Applicability of Chronic Multiple Linear Regression Models for Predicting Zinc Toxicity in Australian and New Zealand Freshwaters.

Bioavailability models, for example, multiple linear regressions (MLRs) of water quality parameters, are increasingly being used to develop bioavailability-based water quality criteria for metals. However, models developed for the Northern Hemisphere cannot be adopted for Australia and New Zealand without first validating them against local species and local water chemistry characteristics. We investigated the applicability of zinc chronic bioavailability models to predict toxicity in a range of uncontaminated natural waters in Australia and New Zealand. Water chemistry data were compiled to guide a selection of waters with different zinc toxicity-modifying factors. Predicted toxicities using several bioavailability models were compared with observed chronic toxicities for the green alga Raphidocelis subcapitata and the native cladocerans Ceriodaphnia cf. dubia and Daphnia thomsoni. The most sensitive species to zinc in five New Zealand freshwaters was R. subcapitata (72-h growth rate), with toxicity ameliorated by high dissolved organic carbon (DOC) or low pH, and hardness having a minimal influence. Zinc toxicity to D. thomsoni (reproduction) was ameliorated by both high DOC and hardness in these same waters. No single trophic level-specific effect concentration, 10% (EC10) MLR was the best predictor of chronic toxicity to the cladocerans, and MLRs based on EC10 values both over- and under-predicted zinc toxicity. The EC50 MLRs better predicted toxicities to both the Australian and New Zealand cladocerans to within a factor of 2 of the observed toxicities in most waters. These findings suggest that existing MLRs may be useful for normalizing local ecotoxicity data to derive water quality criteria for Australia and New Zealand. The final choice of models will depend on their predictive ability, level of protection, and ease of use. Environ Toxicol Chem 2023;42:2614-2629. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency.

Malonyl-CoA-acyl carrier protein transacylase (MCAT) is an enzyme involved in mitochondrial fatty acid synthesis (mtFAS) and catalyzes the transfer of the malonyl moiety of malonyl-CoA to the mitochondrial acyl carrier protein (ACP). Previously, we showed that loss-of-function of mtFAS genes, including Mcat, is associated with severe loss of electron transport chain (ETC) complexes in mouse immortalized skeletal myoblasts (Nowinski et al., 2020). Here, we report a proband presenting with hypotonia, failure to thrive, nystagmus, and abnormal brain MRI findings. Using whole exome sequencing, we identified biallelic variants in MCAT. Protein levels for NDUFB8 and COXII, subunits of complex I and IV respectively, were markedly reduced in lymphoblasts and fibroblasts, as well as SDHB for complex II in fibroblasts. ETC enzyme activities were decreased in parallel. Re-expression of wild-type MCAT rescued the phenotype in patient fibroblasts. This is the first report of a patient with MCAT pathogenic variants and combined oxidative phosphorylation deficiency.

Leveraging transcriptomics for precision diagnosis: Lessons learned from cancer and sepsis.

Diagnostics require precision and predictive ability to be clinically useful. Integration of multi-omic with clinical data is crucial to our understanding of disease pathogenesis and diagnosis. However, interpretation of overwhelming amounts of information at the individual level requires sophisticated computational tools for extraction of clinically meaningful outputs. Moreover, evolution of technical and analytical methods often outpaces standardisation strategies. RNA is the most dynamic component of all -omics technologies carrying an abundance of regulatory information that is least harnessed for use in clinical diagnostics. Gene expression-based tests capture genetic and non-genetic heterogeneity and have been implemented in certain diseases. For example patients with early breast cancer are spared toxic unnecessary treatments with scores based on the expression of a set of genes (e.g., Oncotype DX). The ability of transcriptomics to portray the transcriptional status at a moment in time has also been used in diagnosis of dynamic diseases such as sepsis. Gene expression profiles identify endotypes in sepsis patients with prognostic value and a potential to discriminate between viral and bacterial infection. The application of transcriptomics for patient stratification in clinical environments and clinical trials thus holds promise. In this review, we discuss the current clinical application in the fields of cancer and infection. We use these paradigms to highlight the impediments in identifying useful diagnostic and prognostic biomarkers and propose approaches to overcome them and aid efforts towards clinical implementation.

Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation.

The development of K-Ras independence may explain the failure of targeted therapy for pancreatic cancer (PC). In this paper, active N as well as K-Ras was shown in all human cell lines tested. In a cell line dependent on mutant K-Ras, it was shown that depleting K-Ras reduced total Ras activity, while cell lines described as independent had no significant decline in total Ras activity. The knockdown of N-Ras showed it had an important role in controlling the relative level of oxidative metabolism, but only K-Ras depletion caused a decrease in G2 cyclins. Proteasome inhibition reversed this, and other targets of APC/c were also decreased by K-Ras depletion. K-Ras depletion did not cause an increase in ubiquitinated G2 cyclins but instead caused exit from the G2 phase to slow relative to completion of the S-phase, suggesting that the mutant K-Ras may inhibit APC/c prior to anaphase and stabilise G2 cyclins independently of this. We propose that, during tumorigenesis, cancer cells expressing wild-type N-Ras protein are selected because the protein protects cancer cells from the deleterious effects of the cell cycle-independent induction of cyclins by mutant K-Ras. Mutation independence results when N-Ras activity becomes adequate to drive cell division, even in cells where K-Ras is inhibited.

Does dispositional preference for solitude predict better psychological outcomes during times of social distancing? Beliefs and reality.

OBJECTIVE: People value solitude for themselves. Yet little is known about how people perceive dispositional preference for solitude in others. Does dispositional preference for solitude represent a protective factor from psychological distress during times of social distancing? And do laypeople have accurate beliefs about the role of preference for solitude? METHOD: To answer these questions, we conducted four studies (three preregistered, Ntotal  = 1418) at the early and a later stage of the COVID-19 pandemic using experimental, longitudinal, and experience sampling designs. RESULTS: People expected targets with a higher solitude preference to be more resilient (e.g., less lonely, more satisfied with life) during social distancing, and consequently prioritize them less when allocating supportive resources for maintaining social connections (Studies 1 and 2). Compared to these beliefs, the actual difference between individuals with higher versus lower solitude preference was smaller (Study 2) or even negligible (Study 3). Did people form more calibrated beliefs two years into the pandemic? Study 4 suggested no. CONCLUSIONS: Together, these studies show that people overestimate the role of preference for solitude in predicting others' psychological experience. As a result, solitude-seeking individuals may miss out on supportive resources, leading to higher risks for mental health issues.

A novel deleterious ETFA promoter variant causative of multiple acyl-CoA dehydrogenase deficiency.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism. We describe a patient identified through newborn screening in which the diagnosis of MADD was confirmed based on metabolic profiling, but clinical molecular sequencing of ETFA, ETFB, and ETFDH was normal. In order to identify the genetic etiology of MADD, we performed whole genome sequencing and identified a novel homozygous promoter variant in ETFA (c.-85G > A). Subsequent studies showed decreased ETFA protein expression in lymphoblasts. A promoter luciferase assay confirmed decreased activity of the mutant promoter. In both assays, the variant displayed considerable residual activity, therefore we speculate that our patient may have a late onset form of MADD (Type III). Our findings may be helpful in establishing a molecular diagnosis in other MADD patients with a characteristic biochemical profile but apparently normal molecular studies.

The Effects of Partner Extraversion and Agreeableness on Trust.

Existing research has documented the social benefits (i.e., higher popularity and liking) of extraversion and agreeableness. Do these positive reputational consequences extend to social dilemma situations that require trust? We found that people do not trust extraverts more than introverts. Instead, people's trust decisions are guided by their partner's level of agreeableness. In a trust game (Studies 1 and 2), individuals were more likely to trust a partner who was described as agreeable (vs. disagreeable); and, in a laboratory study of work groups, participants trusted more (vs. less) agreeable group members (Study 3). Individuals anticipated others' preferences for agreeable partners and tried to come across as more agreeable, but not more extraverted, in social dilemmas (Study 4). These findings suggest that the social benefits of agreeableness (but not extraversion) extend to social interactions involving trust and highlight the importance of target personality traits in shaping trust decisions.

