Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.

Genetic mutations causing primary mitochondrial disease (i.e those compromising oxidative phosphorylation [OxPhos]) resulting in reduced bioenergetic output display great variability in their clinical features, but the reason for this is unknown. We hypothesized that disruption of the communication between endoplasmic reticulum (ER) and mitochondria at mitochondria-associated ER membranes (MAM) might play a role in this variability. To test this, we assayed MAM function and ER-mitochondrial communication in OxPhos-deficient cells, including cybrids from patients with selected pathogenic mtDNA mutations. Our results show that each of the various mutations studied indeed altered MAM functions, but notably, each disorder presented with a different MAM "signature". We also found that mitochondrial membrane potential is a key driver of ER-mitochondrial connectivity. Moreover, our findings demonstrate that disruption in ER-mitochondrial communication has consequences for cell survivability that go well beyond that of reduced ATP output. The findings of a "MAM-OxPhos" axis, the role of mitochondrial membrane potential in controlling this process, and the contribution of MAM dysfunction to cell death, reveal a new relationship between mitochondria and the rest of the cell, as well as providing new insights into the diagnosis and treatment of these devastating disorders.

Prospective manipulation of the gut microbiome with microbial ecosystem therapeutic 4 (MET4) in HPV-related locoregionally-advanced oropharyngeal cancer squamous cell carcinoma (LA-OPSCC) undergoing primary chemoradiation: ROMA2 study.

BACKGROUND: Gut microbiome modulation to boost antitumor immune responses is under investigation. METHODS: ROMA-2 evaluated the microbial ecosystem therapeutic (MET)-4 oral consortia, a mixture of cultured human stool-derived immune-responsiveness associated bacteria, given with chemoradiation (CRT) in HPV-related oropharyngeal cancer patients. Co-primary endpoints were safety and changes in stool cumulative MET-4 taxa relative abundance (RA) by 16SRNA sequencing. Stools and plasma were collected pre/post-MET-4 intervention for microbiome and metabolome analysis. RESULTS: Twenty-nine patients received ≥1 dose of MET-4 and were evaluable for safety: drug-related adverse events (AEs) occurred in 13/29 patients: all grade 1-2 except one grade 3 (diarrhea). MET-4 was discontinued early in 7/29 patients due to CRT-induced toxicity, and in 1/29 due to MET-4 AEs. Twenty patients were evaluable for ecological endpoints: there was no increase in stool MET-4 RA post-intervention but trended to increase in stage III patients (p = 0.06). MET-4 RA was higher in stage III vs I-II patients at week 4 (p = 0.03) and 2-month follow-up (p = 0.01), which correlated with changes in plasma and stool targeted metabolomics. CONCLUSIONS: ROMA-2 did not meet its primary ecologic endpoint, as no engraftment was observed in the overall cohort. Exploratory findings of engraftment in stage III patients warrants further investigation of microbiome interventions in this subgroup.

Exploring ketamine's reinforcement, cue-induced reinstatement, and nucleus accumbens cFos activation in male and female long evans rats.

Ketamine (KET), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid onset of antidepressant effects in Treatment-Resistant Depression patients and repeated infusions are required to sustain its antidepressant properties. However, KET is an addictive drug, and so more preclinical and clinical research is needed to assess the safety of recurring treatments in both sexes. Thus, the aim of this study was to investigate the reinforcing properties of various doses of KET (0-, 0.125-, 0.25-, 0.5 mg/kg/infusion) and assess KET's cue-induced reinstatement and neuronal activation in both sexes of Long Evans rats. Neuronal activation was assessed using the protein expression of the immediate early gene cFos in the nucleus accumbens (Nac), an important brain area implicated in reward, reinforcement and reinstatement to most drug-related cues. Our findings show that KET has reinforcing effects in both male and female rats, albeit exclusively at the highest two doses (0.25 and 0.5 mg/kg/infusion). Furthermore, we noted sex differences, particularly at the highest dose of ketamine, with female rats displaying a higher rate of self-administration. Interestingly, all groups that self-administered KET reinstated to drug-cues. Following drug cue-induced reinstatement test in rats exposed to KET (0.25 mg/kg/infusion) or saline, there was higher cFos protein expression in KET-treated animals compared to saline controls, and higher cFos expression in the core compared to the shell subregions of the Nac. As for reinstatement, there were no notable sex differences reported for cFos expression in the Nac. These findings reveal some sex and dose dependent effects in KET's reinforcing properties and that KET at all doses induced similar reinstatement in both sexes. This study also demonstrated that cues associated with ketamine induce comparable neuronal activation in the Nac of both male and female rats. This work warrants further research into the potential addictive properties of KET, especially when administered at lower doses which are now being used in the clinic for treating various psychopathologies.

