A Multi-Omic Mosaic Model of Acetaminophen Induced Alanine Aminotransferase Elevation.

BACKGROUND: Acetaminophen (APAP) is the most common cause liver injury following alcohol in US patients. Predicting liver injury and subsequent hepatic regeneration in patients taking therapeutic doses of APAP may be possible using new 'omic methods such as metabolomics and genomics. Multi'omic techniques increase our ability to find new mechanisms of injury and regeneration. METHODS: We used metabolomic and genomic data from a randomized controlled trial of patients administered 4 g of APAP per day for 14 days or longer with blood samples obtained at 0 (baseline), 4, 7, 10, 13 and 16 days. We used the highest ALT as the clinical outcome to be predicted in our integrated analysis. We used penalized regression to model the relationship between genetic variants and day 0 metabolite level, and then performed a metabolite-wide colocalization scan to associate the genetically regulated component of metabolite expression with ALT elevation. Genome-wide association study (GWAS) analyses were conducted for ALT elevation and metabolite level using linear regression, with age, sex, and the first five principal components included as covariates. Colocalization was tested via a weighted sum test. RESULTS: Out of the 164 metabolites modeled, 120 met the criteria for predictive accuracy and were retained for genetic analyses. After genomic examination, eight metabolites were found to be under genetic control and predictive of ALT elevation due to therapeutic acetaminophen. The metabolites were: 3-oxalomalate, allantoate, diphosphate, L-carnitine, L-proline, maltose, and ornithine. These genes are important in the tricarboxylic acid cycle (TCA), urea breakdown pathway, glutathione production, mitochondrial energy production, and maltose metabolism. CONCLUSIONS: This multi'omic approach can be used to integrate metabolomic and genomic data allowing identification of genes that control downstream metabolites. These findings confirm prior work that have identified mitochondrial energy production as critical to APAP induced liver injury and have confirmed our prior work that demonstrate the importance of the urea cycle in therapeutic APAP liver injury.

Validity of a Revised Obsessive-Compulsive Personality Disorder (OCPD) Trait Profile and Its Relationship with Social Interaction Anxiety and Coping.

There is evidence suggesting that the conceptualization and operationalization of Obsessive-Compulsive Personality Disorder (OCPD) is not satisfactory (Watters et al., 2019). In this study, we used an online sample (N = 1008) to investigate the construct validity of the PID-5 OCPD trait measure. Regression analyses supported our hypothesis that rigid perfectionism captured the core phenomenology of OCPD whereas restricted affectivity and intimacy avoidance were not conceptually related to the OCPD construct. Based on the biosocial theory for overcontrol (Lynch, 2018), we introduced anxiousness and workaholism to the PID-5 OCPD trait profile. In establishing the validity of the revised OCPD trait profile, we investigated, for the first time, the role of social interaction anxiety and maladaptive coping in OCPD. Our revised OCPD profile showed good validity and was characterized by marked social interaction anxiety and dysfunctional coping mechanisms. The findings may lead to a new conceptualization of OCPD which prioritizes deficits in social interaction and coping. We identify areas that need to be prioritized in the evaluation of OCPD by mental health professionals and offer avenues for new clinical research in the field.

Incidental Detection of Classical Galactosemia through Newborn Screening for Phenylketonuria: A 10-Year Retrospective Audit to Determine the Efficacy of This Approach.

