hips); the incidence of AVN after closed reduction with a detectable waveform was 30% (6 of 20 hips). There was no significant association between time to surgery ( P =0.416) or type of reduction ( P =0.218) and the incidence of AVN. CONCLUSIONS: In this series, intraoperative epiphyseal perfusion monitoring did not reliably predict the development of osteonecrosis. To our knowledge, this is the first study to report AVN after demonstrable intraoperative epiphyseal perfusion following closed reduction of unstable slips. LEVEL OF EVIDENCE: Level IV: case series-therapeutic study.

A Neglected Fracture: Treatment and Infection of Seymour Fractures of the Hallux in the Pediatric Population.

INTRODUCTION: Seymour physeal fractures of the distal phalanx of the Hallux in children are common but rarely described in the literature. There is limited literature investigating how these fractures should be specifically treated. Generally, good results are reported when open fractures are treated with debridement and antibiotics. This large retrospective review evaluates incidence of infection and compares outcomes of various treatments for Seymour physeal fractures of the distal phalanx of the Hallux in children. METHODS: This study included patients ≤18 years of age treated for Seymour fractures of the Hallux between January 1, 2007, and November 20, 2018, at a single tertiary-care urban children's hospital. Demographic, injury, and treatment data were obtained via a retrospective review of electronic medical records, including closed versus open fracture status, time to treatment, and whether antibiotics were prescribed and taken. Initial radiographic imaging was examined by a single attending surgeon for angulation (degrees) and widening (mm). Outcome variables included the development of infection and the rate and success of healing. RESULTS: One hundred thirty-eight patients were included in our analysis. Most (84/138, 61%) fractures were closed and treated successfully without antibiotics. Treatment for open fractures varied greatly, with many of these fractures undergoing an incision and drainage procedure (I&D) (33/54, 61%) and antibiotic prescription (43/54, 76%). Most (47/54, 87%) open fractures did not develop infection. However, 7/54 open fractures presented with an active infection. Four out of seven (29%) of these fractures did not receive any treatment before infection presentation. Two others who presented with infection both had delayed antibiotics and neither underwent I&D. Fractures that either presented with or developed an infection presented significantly later than those fractures that did not develop infection (P<0.001). Neither angulation nor displacement correlated to the time of healing or development of infection. CONCLUSIONS: In our large cohort, the majority of open Seymour fractures of the Hallux treated in a timely manner did not develop infection, regardless of treatment. However, open fractures that presented multiple days after injury had an increased incidence of infection. Thus, for open fractures, we recommend timely antibiotics and I&D. Closed fractures may be treated conservatively, with no indication for reduction or use of antibiotics.

New Classification for Pediatric Proximal Fifth Metatarsal Fractures.

Proximal fifth metatarsal fractures are the most common foot fractures in children. Attempts to classify these injuries are misapplied and inadequately predict outcomes. This is the first study to identify factors associated with healing in pediatric fifth metatarsal fractures. In this retrospective cohort study (N = 305), proximal fifth metatarsal fractures were classified on radiographs by location on the bone, alignment (transverse or oblique), displacement (>2 mm), and completion through the bone. Based on the literature, they were secondarily sorted by category: apophyseal, intra-articular metaphyseal, extra-articular metaphyseal, and diaphyseal. Primary outcomes included times to healing, indicated by clinical symptoms, immobilization, and return to sports, as well as radiographic callus formation, bridging, and remodeling. Healing times were compared by ANOVA and linear regression. Location had a significant effect on times of immobilization and return to sports, but alignment, displacement, and completion were not associated with healing. When re-classified, the categories were also associated with immobilization and return to sports. Apophyseal fractures healed fastest and diaphyseal fractures required the most time to heal. There was no difference between extra- and intra-articular fractures. For every year of age, symptoms resolved about 2 days sooner. Neither gender nor body mass index (BMI) was positively or negatively associated with healing times. In conclusion, classifying fractures by apophyseal, metaphyseal, and diaphyseal is the most concise, accurate, and useful system. This is the largest series of nonoperatively treated proximal fifth metatarsal fractures in children and a robust standard to which surgical management can be compared.