Evaluation of Nursing Coursework for Biased Content.

ABSTRACT: Bias-free content in nursing education prepares students to provide equitable care. The process of assessing content promotes the dismantling of systemic bias in health care, advancing social justice, diversity, equity, and inclusion. Unfortunately, there are no published studies to guide the evaluation of nursing curricula for the presence of bias. This innovative project aimed to identify bias in a course and develop a structure to guide the wider evaluation of the curriculum to identify and remove biased content. A modified version of the Upstate Bias Checklist was applied to a 15-week, three-semester hour, prelicensure, graduate-level nursing course.

Selinexor for the treatment of recurrent or metastatic salivary gland tumors: Results from the GEMS-001 clinical trial.

OBJECTIVES: We aimed to evaluate the activity of selinexor, an oral selective inhibitor of nuclear export, in patients with recurrent or metastatic salivary gland tumors (SGT). METHODS: GEMS-001 is an open-label Phase 2 study for patients with recurrent or metastatic SGT with two parts. In Part 1 of the protocol, patients had tumor samples profiled with targeted next generation sequencing as well as immunohistochemistry for androgen receptor, HER-2 and ALK. For Part 2, patients with no targeted therapies available were eligible to receive selinexor 60 mg given twice weekly every 28 days. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS) and prevalence of druggable alterations across SGT. RESULTS: One hundred patients were enrolled in GEMS-001 and underwent genomic and immunohistochemistry profiling. A total of 21 patients who lacked available matched therapies were treated with selinexor. SGT subtypes (WHO classification) included adenoid cystic carcinoma (n = 10), salivary duct carcinoma (n = 3), acinic cell carcinoma (n = 2), myoepithelial carcinoma (n = 2), carcinoma ex pleomorphic adenoma (n = 2) and other (n = 2). Of 18 evaluable patients, stable disease (SD) was observed in 17 patients (94%) (SD ≥6 months in 7 patients (39%)). However, no objective responses were observed. The median PFS was 4.9 months (95% confidence interval, 3.4-10). The most common treatment-related Grade 1-2 adverse events were nausea [17 patients (81%)], fatigue [16 patients (76%)], and dysgeusia [12 patients (57%)]. Most common treatment-related Grade 3-4 adverse events were hyponatremia [3 patients (14%)], neutrophil count decrease [3 patients (14%)] and cataracts [2 patients (10%)]. No treatment-related deaths were observed. CONCLUSIONS: Although tumor reduction was observed across participants, single agent selinexor anti-tumor activity was limited.

Feather chemicals contain information about the major histocompatibility complex in a highly scented seabird.