In the UK, Classical Galactosaemia (CG) is identified incidentally from the Newborn Screening (NBS) for phenylketonuria (PKU) using an "Other disorder suspected" (ODS) pathway when phenylalanine (Phe) and tyrosine (Tyr) concentrations are increased. We aimed to determine the efficacy of CG detection via NBS and estimate the incidence of CG in live births in the UK. A survey was sent to all UK NBS laboratories to collate CG cases diagnosed in the UK from 2010 to 2020. Cases of CG diagnosed were determined if detected clinically, NBS, or by family screening, as well as age at diagnosis. Cases referred via the ODS pathway were also collated, including the final diagnosis made. Responses were obtained from 13/16 laboratories. Between 2010 and 2020, a total of 6,642,787 babies were screened, and 172 cases of CG were identified. It should be noted that 85/172 presented clinically, 52/172 were identified by NBS, and 17/172 came from family screening. A total of 117 referrals were made via the ODS pathway, and 45/117 were subsequently diagnosed with CG. Median (interquartile range) age at diagnosis by NBS and clinically was 8 days (7-11) and 10 days (7-16), respectively (Mann-Whitney U test, U = 836.5, p-value = 0.082). The incidence of CG is 1:38,621 live births. The incidence of CG in the UK is comparable with that of other European/western countries. No statistical difference was seen in the timing of diagnosis between NBS and clinical presentation based on the current practice of sampling on day 5. Bringing forward the day of NBS sampling to day 3 would increase the proportion diagnosed with CG by NBS from 52/172 (30.2%) to 66/172 (38.4%).

Non-canonical EphA2 activation underpins PTEN-mediated metastatic migration and poor clinical outcome in prostate cancer.

BACKGROUND: The key process of mesenchymal to amoeboid transition (MAT), which enables prostate cancer (PCa) transendothelial migration and subsequent development of metastases in red bone marrow stroma, is driven by phosphorylation of EphA2S897 by pAkt, which is induced by the omega-6 polyunsaturated fatty acid arachidonic acid. Here we investigate the influence of EphA2 signalling in PCa progression and long-term survival. METHODS: The mechanisms underpinning metastatic biopotential of altered EphA2 signalling in relation to PTEN status were assessed in vitro using canonical (EphA2D739N) and non-canonical (EphA2S897G) PC3-M mutants, interrogation of publicly available PTEN-stratified databases and clinical validation using a PCa TMA (n = 177) with long-term follow-up data. Spatial heterogeneity of EphA2 was assessed using a radical prostatectomy cohort (n = 67). RESULTS: Non-canonical EphA2 signalling via pEphA2S897 is required for PCa transendothelial invasion of bone marrow endothelium. High expression of EphA2 or pEphA2S897 in a PTENlow background is associated with poor overall survival. Expression of EphA2, pEphA2S897 and the associated MAT marker pMLC2 are spatially regulated with the highest levels found within lesion areas within 500 µm of the prostate margin. CONCLUSION: EphA2 MAT-related signalling confers transendothelial invasion. This is associated with a substantially worse prognosis in PTEN-deficient PCa.

Automated quantitative high-throughput multiplex immunofluorescence pipeline to evaluate OXPHOS defects in formalin-fixed human prostate tissue.

Advances in multiplex immunofluorescence (mIF) and digital image analysis has enabled simultaneous assessment of protein defects in electron transport chain components. However, current manual methodology is time consuming and labour intensive. Therefore, we developed an automated high-throughput mIF workflow for quantitative single-cell level assessment of formalin fixed paraffin embedded tissue (FFPE), leveraging tyramide signal amplification on a Ventana Ultra platform coupled with automated multispectral imaging on a Vectra 3 platform. Utilising this protocol, we assessed the mitochondrial oxidative phosphorylation (OXPHOS) protein alterations in a cohort of benign and malignant prostate samples. Mitochondrial OXPHOS plays a critical role in cell metabolism, and OXPHOS perturbation is implicated in carcinogenesis. Marked inter-patient, intra-patient and spatial cellular heterogeneity in OXPHOS protein abundance was observed. We noted frequent Complex IV loss in benign prostate tissue and Complex I loss in age matched prostate cancer tissues. Malignant regions within prostate cancer samples more frequently contained cells with low Complex I & IV and high mitochondrial mass in comparison to benign-adjacent regions. This methodology can now be applied more widely to study the frequency and distribution of OXPHOS alterations in formalin-fixed tissues, and their impact on long-term clinical outcomes.

Narcissism and conspicuous consumption.