Intracellular Accumulation of α-Synuclein Aggregates Promotes S-Nitrosylation of MAP1A Leading to Decreased NMDAR-Evoked Calcium Influx and Loss of Mature Synaptic Spines.

Cortical synucleinopathies, including dementia with Lewy bodies and Parkinson's disease dementia, collectively known as Lewy body dementia, are characterized by the aberrant aggregation of misfolded α-synuclein (α-syn) protein into large inclusions in cortical tissue, leading to impairments in proteostasis and synaptic connectivity and eventually resulting in neurodegeneration. Here, we show that male and female rat cortical neurons exposed to exogenous α-syn preformed fibrils accumulate large, detergent-insoluble, PS129-labeled deposits at synaptic terminals. Live-cell imaging of calcium dynamics coupled with assessment of network activity reveals that aberrant intracellular accumulation of α-syn inhibits synaptic response to glutamate through NMDARs, although deficits manifest slowly over a 7 d period. Impairments in NMDAR activity temporally correlated with increased nitric oxide synthesis and S-nitrosylation of the dendritic scaffold protein, microtubule-associated protein 1A. Inhibition of nitric oxide synthesis via the nitric oxide synthase inhibitor l-NG-nitroarginine methyl ester blocked microtubule-associated protein 1A S-nitrosylation and normalized NMDAR-dependent inward calcium transients and overall network activity. Collectively, these data suggest that loss of synaptic function in Lewy body dementia may result from synucleinopathy-evoked nitrosative stress and subsequent NMDAR dysfunction.SIGNIFICANCE STATEMENT This work shows the importance of the redox state of microtubule-associated protein 1A in the maintenance of synaptic function through regulation of NMDAR. We show that α-syn preformed fibrils promote nitric oxide synthesis, which triggers S-nitrosylation of microtubule-associated protein 1A, leading to impairment of NMDAR-dependent glutamate responses. This offers insight into the mechanism of synaptic dysfunction in Lewy body dementia.

Cross-study analyses of microbial abundance using generalized common factor methods.

BACKGROUND: By creating networks of biochemical pathways, communities of micro-organisms are able to modulate the properties of their environment and even the metabolic processes within their hosts. Next-generation high-throughput sequencing has led to a new frontier in microbial ecology, promising the ability to leverage the microbiome to make crucial advancements in the environmental and biomedical sciences. However, this is challenging, as genomic data are high-dimensional, sparse, and noisy. Much of this noise reflects the exact conditions under which sequencing took place, and is so significant that it limits consensus-based validation of study results. RESULTS: We propose an ensemble approach for cross-study exploratory analyses of microbial abundance data in which we first estimate the variance-covariance matrix of the underlying abundances from each dataset on the log scale assuming Poisson sampling, and subsequently model these covariances jointly so as to find a shared low-dimensional subspace of the feature space. CONCLUSIONS: By viewing the projection of the latent true abundances onto this common structure, the variation is pared down to that which is shared among all datasets, and is likely to reflect more generalizable biological signal than can be inferred from individual datasets. We investigate several ways of achieving this, demonstrate that they work well on simulated and real metagenomic data in terms of signal retention and interpretability, and recommend a particular implementation.

Integrating phylogenetic and functional data in microbiome studies.

