NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids.

Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies.

Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses.

Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions, but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent response pathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomic methods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formation within the peritoneal cavities of mice. Foam cell formation was associated with significant changes in hundreds of lipid species and unexpected suppression, rather than activation, of inflammatory gene expression. We provide evidence that regulated accumulation of desmosterol underlies many of the homeostatic responses, including activation of LXR target genes, inhibition of SREBP target genes, selective reprogramming of fatty acid metabolism, and suppression of inflammatory-response genes, observed in macrophage foam cells. These observations suggest that macrophage activation in atherosclerotic lesions results from extrinsic, proinflammatory signals generated within the artery wall that suppress homeostatic and anti-inflammatory functions of desmosterol.

Spiritual coping within medical professions: A psychometric analysis of the Numinous Motivations Inventory short form.

AIM: To examine the psychometric properties of a short form version of the Numinous Motivation Inventory (NMI) for use with healthcare providers in measuring their existential engagement with life and to assess its relationship with spiritual coping and emotional dysphoria. DESIGN: Correlational and psychometric study. METHOD: Data were collected from June to December 2022. Participants included 102 physicians, recruited from across the United States. Qualtrics was utilized to collect data, and they were evaluated with the NMI short form, Spiritual Coping Questionnaire and Depression, Anxiety, and Stress scale (DASS-21). RESULTS: Obtained fit statistics from structural equation modelling analysis indicated close fit of the NMI short form with the original model. Multiple regression analyses demonstrated the value of the NMI as a predictor of negative affect independent of spiritual coping. The NMI did not interact with Spiritual Coping, which was independent of negative affect. CONCLUSIONS: The Numinous represents an important aspect of physicians' coping. The constructs can be utilized in training and clinical settings as a valuable and easy-to-use metric for promoting and assessing wellness. The implications of these findings and the value of the NMI were discussed. IMPACT: An understanding of existential drivers can equip one to cope with the stressors of healthcare. The NMI short form has the capability to explore an individual's existential drivers through the understanding of three domains. REPORTING METHOD: Adhered to proper EQUATOR guidelines (GRRAS). PUBLIC CONTRIBUTION: No patient or public contribution.

Validation of a Circulating Tumor DNA-Based Next-Generation Sequencing Assay in a Cohort of Patients with Solid tumors: A Proposed Solution for Decentralized Plasma Testing.

BACKGROUND: Characterization of circulating tumor DNA (ctDNA) has been integrated into clinical practice. Although labs have standardized validation procedures to develop single locus tests, the efficacy of on-site plasma-based next-generation sequencing (NGS) assays still needs to be proved. MATERIALS AND METHODS: In this retrospective study, we profiled DNA from matched tissue and plasma samples from 75 patients with cancer. We applied an NGS test that detects clinically relevant alterations in 33 genes and microsatellite instability (MSI) to analyze plasma cell-free DNA (cfDNA). RESULTS: The concordance between alterations detected in both tissue and plasma samples was higher in patients with metastatic disease. The NGS test detected 77% of sequence alterations, amplifications, and fusions that were found in metastatic samples compared with 45% of those alterations found in the primary tumor samples (p = .00005). There was 87% agreement on MSI status between the NGS test and tumor tissue results. In three patients, MSI-high ctDNA correlated with response to immunotherapy. In addition, the NGS test revealed an FGFR2 amplification that was not detected in tumor tissue from a patient with metastatic gastric cancer, emphasizing the importance of profiling plasma samples in patients with advanced cancer. CONCLUSION: Our validation experience of a plasma-based NGS assay advances current knowledge about translating cfDNA testing into clinical practice and supports the application of plasma assays in the management of oncology patients with metastatic disease. With an in-house method that minimizes the need for invasive procedures, on-site cfDNA testing supplements tissue biopsy to guide precision therapy and is entitled to become a routine practice. IMPLICATIONS FOR PRACTICE: This study proposes a solution for decentralized liquid biopsy testing based on validation of a next-generation sequencing (NGS) test that detects four classes of genomic alterations in blood: sequence mutations (single nucleotide substitutions or insertions and deletions), fusions, amplifications, and microsatellite instability (MSI). Although there are reference labs that perform single-site comprehensive liquid biopsy testing, the targeted assay this study validated can be established locally in any lab with capacity to offer clinical molecular pathology assays. To the authors' knowledge, this is the first report that validates evaluating an on-site plasma-based NGS test that detects the MSI status along with common sequence alterations encountered in solid tumors.