The Relative Importance of Joke and Audience Characteristics in Eliciting Amusement.

The current work estimated the relative importance of joke and audience characteristics for the occurrence of amusement. Much psychological research has focused on stimulus characteristics when searching for sources of funniness. Some researchers have instead highlighted the importance of perceiver characteristics, such as dispositional cheerfulness. Across five preregistered studies (Ns = 118-54,905) with varied stimuli and perceiver samples (website visitors, students, Mechanical Turk and Prolific users), variance-decomposition analyses found that perceiver characteristics account for more variance in funniness ratings than stimulus characteristics. Thus, psychological theories focusing on between-persons differences have a relatively high potential for explaining and predicting humor appreciation (here, funniness ratings). Crucially, perceiver-by-stimulus interactions explained the largest amount of variance, highlighting the importance of fit between joke and audience characteristics when predicting amusement. Implications for humor-appreciation theories and applications are discussed.

Carnosol, a diterpene present in rosemary, increases ELP1 levels in familial dysautonomia patient-derived cells and healthy adults: a possible therapy for FD.

Recent research on familial dysautonomia (FD) has focused on the development of therapeutics that facilitate the production of the correctly spliced, exon 20-containing, transcript in cells and individuals bearing the splice-altering, FD-causing mutation in the elongator acetyltransferase complex subunit I (ELP1) gene. We report here the ability of carnosol, a diterpene present in plant species of the Lamiaceae family, including rosemary, to enhance the cellular presence of the correctly spliced ELP1 transcript in FD patient-derived fibroblasts by upregulating transcription of the ELP1 gene and correcting the aberrant splicing of the ELP1 transcript. Carnosol treatment also elevates the level of the RNA binding motif protein 24 (RBM24) and RNA binding motif protein 38 (RBM38) proteins, two multifunctional RNA-binding proteins. Transfection-mediated expression of either of these RNA binding motif (RBMs) facilitates the inclusion of exon 20 sequence into the transcript generated from a minigene-bearing ELP1 genomic sequence containing the FD-causing mutation. Suppression of the carnosol-mediated induction of either of these RBMs, using targeting siRNAs, limited the carnosol-mediated inclusion of the ELP1 exon 20 sequence. Carnosol treatment of FD patient peripheral blood mononuclear cells facilitates the inclusion of exon 20 into the ELP1 transcript. The increased levels of the ELP1 and RBM38 transcripts and the alternative splicing of the sirtuin 2 (SIRT2) transcript, a sentinel for exon 20 inclusion in the FD-derived ELP1 transcript, are observed in RNA isolated from whole blood of healthy adults following the ingestion of carnosol-containing rosemary extract. These findings and the excellent safety profile of rosemary together justify an expedited clinical study of the impact of carnosol on the FD patient population.

Blood levels of adiponectin and IL-1Ra distinguish type 3c from type 2 diabetes: Implications for earlier pancreatic cancer detection in new-onset diabetes.

BACKGROUND: Screening for pancreatic ductal adenocarcinoma (PDAC) in populations at high risk is recommended. Individuals with new-onset type 2 diabetes mellitus (NOD) are the largest high-risk group for PDAC. To facilitate screening, we sought biomarkers capable of stratifying NOD subjects into those with type 2 diabetes mellitus (T2DM) and those with the less prevalent PDAC-related diabetes (PDAC-DM), a form of type 3c DM commonly misdiagnosed as T2DM. METHODS: Using mass spectrometry- and immunoassay-based methodologies in a multi-stage analysis of independent sample sets (n=443 samples), blood levels of 264 proteins were considered using Ingenuity Pathway Analysis, literature review and targeted training and validation. FINDINGS: Of 30 candidate biomarkers evaluated in up to four independent patient sets, 12 showed statistically significant differences in levels between PDAC-DM and T2DM. The combination of adiponectin and interleukin-1 receptor antagonist (IL-1Ra) showed strong diagnostic potential, (AUC of 0.91; 95% CI: 0.84-0.99) for the distinction of T3cDM from T2DM. INTERPRETATION: Adiponectin and IL-1Ra warrant further consideration for use in screening for PDAC in individuals newly-diagnosed with T2DM. FUNDING: North West Cancer Research, UK, Cancer Research UK, Pancreatic Cancer Action, UK.