Mate choice informed by the immune genes of the major histocompatibility complex (MHC) may provide fitness benefits including offspring with increased immunocompetence. Olfactory cues are considered the primary mechanism organisms use to evaluate the MHC of potential mates, yet this idea has received limited attention in birds. Motivated by a finding of MHC-dependent mate choice in the Leach's storm-petrel (Oceanodroma leucorhoa), we examined whether the chemical profiles of this highly scented seabird contain information about MHC genes. Whereas previous studies in birds examined non-volatile compounds, we used gas chromatography-mass spectrometry to measure the volatile compounds emitted from feathers that potentially serve as olfactory infochemicals about MHC and coupled this with locus-specific genotyping of MHC IIB genes. We found that feather chemicals reflected individual MHC diversity through interactions with sex and breeding status. Furthermore, similarity in MHC genotype was correlated with similarity in chemical profiles within female-female and male-female dyads. We provide the first evidence that volatile chemicals from bird feathers can encode information about the MHC. Our findings suggest that olfaction likely aids MHC-based mate choice in this species and highlight a role for chemicals in mediating genetic mate choice in birds where this mode of communication has been largely overlooked.

Ocean resource use: building the coastal blue economy.

Humans have relied on coastal resources for centuries. However, current growth in population and increased accessibility of coastal resources through technology have resulted in overcrowded and often conflicted spaces. The recent global move towards development of national blue economy strategies further highlights the increased focus on coastal resources to address a broad range of blue growth industries. The need to manage sustainable development and future exploitation of both over-utilised and emergent coastal resources is both a political and environmental complexity. To address this complexity, we draw on the perspectives of a multi-disciplinary team, utilising two in depth exemplary case studies in New Zealand and within the Myanmar Delta Landscape, to showcase barriers, pathways and actions that facilitate a move from Business as Usual (BAU) to a future aligned with the Sustainable Development Goals (SDGs) and the UN International Decade of Ocean Science for Sustainable Development 2021-2030. We provide key recommendations to guide interest groups, and nations globally, towards sustainable utilisation, conservation and preservation of their marine environments in a fair and equitable way, and in collaboration with those who directly rely upon coastal ecosystems. We envision a sustainable future driven by conflict mitigation and resolution,  where:(i)Change is motivated and facilitated(ii)Coastal ecosystems are co-managed by multiple reliant groups(iii)Networks that maintain and enhance biodiversity are implemented(iv)Decision-making is equitable and based on ecosystem services(v)Knowledge of the marine realm is strengthened-'mapping the ocean of life'(vi)The interests of diverse user groups are balanced with a fair distribution of benefits.

Deep aspirations: towards a sustainable offshore Blue Economy.

Abstract: The ocean economy is experiencing rapid growth that will provide benefits but will also pose environmental and social risks. With limited space and degraded resources in coastal areas, offshore waters will be a particular focus of Blue Economy expansion over the next decade. When emerging and established economic sectors expand in offshore waters (within national Exclusive Economic Zones), different potential Blue Economy opportunities and challenges will arise. Following a series of interdisciplinary workshops, we imagine two technically possible futures for the offshore Blue Economy and we identify the actions required to achieve the more sustainable outcome. Under a business as usual scenario the focus will remain on economic growth, the commodification of nature, the dominance of private over public and cultural interests, and prioritisation of the interests of current over future generations. A more sustainable scenario would meet multiple UN Sustainable Development Goals and ensure inclusive economic developments, environmental sustainability, and fair and equitable access to resources and technologies across users, nations, and generations. Challenges to this more sustainable future are a lack of infrastructure and technology to support emerging offshore sectors, limited understanding of environmental impacts, inequitable outcomes, and a lack of planning and governmental oversight. Addressing these challenges will require a shift in societal values, a more balanced allocation of funding to offshore activities, transparency in information sharing between industries and across nations, and adjustment of international legal and institutional mechanisms. The sustainable and equitable offshore Blue Economy we envisage is achievable and provides a unique opportunity to build global capacity and partnership.

Stability and change in autobiographical reasoning: A 4-year longitudinal study of narrative identity development.