Clean and Contain: Initial Development of a Measure of Infection Prevention Behaviors During the COVID-19 Pandemic.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) offer behavioral guidance to prevent the spread of infectious diseases like COVID-19. Cleaning (e.g., cleaning surfaces, washing and sanitizing hands) and containing (e.g., covering coughs, keeping distance from others, especially sick people) behaviors are recommended. PURPOSE: To develop the Clean and Contain Measure, a brief measure of compliance with CDC recommendations for prevention of infectious disease, and validate the measure in individuals experiencing the COVID-19 pandemic. METHODS: Participants were recruited from Amazon Mechanical Turk and social media. RESULTS: In Study 1 (N = 97), exploratory factor analysis revealed two scales: (a) five items assessing cleaning behaviors and (b) four items assessing containing behaviors. Simple structure was obtained and alpha coefficients for both scales were >.83. In Studies 2 (N = 204) and 3 (N = 527), confirmatory factor analysis verified the identical factor structure found in Study 1. All loadings were statistically significant at p < .001. Alpha coefficients for both scales were >.84 for Studies 2 and 3. CONCLUSIONS: Our measure is a reliable and valid indicator of compliance with cleaning and containing health behaviors that help to prevent the spread of diseases like COVID-19. Future research should replicate construct validity in more diverse samples and continue to refine items, examine construct validity, including predictive and discriminant validity, and improve the measure for future use. With continued use and refinement, this measure could allow health officials and researchers to accurately assess compliance with important infection prevention behavior guidelines.

Co-Assembly of 40S and 60S Ribosomal Proteins in Early Steps of Eukaryotic Ribosome Assembly.

In eukaryotes three of the four ribosomal RNA (rRNA) molecules are transcribed as a long precursor that is processed into mature rRNAs concurrently with the assembly of ribosomal subunits. However, the relative timing of association of ribosomal proteins with the ribosomal precursor particles and the cleavage of the precursor rRNA into the subunit-specific moieties is not known. To address this question, we searched for ribosomal precursors containing components from both subunits. Particles containing specific ribosomal proteins were targeted by inducing synthesis of epitope-tagged ribosomal proteins followed by pull-down with antibodies targeting the tagged protein. By identifying other ribosomal proteins and internal rRNA transcribed spacers (ITS1 and ITS2) in the immuno-purified ribosomal particles, we showed that eS7/S7 and uL4/L4 bind to nascent ribosomes prior to the separation of 40S and 60S specific segments, while uS4/S9, uL22, and eL13/L13 are bound after, or simultaneously with, the separation. Thus, the incorporation of ribosomal proteins from the two subunits begins as a co-assembly with a single rRNA molecule, but is finished as an assembly onto separate precursors for the two subunits.

Using Targeted Sequencing of Paralogous Sequences for Noninvasive Detection of Selected Fetal Aneuploidies.