Ecological dimensions explain the past but do not predict future changes in trust.

Concerns about declining trust and rising cynicism are recurrent in academic research and the media. Yet, prior studies focused on explaining, rather than predicting, temporal changes in trust. We tested prediction models of trust change across (up to) 98 countries over six measurement waves (from 1981 to 2014). We tested whether different ecological predictors (e.g., pathogen prevalence, population diversity, inequality) explain the past and predict future trust levels across countries. We used societal growth curve models to disentangle between- from within-country effects and evaluated the accuracy of the models' out-of-sample predictions using the train-test split method: We used data from 1981-2009 to "train" the models and obtain predictions of trust for the period of 2010-2014. None of our models was more accurate in predicting future trust than a simpler baseline model. Moreover, we did not observe a universal decline in trust. Instead, temporal changes in trust were country-specific, highlighting the locality of cultural change. Most ecological predictors were correlated with between-country differences in trust. Only resource availability and moral opinion polarization were associated with within-country changes in trust: Countries that became less wealthy and more morally polarized over time also became less trustful. These results highlight important differences between explanatory and predictive models and suggest that ecological theories of trust might be of limited use when predicting future cultural shifts. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA.

Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.

Missense NAA20 variants impairing the NatB protein N-terminal acetyltransferase cause autosomal recessive developmental delay, intellectual disability, and microcephaly.

PURPOSE: N-terminal acetyltransferases modify proteins by adding an acetyl moiety to the first amino acid and are vital for protein and cell function. The NatB complex acetylates 20% of the human proteome and is composed of the catalytic subunit NAA20 and the auxiliary subunit NAA25. In five individuals with overlapping phenotypes, we identified recessive homozygous missense variants in NAA20. METHODS: Two different NAA20 variants were identified in affected individuals in two consanguineous families by exome and genome sequencing. Biochemical studies were employed to assess the impact of the NAA20 variants on NatB complex formation and catalytic activity. RESULTS: Two homozygous variants, NAA20 p.Met54Val and p.Ala80Val (GenBank: NM_016100.4, c.160A>G and c.239C>T), segregated with affected individuals in two unrelated families presenting with developmental delay, intellectual disability, and microcephaly. Both NAA20-M54V and NAA20-A80V were impaired in their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates. Thus, both NAA20 variants are impaired in their ability to perform cellular NatB-mediated N-terminal acetylation. CONCLUSION: We present here a report of pathogenic NAA20 variants causing human disease and data supporting an essential role for NatB-mediated N-terminal acetylation in human development and physiology.

Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor.

De novo, heterozygous, loss-of-function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole-exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared with wild type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome.

The holding temperature of blood during a delay to processing can affect serum and plasma protein measurements.

Accurate blood-borne biomarkers are sought for diagnosis, prognosis and treatment stratification. Consistent handling of blood is essential for meaningful data interpretation, however, delays during processing are occasionally unavoidable. We investigated the effects of immediately placing blood samples on ice versus room temperature for 1 h (reference protocol), and holding samples on ice versus room temperature during a 3 h delay to processing. Using Luminex multi-plex assays to assess cytokines (n = 29) and diabetes-associated proteins (n = 15) in healthy subjects, we observed that placing blood samples immediately on ice decreased the serum levels of several cytokines, including PAI-1, MIP1-ß, IL-9, RANTES and IL-8. During a delay to processing, some analytes, e.g. leptin and insulin, showed little change in serum or plasma values. However, for approximately half of the analytes studied, a delay, regardless of the holding temperature, altered the measured levels compared to the reference protocol. Effects differed between serum and plasma and for some analytes the direction of change in level varied across individuals. The optimal holding temperature for samples during a delay was analyte-specific. In conclusion, deviations from protocol can lead to significant changes in blood analyte levels. Where possible, protocols for blood handling should be pre-determined in an analyte-specific manner.