MOTIVATION: Microbiome functional data are frequently analyzed to identify associations between microbial functions (e.g. genes) and sample groups of interest. However, it is challenging to distinguish between different possible explanations for variation in community-wide functional profiles by considering functions alone. To help address this problem, we have developed POMS, a package that implements multiple phylogeny-aware frameworks to more robustly identify enriched functions. RESULTS: The key contribution is an extended balance-tree workflow that incorporates functional and taxonomic information to identify functions that are consistently enriched in sample groups across independent taxonomic lineages. Our package also includes a workflow for running phylogenetic regression. Based on simulated data we demonstrate that these approaches more accurately identify gene families that confer a selective advantage compared with commonly used tools. We also show that POMS in particular can identify enriched functions in real-world metagenomics datasets that are potential targets of strong selection on multiple members of the microbiome. AVAILABILITY AND IMPLEMENTATION: These workflows are freely available in the POMS R package at https://github.com/gavinmdouglas/POMS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Angular Correlations in the ß Decay of

We present the first measurement of the α-ß-ν angular correlation in the Gamow-Teller ß^{+} decay of ^{8}B. This was accomplished using the Beta-decay Paul Trap, expanding on our previous work on the ß^{-} decay of ^{8}Li. The ^{8}B result is consistent with the V-A electroweak interaction of the standard model and, on its own, provides a limit on the exotic right-handed tensor current relative to the axial-vector current of |C_{T}/C_{A}|^{2}<0.013 at the 95.5% confidence level. This represents the first high-precision angular correlation measurements in mirror decays and was made possible through the use of an ion trap. By combining this ^{8}B result with our previous ^{8}Li results, we demonstrate a new pathway for increased precision in searches for exotic currents.

Direct Mass Measurements to Inform the Behavior of

Nuclear isomer effects are pivotal in understanding nuclear astrophysics, particularly in the rapid neutron-capture process where the population of metastable isomers can alter the radioactive decay paths of nuclei produced during astrophysical events. The ß-decaying isomer ^{128m}Sb was identified as potentially impactful since the ß-decay pathway along the A=128 isobar funnels into this state bypassing the ground state. We report the first direct mass measurements of the ^{128}Sb isomer and ground state using the Canadian Penning Trap mass spectrometer at Argonne National Laboratory. We find mass excesses of -84564.8(25) keV and -84608.8(21) keV, respectively, resulting in an excitation energy for the isomer of 43.9(33) keV. These results provide the first key nuclear data input for understanding the role of ^{128m}Sb in nucleosynthesis, and we show that it will influence the flow of the rapid neutron-capture process.

Socioeconomic Deprivation and its Associations With Follow-up Compliance After In Situ Pinning of Slipped Capital Femoral Epiphysis.

BACKGROUND: Slipped capital femoral epiphysis (SCFE) is a common cause of hip pain in adolescents and is most often treated by in situ screw fixation. Orthopaedic follow-up is critical after treatment for SCFE due to risks of complications and subsequent contralateral slip. Recent studies have shown that socioeconomic deprivation is associated with decreased fracture care compliance, but no studies have explored this relationship with SCFEs. The study aims to determine the relationship between socioeconomic deprivation and SCFE follow-up care compliance. METHODS: This study included pediatric patients treated with in situ pinning of SCFE between 2011 and 2019 at a single tertiary-care urban children's hospital. Demographic and clinical information were obtained from electronic medical records. The Area Deprivation Index (ADI) was used to quantify the socioeconomic deprivation of each. Outcome variables included patient age and status of physeal closure at the most recent appointment, in addition to the length of follow-up (mo). Statistical relationships were evaluated using nonparametric bivariate analysis and correlation. RESULTS: We identified 247 evaluable patients; 57.1% were male, and the median age was 12.4 years. Most slips were stable (95.1%) and treated with isolated unilateral pinning (55.9%). Median length of follow-up was 11.9 months (interquartile range, 4.95 to 23.1) with median patient age at final visit of 13.6 years (interquartile range, 12.4 to 15.1). Only 37.2% of patients were followed until physeal closure. The mean ADI spread in this sample was similar to the national distribution. However, patients in the most deprived quartile were lost to follow-up significantly earlier (median, 6.5 mo) than those in the least deprived quartile (median, 12.5 mo; P <0.001). Throughout the entire cohort, there was a significant, inverse relationship between deprivation and follow-up length ( rs (238) = -0.3; P <0.001), with this relationship most pronounced in the most deprived quartile. CONCLUSIONS: In this sample, ADI spread was representative of national trends, and the incidence of SCFE was distributed evenly across deprivation quartiles. However, follow-up length does not mirror this relationship; increased socioeconomic deprivation is associated with an earlier loss to follow-up (often well before physeal closure). LEVEL OF EVIDENCE: Level II-retrospective prognostic study.