Narcissists are prone to conspicuous consumption, that is, preference for luxury over mundane products. We analyze four reasons for their conspicuous consumption: positive distinctiveness (individuation and status), meaning in life, materialism, and sexual signaling. Empirical support for these reasons ranges from good to preliminary. We then discuss directions that this nascent literature could take. These include a consideration of different forms of narcissism (grandiose vs. vulnerable, agentic vs. communal, admirative vs. rivalrous), the value of experimentation in clarifying the causal flow from narcisissm to conspicuous consumption and also from conspicuous consumption to state narcissism, as well as the (mostly negative) consequences of conspicuous consumptions for narcisissm and society.

Development of an Offline-Friend Addiction Questionnaire (O-FAQ): Are most people really social addicts?

A growing number of self-report measures aim to define interactions with social media in a pathological behavior framework, often using terminology focused on identifying those who are 'addicted' to engaging with others online. Specifically, measures of 'social media addiction' focus on motivations for online social information seeking, which could relate to motivations for offline social information seeking. However, it could be the case that these same measures could reveal a pattern of friend addiction in general. This study develops the Offline-Friend Addiction Questionnaire (O-FAQ) by re-wording items from highly cited pathological social media use scales to reflect "spending time with friends". Our methodology for validation follows the current literature precedent in the development of social media 'addiction' scales. The O-FAQ had a three-factor solution in an exploratory sample of N = 807 and these factors were stable in a 4-week retest (r = .72 to .86) and was validated against personality traits, and risk-taking behavior, in conceptually plausible directions. Using the same polythetic classification techniques as pathological social media use studies, we were able to classify 69% of our sample as addicted to spending time with their friends. The discussion of our satirical research is a critical reflection on the role of measurement and human sociality in social media research. We question the extent to which connecting with others can be considered an 'addiction' and discuss issues concerning the validation of new 'addiction' measures without relevant medical constructs. Readers should approach our measure with a level of skepticism that should be afforded to current social media addiction measures.

Microenvironmental IL1ß promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling.

Dissemination of tumour cells to the bone marrow is an early event in breast cancer, however cells may lie dormant for many years before bone metastases develop. Treatment for bone metastases is not curative, therefore new adjuvant therapies which prevent the colonisation of disseminated cells into metastatic lesions are required. There is evidence that cancer stem cells (CSCs) within breast tumours are capable of metastasis, but the mechanism by which these colonise bone is unknown. Here, we establish that bone marrow-derived IL1ß stimulates breast cancer cell colonisation in the bone by inducing intracellular NFkB and CREB signalling in breast cancer cells, leading to autocrine Wnt signalling and CSC colony formation. Importantly, we show that inhibition of this pathway prevents both CSC colony formation in the bone environment, and bone metastasis. These findings establish that targeting IL1ß-NFKB/CREB-Wnt signalling should be considered for adjuvant therapy to prevent breast cancer bone metastasis.

Primary Mutational Landscape Linked with Pre-Docetaxel Lactate Dehydrogenase Levels Predicts Docetaxel Response in Metastatic Castrate-Resistant Prostate Cancer.