BACKGROUND: Current methods for noninvasive prenatal testing (NIPT) ascertain fetal aneuploidies using either direct counting measures of DNA fragments from specific genomic regions or relative measures of single nucleotide polymorphism frequencies. Alternatively, the ratios of paralogous sequence pairs were predicted to reflect fetal aneuploidy. We developed a NIPT assay that uses paralog sequences to enable noninvasive detection of fetal trisomy 21 (T21) and trisomy 18 (T18) using cell-free DNA (cfDNA) from maternal plasma. METHODS: A total of 1060 primer pairs were designed to determine fetal aneuploidy status, fetal sex, and fetal fraction. Each library was prepared from cfDNA by coamplifying all 1060 target pairs together in a single reaction well. Products were measured using massively parallel sequencing and deviations from expected paralog ratios were determined based on the read depth from each paralog. RESULTS: We evaluated this assay in a blinded set of 480 cfDNA samples with fetal aneuploidy status determined by the MaterniT21® PLUS assay. Samples were sequenced (mean = 2.3 million reads) with 432 samples returning a result. Using the MaterniT21 PLUS assay for paired plasma aliquots from the same individuals as a reference, all 385 euploid samples, all 31 T21 samples, and 14 of 16 T18 samples were detected with no false positive results observed. CONCLUSIONS: This study introduces a novel NIPT aneuploidy detection approach using targeted sequencing of paralog motifs and establishes proof-of-concept for a potentially low-cost, highly scalable method for the identification of selected fetal aneuploidies with performance and nonreportable rate similar to other published methods.

Men's harassment behavior in online video games: Personality traits and game factors.

Online video games afford co-play and social interaction, often anonymous, among players from around the world. As predicted by the social identity model of deindividuation effects, undesirable behavior is not uncommon in online gaming environments, and online harassment has become a pervasive issue in the gaming community. In this study, we sought to determine what personality traits and game-related variables predicted two types of online aggression in video games: general harassment (e.g., skill-based taunting, insulting others' intelligence) and sexual harassment (e.g., sexist comments, rape threats). Men who play online video games (N = 425) participated in an anonymous online survey. Social dominance orientation and hostile sexism predicted higher levels of both sexual harassment and general harassment in online games. Game involvement and hours of weekly gameplay were additional predictors of general harassment. We discuss implications of online social aggression and online sexual harassment for online gaming. We also apply our findings to the broader understanding of online harassment, cyberaggression, cyberbullying, and other forms of online hostility in computer-mediated communication contexts. Aggr. Behav. 42:513-521, 2016. © 2016 Wiley Periodicals, Inc.

25-Hydroxycholesterol activates the integrated stress response to reprogram transcription and translation in macrophages.

25-Hydroxycholesterol (25OHC) is an enzymatically derived oxidation product of cholesterol that modulates lipid metabolism and immunity. 25OHC is synthesized in response to interferons and exerts broad antiviral activity by as yet poorly characterized mechanisms. To gain further insights into the basis for antiviral activity, we evaluated time-dependent responses of the macrophage lipidome and transcriptome to 25OHC treatment. In addition to altering specific aspects of cholesterol and sphingolipid metabolism, we found that 25OHC activates integrated stress response (ISR) genes and reprograms protein translation. Effects of 25OHC on ISR gene expression were independent of liver X receptors and sterol-response element-binding proteins and instead primarily resulted from activation of the GCN2/eIF2α/ATF4 branch of the ISR pathway. These studies reveal that 25OHC activates the integrated stress response, which may contribute to its antiviral activity.

How social media images of sexualized young women elicit appearance commentary from their peers and reinforce objectification.

Social media platforms like Instagram enable users to share, view, and provide feedback on images, including photographs of oneself (e.g., selfies). In a 3 × 2 between-subjects online experiment, we investigated how women evaluate and react to photographs of their peers on social media and the role that feedback might play in both objectification of others and oneself. U.S. adult young women (N = 256; Mage = 20.06, SDage = 1.57) viewed social media images of sexualized peers, non-sexualized peers, or landscapes (control). Then, they provided feedback on the images via social media hashtags (#) or not (tagging vs. no tagging). Results revealed that participants who viewed sexualized peers demonstrated the highest levels of state self-objectification and were more likely to dehumanize the women in the photos. Hashtags generated by participants indicated that those who viewed sexualized peers engaged in greater appearance-related objectification, specifically related to body parts, and sexual objectification than those who viewed non-sexualized peers. In addition, generating hashtags that specifically focused on body parts heightened viewers' state self-objectification. These findings illustrate the complexities of social media content production and consumption, particularly for young women.