Defective Mitochondrial Dynamics and Protein Degradation Pathways Underlie Cadmium-Induced Neurotoxicity and Cell Death in Huntington's Disease Striatal Cells.

Exposure to heavy metals, including cadmium (Cd), can induce neurotoxicity and cell death. Cd is abundant in the environment and accumulates in the striatum, the primary brain region selectively affected by Huntington's disease (HD). We have previously reported that mutant huntingtin protein (mHTT) combined with chronic Cd exposure induces oxidative stress and promotes metal dyshomeostasis, resulting in cell death in a striatal cell model of HD. To understand the effect of acute Cd exposure on mitochondrial health and protein degradation pathways, we hypothesized that expression of mHTT coupled with acute Cd exposure would cooperatively alter mitochondrial bioenergetics and protein degradation mechanisms in striatal STHdh cells to reveal novel pathways that augment Cd cytotoxicity and HD pathogenicity. We report that mHTT cells are significantly more susceptible to acute Cd-induced cell death as early as 6 h after 40 µM CdCl2 exposure compared with wild-type (WT). Confocal microscopy, biochemical assays, and immunoblotting analysis revealed that mHTT and acute Cd exposure synergistically impair mitochondrial bioenergetics by reducing mitochondrial potential and cellular ATP levels and down-regulating the essential pro-fusion proteins MFN1 and MFN2. These pathogenic effects triggered cell death. Furthermore, Cd exposure increases the expression of autophagic markers, such as p62, LC3, and ATG5, and reduces the activity of the ubiquitin-proteasome system to promote neurodegeneration in HD striatal cells. Overall, these results reveal a novel mechanism to further establish Cd as a pathogenic neuromodulator in striatal HD cells via Cd-triggered neurotoxicity and cell death mediated by an impairment in mitochondrial bioenergetics and autophagy with subsequent alteration in protein degradation pathways.

Exploring the microbiome of oral epithelial dysplasia as a predictor of malignant progression.

A growing body of research associates the oral microbiome and oral cancer. Well-characterized clinical samples with outcome data are required to establish relevant associations between the microbiota and disease. The objective of this study was to characterize the community variations and the functional implications of the microbiome in low-grade oral epithelial dysplasia (OED) using 16S rRNA gene sequencing from annotated archival swabs in progressing (P) and non-progressing (NP) OED. We characterised the microbial community in 90 OED samples - 30 swabs from low-grade OED that progressed to cancer (cases) and 60 swabs from low-grade OED that did not progress after a minimum of 5 years of follow up (matched control subjects). There were small but significant differences between P and NP samples in terms of alpha diversity as well as beta diversity in conjunction with other clinical factors such as age and smoking status for both taxa and functional predictions. Across all samples, the most abundant genus was Streptococcus, followed by Haemophilus, Rothia, and Neisseria. Taxa and predicted functions were identified that were significantly differentially abundant with progression status (all Ps and NPs), when samples were grouped broadly by the number of years between sampling and progression or in specific time to progression for Ps only. However, these differentially abundant features were typically present only at low abundances. For example, Campylobacter was present in slightly higher abundance in Ps (1.72%) than NPs (1.41%) and this difference was significant when Ps were grouped by time to progression. Furthermore, several of the significantly differentially abundant functions were linked to the Campylobacteraceae family in Ps and may justify further investigation. Larger cohort studies to further explore the microbiome as a potential biomarker of risk in OED are warranted.