BACKGROUND: Docetaxel chemotherapy is a standard of care for metastatic castrate-resistant prostate cancer (mCRPC): 40-50% of patients achieve a biochemical response. However, there is a lack of response predictive biomarkers. OBJECTIVE: To assess lactate dehydrogenase (LDH) as a docetaxel response biomarker in mCRPC and to examine the association of LDH with genomic alterations in primary diagnostic biopsies. DESIGN, SETTING, AND PARTICIPANTS: Clinical and associated primary tumour-targeted next-generation sequencing data from matched training (n=150) and test (n=120) cohorts of progressive mCRPC patients receiving docetaxel therapy were analysed. Data were correlated with large-scale prostate cancer genomic datasets. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate-specific antigen (PSA) response, radiographic response, biochemical progression-free survival (PFS), overall survival (OS), genomic analysis of primary biopsies, and genomic datasets (Memorial Sloan Kettering Cancer Center [MSKCC] and SU2C/PCF). RESULTS AND LIMITATIONS: Serum LDH ≥450U/l is a reliable prognostic biomarker (area under the curve: 0.757 [standard deviation 0.054, 95% confidence interval [CI] 0.650-0.864, p<0.001]) in progressive mCRPC, predicting PFS at 3 mo. Patients with LDH ≥450U/l were poorer PSA responders, with shorter PFS (213 vs 372 d, hazard ratio [HR] 1.876, 95% CI 1.289-2.7300) and OS (362 vs 563 d, HR 1.630, 95% CI 1.127-2.357). High LDH is an independent surrogate marker for survival following docetaxel and predicts a poor radiological response (p=0.043). Of the 14 patients with LDH ≥450U/l available for next-generation sequencing, nine (64.3%) were more likely to have DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2, Fanconi anaemia gene) in their primary biopsy. Cross correlation with MSKCC and SU2C/PCF databases revealed a positive correlation between LDHA, PARP1 (r=0.667, p<0.01), and other DNA repair genes. CONCLUSIONS: Genomic abnormalities of LDHA and DNA repair in primary biopsies link to high pretreatment LDH and poor response to docetaxel in mCRPC. PATIENT SUMMARY: The presence of mutations of the lactate dehydrogenase and DNA repair pathways are associated with aggressive prostate cancer and poor response to chemotherapy later in the disease.

Lipid degradation promotes prostate cancer cell survival.

Prostate cancer is the most common male cancer and androgen receptor (AR) is the major driver of the disease. Here we show that Enoyl-CoA delta isomerase 2 (ECI2) is a novel AR-target that promotes prostate cancer cell survival. Increased ECI2 expression predicts mortality in prostate cancer patients (p = 0.0086). ECI2 encodes for an enzyme involved in lipid metabolism, and we use multiple metabolite profiling platforms and RNA-seq to show that inhibition of ECI2 expression leads to decreased glucose utilization, accumulation of fatty acids and down-regulation of cell cycle related genes. In normal cells, decrease in fatty acid degradation is compensated by increased consumption of glucose, and here we demonstrate that prostate cancer cells are not able to respond to decreased fatty acid degradation. Instead, prostate cancer cells activate incomplete autophagy, which is followed by activation of the cell death response. Finally, we identified a clinically approved compound, perhexiline, which inhibits fatty acid degradation, and replicates the major findings for ECI2 knockdown. This work shows that prostate cancer cells require lipid degradation for survival and identifies a small molecule inhibitor with therapeutic potential.

Holding Back the Tears: Individual Differences in Adult Crying Proneness Reflect Attachment Orientation and Attitudes to Crying.

Despite being a universal human attachment behavior, little is known about individual differences in crying. To facilitate such examination we first recommend shortened versions of the attitudes and proneness sections of the Adult Crying Inventory using two independent samples. Importantly, we examine attachment orientation differences in crying proneness and test the mediating role of attitudes toward crying in this relationship. Participants (Sample 1 N = 623, Sample 2 N = 781), completed online measures of adult attachment dimensions (avoidance and anxiety), attitudes toward crying, and crying proneness. Exploratory factor analyses in Sample 1 revealed four factors for crying attitudes: crying helps one feel better; crying is healthy; hatred of crying; and crying is controllable; and three factors for crying proneness: threat to self; sadness; and joy. Confirmatory factor analyses in Sample 2 replicated these structures. Theoretically and statistically justified short forms of each scale were created. Multiple mediation analyses revealed similar patterns of results across the two samples, with the attitudes "crying is healthy" and "crying is controllable" consistently mediating the positive links between attachment anxiety and crying proneness, and the negative links between attachment avoidance and crying proneness. Results are discussed in relation to attachment and emotion regulation literature.

Stroma-induced Jagged1 expression drives PC3 prostate cancer cell migration; disparate effects of RIP-generated proteolytic fragments on cell behaviour and Notch signaling.