Characterization of Dnajc12 knockout mice, a model of hypodopaminergia.

Homozygous DNAJC12 c.79-2A>G (p. V27Wfs*14) loss-of-function mutations were first reported as a cause of young-onset Parkinson's disease. However, bi-allelic autosomal recessive pathogenic variants in DNAJC12 may lead to an alternative constellation of neurological features including infantile dystonia, developmental delay, intellectual disability and neuropsychiatric disorders. DNAJC12 is understood to co-chaperone aromatic amino acid hydroxylases to enhance the synthesis of biogenic amines. In vitro , we confirm overexpressed DNAJC12 forms a complex with tyrosine hydroxylase, the rate-limiting enzyme in dopamine (DA) synthesis. Now we describe a conditional knockout mouse (cDKO) in which loxP sites flanking Dnajc12 exon 2 enable its excision by cre-recombinase to create a constitutive Dnajc12 knock out (DKO). At three months of age, DKO animals exhibit reduced locomotion and exploratory behavior in automated open-field testing. DKO mice also manifest increased plasma phenylalanine levels, a cardinal feature of patients with DNAJC12 pathogenic variants. In striatal tissue, total DA and serotonin, and their metabolites, are reduced. Biochemical alterations in synaptic proteins and tyrosine hydroxylase are also apparent, with enhanced phosphorylation of pSer31 and pSer40 sites that may reflect biological compensation. Electrically-evoked striatal DA is reduced. Most immediately, cDKO and DKO mice present models to develop and refined therapeutic approaches for the treatment of DNAJC12 dystonia and parkinsonism. These models may also enable the pleiotropic functions of biogenic amines (including DA) to be individually investigated in the brain and periphery.

Enhancing training in spiritual and religious competencies in mental health graduate education: Evaluation of an integrated curricular approach.

Despite practice guidelines for multiculturally competent care, including spiritual/religious diversity, most mental health graduate training programs do not formally address spiritual/religious competencies. Thus, we enhanced the Spiritual Competency Training in Mental Health (SCT-MH) course curriculum to train graduate students in foundational attitudes, knowledge, and skills for addressing clients' spirituality and/or religion (S/R). The hybrid (online and in-person) SCT-MH course curriculum was integrated into existing required graduate clinical courses (replacing 15% of a course's curriculum) and taught to 309 students by 20 instructors in 20 different graduate training programs across counseling, psychology, and social work disciplines. Using a multiple baseline waitlist control design in which students served as their own controls, students completed validated assessments at three timepoints evaluating their spiritual/religious competencies for understanding the intersection between S/R and mental health. We also collected qualitative data from the students to evaluate acceptability of the content and format of the training program. Students' scores on all seven measures of spiritual/religious competencies had a statistically significant positive increase after engaging with the SCT-MH curriculum compared to the control period. At the end of the course, 97% of the students envisioned using spiritually integrated therapy techniques with their clients at least some of the time, 92% or more rated the materials as helpful and relevant, and 96% were satisfied with the training modules. Results demonstrate that dedicating a small (i.e., 6 hours of class time; 10 hours outside class time) but intentional amount of course time to teaching spiritual/religious competencies increases students' attitudes, knowledge, and skills for attending to clients' S/R in clinical practice. The SCT-MH hybrid course content is freely available to all graduate programs on our website. https://www.spiritualandreligiouscompetenciesproject.com/resources/sct-mh.

A pathogenic variant in RAB32 causes autosomal dominant Parkinson's disease and activates LRRK2 kinase.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD. Methods: Affected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed. Findings: We found RAB32 c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. RAB32 Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, RAB32 Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase. Interpretation: Our study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD. Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses.

BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. METHODS: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. FINDINGS: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. INTERPRETATION: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. FUNDING: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

Enhancing competencies for the ethical integration of religion and spirituality in psychological services.

Advancement of Spiritual and religious competencies aligns with increasing attention to the pivotal role of multiculturalism and intersectionality, as well as shifts in organizational values and strategies, that shape the delivery of psychological services (e.g., evidence-based practice). A growing evidence base also attests to ethical integration of peoples' religious faith and/or spirituality (R/S) in their mental care as enhancing the utilization and efficacy of psychological services. When considering the essential attitudes, knowledge, and skills for addressing religious and spiritual aspects of clients' lives, lack of R/S competencies among psychologists and other mental health professionals impedes ethical and effective practice. The purpose of this article is to discuss the following: (a) skills for negotiating ethical challenges with spiritually integrated care; and (b) strategies for assessing a client's R/S. We also describe systemic barriers to ethical integration of R/S in mental health professions and briefly introduce our Spiritual and Religious Competencies project. Looking ahead, a strategic, interdisciplinary, and comprehensive approach is needed to transform the practice of mental health care in a manner that more fully aligns with the values, principles, and expectations across our disciplines' professional ethical codes and accreditation standards. We propose that explicit training across mental health professions is necessary to more fully honor R/S diversity and the importance of this layer of identity and intersectionality in many peoples' lives. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Crucial neuroprotective roles of the metabolite BH4 in dopaminergic neurons.

Dopa-responsive dystonia (DRD) and Parkinson's disease (PD) are movement disorders caused by the dysfunction of nigrostriatal dopaminergic neurons. Identifying druggable pathways and biomarkers for guiding therapies is crucial due to the debilitating nature of these disorders. Recent genetic studies have identified variants of GTP cyclohydrolase-1 (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis, as causative for these movement disorders. Here, we show that genetic and pharmacological inhibition of BH4 synthesis in mice and human midbrain-like organoids accurately recapitulates motor, behavioral and biochemical characteristics of these human diseases, with severity of the phenotype correlating with extent of BH4 deficiency. We also show that BH4 deficiency increases sensitivities to several PD-related stressors in mice and PD human cells, resulting in worse behavioral and physiological outcomes. Conversely, genetic and pharmacological augmentation of BH4 protects mice from genetically- and chemically induced PD-related stressors. Importantly, increasing BH4 levels also protects primary cells from PD-affected individuals and human midbrain-like organoids (hMLOs) from these stressors. Mechanistically, BH4 not only serves as an essential cofactor for dopamine synthesis, but also independently regulates tyrosine hydroxylase levels, protects against ferroptosis, scavenges mitochondrial ROS, maintains neuronal excitability and promotes mitochondrial ATP production, thereby enhancing mitochondrial fitness and cellular respiration in multiple preclinical PD animal models, human dopaminergic midbrain-like organoids and primary cells from PD-affected individuals. Our findings pinpoint the BH4 pathway as a key metabolic program at the intersection of multiple protective mechanisms for the health and function of midbrain dopaminergic neurons, identifying it as a potential therapeutic target for PD.

Tumor-immune microenvironment revealed by Imaging Mass Cytometry in a metastatic sarcomatoid urothelial carcinoma with a prolonged response to pembrolizumab.

Sarcomatoid urothelial carcinoma (SUC) is a rare subtype of urothelial carcinoma (UC) that typically presents at an advanced stage compared to more common variants of UC. Locally advanced and metastatic UC have a poor long-term survival following progression on first-line platinum-based chemotherapy. Antibodies directed against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1) are now approved to be used in these scenarios. The need for reliable biomarkers for treatment stratification is still under research. Here, we present a novel case report of the first Imaging Mass Cytometry (IMC) analysis done in SUC to investigate the immune cell repertoire and PD-L1 expression in a patient who presented with metastatic SUC and experienced a prolonged response to the anti-PD1 immune checkpoint inhibitor pembrolizumab after progression on first-line chemotherapy. This case report provides an important platform for translating these findings to a larger cohort of UC and UC variants.