Improved Limit on Tensor Currents in the Weak Interaction from

The electroweak interaction in the standard model is described by a pure vector-axial-vector structure, though any Lorentz-invariant component could contribute. In this Letter, we present the most precise measurement of tensor currents in the low-energy regime by examining the ß-ν[over ¯] correlation of trapped ^{8}Li ions with the Beta-decay Paul Trap. We find a_{ßν}=-0.3325±0.0013_{stat}±0.0019_{syst} at 1σ for the case of coupling to right-handed neutrinos (C_{T}=-C_{T}^{'}), which is consistent with the standard model prediction.

Experiences of Female Partners of People Transitioning Gender: A Feminist Interpretive Metasynthesis.

The needs of romantic partners of people transitioning gender remain neglected within academia and gender services. Following a systematic search, nine studies relating to female partners' experiences were subjected to a thematic metasynthesis. Four themes were generated and entitled Changes in sexual relationship; New roles and responsibilities; Identity and belonging; and Transformation and loss Results are considered in relation to the dominance of the gender-affirmation discourse. Limitations of the review and reviewed studies are highlighted. Clinical implications for couples and partners of people transitioning gender are offered.

The Psychology of Moral Conviction.

This review covers theory and research on the psychological characteristics and consequences of attitudes that are experienced as moral convictions, that is, attitudes that people perceive as grounded in a fundamental distinction between right and wrong. Morally convicted attitudes represent something psychologically distinct from other constructs (e.g., strong but nonmoral attitudes or religious beliefs), are perceived as universally and objectively true, and are comparatively immune to authority or peer influence. Variance in moral conviction also predicts important social and political consequences. Stronger moral conviction about a given attitude object, for example, is associated with greater intolerance of attitude dissimilarity, resistance to procedural solutions for conflict about that issue, and increased political engagement and volunteerism in that attitude domain. Finally, we review recent research that explores the processes that lead to attitude moralization; we integrate these efforts and conclude with a new domain theory of attitude moralization.

Axonal pathology in hPSC-based models of Parkinson's disease results from loss of Nrf2 transcriptional activity at the Map1b gene locus.

While mutations in the SNCA gene (α-synuclein [α-syn]) are causal in rare familial forms of Parkinson's disease (PD), the prevalence of α-syn aggregates in the cortices of sporadic disease cases emphasizes the need to understand the link between α-syn accumulation and disease pathogenesis. By employing a combination of human pluripotent stem cells (hPSCs) that harbor the SNCA-A53T mutation contrasted against isogenic controls, we evaluated the consequences of α-syn accumulation in human A9-type dopaminergic (DA) neurons (hNs). We show that the early accumulation of α-syn in SNCA-A53T hNs results in changes in gene expression consistent with the expression profile of the substantia nigra (SN) from PD patients, analyzed post mortem. Differentially expressed genes from both PD patient SN and SNCA-A53T hNs were associated with regulatory motifs transcriptionally activated by the antioxidant response pathway, particularly Nrf2 gene targets. Differentially expressed gene targets were also enriched for gene ontologies related to microtubule binding processes. We thus assessed the relationship between Nrf2-mediated gene expression and neuritic pathology in SNCA-A53T hNs. We show that SNCA-mutant hNs have deficits in neuritic length and complexity relative to isogenic controls as well as contorted axons with Tau-positive varicosities. Furthermore, we show that mutant α-syn fails to complex with protein kinase C (PKC), which, in turn, results in impaired activation of Nrf2. These neuritic defects result from impaired Nrf2 activity on antioxidant response elements (AREs) localized to a microtubule-associated protein (Map1b) gene enhancer and are rescued by forced expression of Map1b as well as by both Nrf2 overexpression and pharmaceutical activation in PD neurons.

Rethinking the role of hydroxychloroquine in the treatment of COVID-19.

There are currently no proven or approved treatments for coronavirus disease 2019 (COVID-19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID-19 are treated with these agents and more evidence accumulates, there continues to be no high-quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto-immune conditions, and provided a component in the original rationale for their use in patients with COVID-19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID-19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID-19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID-19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case-by-case basis after rigorous consideration of the risks and benefits of this therapeutic approach.