The Notch ligand Jagged1 is subject to regulated intramembrane proteolysis (RIP) which yields a soluble ectodomain (sJag) and a soluble Jagged1 intracellular domain (JICD). The full-length Jagged1 protein enhances prostate cancer (PCa) cell proliferation and is highly expressed in metastatic cells. However, little is known regarding the mechanisms by which Jagged1 or its RIP-generated fragments might promote PCa bone metastasis. In the current study we show that bone marrow stroma (BMS) induces Jagged1 expression in bone metastatic prostate cancer PC3 cells and that this enhanced expression is mechanistically linked to the promotion of cell migration. We also show that RIP-generated Jagged1 fragments exert disparate effects on PC3 cell behaviour and Notch signaling. In conclusion, the expression of both the full-length ligand and its RIP-generated fragments must be considered in tandem when attempting to regulate Jagged1 as a possible PCa therapy.

Accountability Accentuates Interindividual-Intergroup Discontinuity by Enforcing Parochialism.

Interindividual-intergroup discontinuity is the tendency for relations between groups to be more competitive than relations between individuals. We examined whether the discontinuity effect arises in part because group members experience normative pressure to favor the ingroup (parochialism). Building on the notion that accountability enhances normative pressure, we hypothesized that the discontinuity effect would be larger when accountability is present (compared to absent). A prisoner's dilemma game experiment supported this prediction. Specifically, intergroup (compared to interindividual) interaction activated an injunctive ingroup-favoring norm, and accountability enhanced the influence of this norm on competitive behavior.

Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations.

Thiamine pyrophosphokinase (TPK) produces thiamine pyrophosphate, a cofactor for a number of enzymes, including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. Episodic encephalopathy type thiamine metabolism dysfunction (OMIM 614458) due to TPK1 mutations is a recently described rare disorder. The mechanism of the disease, its phenotype and treatment are not entirely clear. We present two patients with novel homozygous TPK1 mutations (Patient 1 with p.Ser160Leu and Patient 2 with p.Asp222His). Unlike the previously described phenotype, Patient 2 presented with a Leigh syndrome like non-episodic early-onset global developmental delay, thus extending the phenotypic spectrum of the disorder. We, therefore, propose that TPK deficiency may be a better name for the condition. The two cases help to further refine the neuroradiological features of TPK deficiency and show that MRI changes can be either fleeting or progressive and can affect either white or gray matter. We also show that in some cases lactic acidosis can be absent and 2-ketoglutaric aciduria may be the only biochemical marker. Furthermore, we have established the assays for TPK enzyme activity measurement and thiamine pyrophosphate quantification in frozen muscle and blood. These tests will help to diagnose or confirm the diagnosis of TPK deficiency in a clinical setting. Early thiamine supplementation prevented encephalopathic episodes and improved developmental progression of Patient 1, emphasizing the importance of early diagnosis and treatment of TPK deficiency. We present evidence suggesting that thiamine supplementation may rescue TPK enzyme activity. Lastly, in silico protein structural analysis shows that the p.Ser160Leu mutation is predicted to interfere with TPK dimerization, which may be a novel mechanism for the disease.

Moving Narcissus: Can Narcissists Be Empathic?

Empathy plays a critical role in fostering and maintaining social relations. Narcissists lack empathy, and this may account for their interpersonal failures. But why do narcissists lack empathy? Are they incapable, or is change possible? Three studies addressed this question. Study 1 showed that the link between narcissism and low empathy generalizes to a specific target person presented in a vignette. The effect was driven by maladaptive narcissistic components (i.e., entitlement, exploitativeness, exhibitionism). Study 2 examined the effect of perspective-taking (vs. control) instructions on self-reported responses to a video. Study 3 examined the effect of the same manipulation on autonomic arousal (heart rate [HR]) during an audio-recording. Perspective-taking ameliorated negative links between maladaptive narcissism and both self-reported empathy and HR. That is, narcissists can be moved by another's suffering, if they take that person's perspective. The findings demonstrate that narcissists' low empathy does not reflect inability, implying potential for intervention.

Narcissism and consumer behaviour: a review and preliminary findings.