Medical Events on Board Aircraft: Reducing Confusion and Misinterpretation in the Scientific Literature.

INTRODUCTION: A topic in aviation medicine that attracts much attention from the scientific community as well as from the media concerns medical incidents on board commercial airline flights. It was noticed that many papers on the subject were written by authors whose specialization was outside that of aviation medicine and that they sometimes made basic errors concerning the application of scientific principles of the subject. A review was undertaken to determine if there were any patterns to the observed errors and, if so, to consider whether recommendations might be provided that could reduce their frequency.METHOD: A literature search was undertaken of MEDLINE using PubMed for English-only articles published between January 1, 1974, and February 1, 2019, employing the following search terms: air emergency, air emergencies, air passenger, air travel, aircraft, airline, aviation, commercial air, flight, and fitness to fly. In addition, other relevant papers held in the personal collection of the authors were reviewed.RESULTS: Many cases of misinterpretation or misunderstanding of aviation medicine were found, which could be classified into eight main categories: references; cabin altitude; pressure/volume relationship; other technical aspects of aircraft operations; regulations; medical events; in-flight deaths; and automated external defibrillator.CONCLUSION: Papers were identified as having questionable statements of fact or of emphasis. Such instances often appeared to result from authors being unfamiliar with the subject of aviation medicine and/or the commercial aviation environment. Simple steps could be taken by authors to reduce the future rate of such instances and recommendations are provided.Thibeault C, Evans AD. Medical events on board aircraft: reducing confusion and misinterpretation in the scientific literature. Aerosp Med Hum Perform. 2021; 92(4):265273.

Leaving the Loners Alone: Dispositional Preference for Solitude Evokes Ostracism.

What are the interpersonal consequences of seeking solitude? Leading theories in developmental research have proposed that having a general preference for solitude may incur significant interpersonal costs, but empirical studies are still lacking. In five studies (total N = 1,823), we tested whether target individuals with a higher preference for solitude were at greater risk for ostracism, a common, yet extremely negative, experience. In studies using self-reported experiences (Study 1) and perceptions of others' experiences (Study 2), individuals with a stronger preference for solitude were more likely to experience ostracism. Moreover, participants were more willing to ostracize targets with a high (vs. low) preference for solitude (Studies 3 and 4). Why do people ostracize solitude-seeking individuals? Participants assumed that interacting with these individuals would be aversive for themselves and the targets (Study 5; preregistered). Together, these studies suggest that seeking time alone has important (and potentially harmful) interpersonal consequences.

Fibroblasts from Distinct Pancreatic Pathologies Exhibit Disease-Specific Properties.

Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown. Here, we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors, and adjacent normal (NA) tissue (N = 34) have distinct mRNA and miRNA profiles. Compared with NA fibroblasts, PDAC-associated fibroblasts were generally less sensitive to an antifibrotic stimulus (NPPB) and more responsive to positive regulators of activation such as TGFß1 and WNT. Of the disease-associated fibroblasts examined, PDAC- and CP-derived fibroblasts shared greatest similarity, yet PDAC-associated fibroblasts expressed higher levels of tenascin C (TNC), a finding attributable to miR-137, a novel regulator of TNC. TNC protein and transcript levels were higher in PDAC tissue versus CP tissue and were associated with greater levels of stromal activation, and conditioned media from TNC-depleted PDAC-associated fibroblasts modestly increased both PDAC cell proliferation and PDAC cell migration, indicating that stromal TNC may have inhibitory effects on PDAC cells. Finally, circulating TNC levels were higher in patients with PDAC compared with CP. Our characterization of pancreatic fibroblast programming as disease-specific has consequences for therapeutic targeting and for the manner in which fibroblasts are used in research. SIGNIFICANCE: Primary fibroblasts derived from various types of pancreatic diseases possess and retain distinct molecular and functional characteristics in culture, providing a series of cellular models for treatment development and disease-specific research.