Focal p53 protein expression and lymphovascular invasion in primary prostate tumors predict metastatic progression.

TP53 is one of the most frequently altered genes in prostate cancer. The precise assessment of its focal alterations in primary tumors by immunohistochemistry (IHC) has significantly enhanced its prognosis. p53 protein expression and lymphovascular invasion (LVI) were evaluated for predicting metastatic progression by IHC staining of representative whole-mounted prostate sections from a cohort of 189 radical prostatectomy patients with up to 20 years of clinical follow-up. Kaplan-Meier survival curves were used to examine time to distant metastasis (DM) as a function of p53 expression and LVI status. TP53 targeted sequencing was performed in ten tumors with the highest expression of p53 staining. Nearly half (49.8%) of prostate tumors examined showed focal p53 expression while 26.6% showed evidence of LVI. p53(+) tumors had higher pathologic T stage, Grade Group, Nuclear Grade, and more frequent LVI. p53 expression of > 5% and LVI, individually and jointly, are associated with poorer DM-free survival. TP53 mutations were detected in seven of ten tumors sequenced. Four tumors with the highest p53 expression harbored likely pathogenic or pathogenic mutations. High levels of p53 expression suggest the likelihood of pathogenic TP53 alterations and, together with LVI status, could enhance early prognostication of prostate cancer progression.

Relationship Development with Humanoid Social Robots: Applying Interpersonal Theories to Human-Robot Interaction.

Humanoid social robots (HSRs) are human-made technologies that can take physical or digital form, resemble people in form or behavior to some degree, and are designed to interact with people. A common assumption is that social robots can and should mimic humans, such that human-robot interaction (HRI) closely resembles human-human (i.e., interpersonal) interaction. Research is often framed from the assumption that rules and theories that apply to interpersonal interaction should apply to HRI (e.g., the computers are social actors framework). Here, we challenge these assumptions and consider more deeply the relevance and applicability of our knowledge about personal relationships to relationships with social robots. First, we describe the typical characteristics of HSRs available to consumers currently, elaborating characteristics relevant to understanding social interactions with robots such as form anthropomorphism and behavioral anthropomorphism. We also consider common social affordances of modern HSRs (persistence, personalization, responsiveness, contingency, and conversational control) and how these align with human capacities and expectations. Next, we present predominant interpersonal theories whose primary claims are foundational to our understanding of human relationship development (social exchange theories, including resource theory, interdependence theory, equity theory, and social penetration theory). We consider whether interpersonal theories are viable frameworks for studying HRI and human-robot relationships given their theoretical assumptions and claims. We conclude by providing suggestions for researchers and designers, including alternatives to equating human-robot relationships to human-human relationships.

Effects of taking selfies on women's self-objectification, mood, self-esteem, and social aggression toward female peers.

This study investigated the effects of taking photos (of the self or objects) on women. Objectification theory states that women are subjected to societal pressure to focus on their physical appearance. The emergence of social media as a communication channel has further reinforced the emphasis on women's appearance, beauty ideals, and body image. On social media, selfies serve as a self-presentation of one's appearance to an online audience. In this 2 × 2 experiment, women (N = 120, Mage = 19.87) took pictures of themselves (i.e., selfies) or objects. They were told beforehand that these pictures would be kept private or that they would be posted online on social media. After taking pictures, we assessed women's self-objectification, mood, and self-esteem. Women then engaged in a photo tagging task in which they selected hashtags for selfies of other women. Selfie takers expressed higher self-objectification, more negative mood, and diminished self-esteem compared to those taking pictures of objects. Selfie takers also demonstrated comparatively less social aggression, using fewer derogatory tags on other women's pictures. Although taking selfies may negatively affect producers, there may be benefits for online social interaction with peers.