We review the literature on the relation between narcissism and consumer behavior. Consumer behavior is sometimes guided by self-related motives (e.g., self-enhancement) rather than by rational economic considerations. Narcissism is a case in point. This personality trait reflects a self-centered, self-aggrandizing, dominant, and manipulative orientation. Narcissists are characterized by exhibitionism and vanity, and they see themselves as superior and entitled. To validate their grandiose self-image, narcissists purchase high-prestige products (i.e., luxurious, exclusive, flashy), show greater interest in the symbolic than utilitarian value of products, and distinguish themselves positively from others via their materialistic possessions. Our review lays the foundation for a novel methodological approach in which we explore how narcissism influences eye movement behavior during consumer decision-making. We conclude with a description of our experimental paradigm and report preliminary results. Our findings will provide insight into the mechanisms underlying narcissists' conspicuous purchases. They will also likely have implications for theories of personality, consumer behavior, marketing, advertising, and visual cognition.

Copper modulates zinc metalloproteinase-dependent ectodomain shedding of key signaling and adhesion proteins and promotes the invasion of prostate cancer epithelial cells.

A disintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs) are zinc metalloproteinases (ZMPs) that catalyze the "ectodomain shedding" of a range of cell surface proteins including signaling and adhesion molecules. These "sheddases" are associated with the invasion and metastasis of a range of cancers. Increased serum and tumor tissue levels of copper are also observed in several cancers, although little is known about how the metal might promote disease progression at the molecular level. In the current study, we investigated whether copper might regulate the ectodomain shedding of two key cell surface proteins implicated in the invasion and metastasis of prostate cancer, the Notch ligand Jagged1 and the adhesion molecule E-cadherin, and whether the metal was able to influence the invasion of the prostate cancer epithelial cell line PC3. Physiological copper concentrations stimulated the ZMP-mediated proteolysis of Jagged1 and E-cadherin in cell culture models, whereas other divalent metals had no effect. Copper-mediated Jagged1 proteolysis was also observed following the pretreatment of cells with cycloheximide and in a cell-free membrane system, indicating a posttranslational mechanism of sheddase activation. Finally, the concentrations of copper that stimulated ZMP-mediated protein shedding also enhanced PC3 invasion; an effect that could be negated using a sheddase inhibitor or copper chelators. Collectively, these data implicate copper as an important factor in promoting prostate cancer cell invasion and indicate that the selective posttranslational activation of ZMP-mediated protein shedding might play a role in this process.

The past makes the present meaningful: nostalgia as an existential resource.

The present research tested the proposition that nostalgia serves an existential function by bolstering a sense of meaning in life. Study 1 found that nostalgia was positively associated with a sense of meaning in life. Study 2 experimentally demonstrated that nostalgia increases a sense of meaning in life. In both studies, the link between nostalgia and increased meaning in life was mediated by feelings of social connectedness. Study 3 evidenced that threatened meaning increases nostalgia. Study 4 illustrated that nostalgia, in turn, reduces defensiveness following a meaning threat. Finally, Studies 5 and 6 showed that nostalgia disrupts the link between meaning deficits and compromised psychological well-being. Collectively, these findings indicate that the provision of existential meaning is a pivotal function of nostalgia.

Motivated expectations of positive feedback in social interactions.

People self-enhance in a variety of ways. For example, they generally expect to perform better than others, to be in control of events, and to have a brighter future. Might they also self-enhance by expecting to receive positive feedback in social interactions? Across five studies, we found that they did. People's desire for feedback correlated with how positive they expected it to be (Study 1), and their feedback expectations were more positive for themselves than for others (Study 2). People's positive feedback expectations also covaried with trait tendencies to self-enhance (i.e., self-esteem and narcissism; Study 3) and with a direct situational manipulation of self-enhancement motivation (Study 4). Finally, people expected to receive positive feedback but did not consistently expect to receive self-verifying feedback (Study 5). These findings are consistent with social expectations being driven in part by the self-enhancement motive.