OBJECTIVE: Research on personality development has traditionally focused on rank-order stability and mean-level change in the context of personality traits. The present study expands this approach to the examination of change and stability at another level of personality-narrative identity-by focusing on autobiographical reasoning. Drawing from theory in personality and developmental science, we examine stability and change in exploratory processing and positive and negative self-event connections. METHOD: We take advantage of a longitudinal study of emerging adult personality and identity development, which includes four waves of data across 4 years, examining reasoning in two domains of identity, academics, and romance (n = 1520 narratives; n = 176-638 participants, depending on the analysis). RESULTS: We found moderate rank-order stability in autobiographical reasoning, but more so for exploratory processing than self-event connections. We found mean-level increases for exploratory processing in the context of romance and stability in the context of academics. For self-event connections, we saw a decrease for positive connections, and for negative connections about romance, with stability for negative connections about academics. CONCLUSIONS: Implications include developmental differences in types of reasoning as well as the sensitivity of narrative identity to revealing the contextual nature of personality development.

Chronic intermittent ethanol during adolescence and adulthood alters dendritic spines in the primary motor and visual cortex in rats.

Prolonged adolescent binge drinking can disrupt sleep quality and increase the likelihood of alcohol-induced sleep disruptions in young adulthood in rodents and in humans. Striking changes in spine density and morphology have been seen in many cortical and subcortical regions after adolescent alcohol exposure in rats. However, there is little known about the impact of alcohol exposure on dendritic spines in the same motor and sensory cortices that EEG sleep is typically recorded from in rats. The aim of this study is to investigate whether an established model of chronic intermittent ethanol vapor in rats that has been demonstrated to disrupt sleep during adolescence or adulthood, also significantly alters cortical dendritic spine density and morphology. To this end, adolescent and adult Wistar rats were exposed to 5 weeks of ethanol vapor or control air exposure. After a 13-day withdrawal, primary motor cortex (M1) and primary/secondary visual cortex (V1/V2) layer V dendrites were analyzed for differences in spine density and morphology. Spines were classified into four categories (stubby, long, filopodia, and mushroom) based on the spine length and the width of the spine head and neck. The main results indicate an age-specific effect of adolescent intermittent ethanol exposure decreasing spine density in the M1 cortex compared to age-matched controls. Reductions in the density of M1 long-shaped spine subclassifications were seen in adolescent ethanol-exposed rats, but not adult-exposed rats, compared to their air-controls. Irrespective of age, there was an overall reduction produced by ethanol exposure on the density of filopodia and the length of long-shaped spines in V1/V2 cortex as compared to their air-exposed controls. Together, these data add to growing evidence that some cortical circuits are vulnerable to the effects of alcohol during adolescence and begin to elucidate potential mechanisms that may influence brain plasticity following early alcohol use.

Upper Gastrointestinal Cancer Risk and Surveillance Outcomes in Li-Fraumeni Syndrome.

INTRODUCTION: To assess the upper gastrointestinal (UGI) cancer risk and surveillance outcomes in Li-Fraumeni syndrome (LFS). METHODS: Analysis of the International Agency for Research on Cancer database and a single-center adult LFS cohort. RESULTS: UGI cancer was present in 7.2% of families and 3.9% of individuals with a pathogenic/likely pathogenic TP53 mutation in International Agency for Research on Cancer; 29% occurred before age 30. Our institutional cohort had 35 individuals (31% of the LFS cohort) with 48 cumulative upper endoscopies; 3 (8.5%) individuals had concerning UGI findings. DISCUSSION: UGI cancer is observed in LFS. Upper endoscopy should be part of a comprehensive LFS surveillance program.

Individual Chemical Profiles in the Leach's Storm-Petrel.

Avian chemical communication, once largely overlooked, is a growing field that has revealed the important role that olfaction plays in the social lives of some birds. Leach's storm-petrels (Oceanodroma leucorhoa) have a remarkable sense of smell and a strong, musky scent. This long-lived, monogamous seabird relies on olfaction for nest relocation and foraging, but whether they use scent for communication is less well studied. They are nocturnally active at the breeding colony and yet successfully reunite with their mate despite poor night-vision, indicating an important role for non-visual communication. We investigated the chemical profiles of Leach's storm-petrels to determine whether there is socially relevant information encoded in their plumage odor. To capture the compounds comprising their strong scent, we developed a method to study the compounds present in the air surrounding their feathers using headspace stir bar sorptive extraction coupled with gas chromatography-mass spectrometry. We collected feathers from Leach's storm-petrels breeding on Bon Portage Island in Nova Scotia, Canada in both 2015 and 2016. Our method detected 142 commonly occurring compounds. We found interannual differences in chemical profiles between the two sampling years. Males and females had similar chemical profiles, while individuals had distinct chemical signatures across the two years. These findings suggest that the scent of the Leach's storm-petrel provides sociochemical information that could facilitate olfactory recognition of individuals and may inform mate choice decisions.

Distinct Region- and Time-Dependent Functional Cortical Adaptations in C57BL/6J Mice after Short and Prolonged Alcohol Drinking.

Alcohol (ethanol) use disorder is associated with changes in frontal cortical areas including the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) that contribute to cognitive deficits, uncontrolled drinking, and relapse. Acute ethanol exposure reduces intrinsic excitability of lateral OFC (lOFC) neurons, while chronic exposure and long-term drinking influence plasticity of intrinsic excitability and function of glutamatergic synapses. However, the time course that these adaptations occur across a history of ethanol drinking is unknown. The current study examined whether short-term and long-term voluntary ethanol consumption using an intermittent access paradigm would alter the biophysical properties of deep-layer pyramidal neurons in the ACC and lOFC. Neuronal spiking varied in the ACC with an initial increase in evoked firing after 1 d of drinking followed by a decrease in firing in mice that consumed ethanol for one week. No difference in lOFC spike number was observed between water controls and 1-d ethanol drinking mice, but mice that consumed ethanol for one week or more showed a significant increase in evoked firing. Voluntary ethanol drinking for 4 weeks also produced a total loss of ethanol inhibition of lOFC neurons. There was no effect of drinking on excitatory or inhibitory synaptic events in ACC or lOFC neurons across all time points in this model. Overall, these results demonstrate that voluntary drinking alters neuronal excitability in the ACC and lOFC in distinct ways and on a different time scale that may contribute to the impairment of prefrontal cortex-dependent behaviors observed in individuals with alcohol use disorder (AUD).

Autonomous adaptation to climate-driven change in marine biodiversity in a global marine hotspot.

While governments and natural resource managers grapple with how to respond to climatic changes, many marine-dependent individuals, organisations and user-groups in fast-changing regions of the world are already adjusting their behaviour to accommodate these. However, we have little information on the nature of these autonomous adaptations that are being initiated by resource user-groups. The east coast of Tasmania, Australia, is one of the world's fastest warming marine regions with extensive climate-driven changes in biodiversity already observed. We present and compare examples of autonomous adaptations from marine users of the region to provide insights into factors that may have constrained or facilitated the available range of autonomous adaptation options and discuss potential interactions with governmental planned adaptations. We aim to support effective adaptation by identifying the suite of changes that marine users are making largely without government or management intervention, i.e. autonomous adaptations, to better understand these and their potential interactions with formal adaptation strategies.

Prevalence of mental health conditions and pain in adults with skeletal dysplasia.

PURPOSE: We sought to examine the prevalence of depression and anxiety in adults with skeletal dysplasias, and to assess any correlations with pain. METHODS: Participation was via an anonymous REDCap survey, which consisted of sociodemographic questions followed by the brief pain inventory-short form (BPI-SF), patient health questionnaire-8 (PHQ-8), and generalized anxiety disorder-7 (GAD-7) questionnaires. These assessed pain, depression, and anxiety respectively. RESULTS: Of the 336 usable responses, 16.1% scored 10 or greater on the PHQ-8 consistent with current depression while 17.3% scored 10 or greater on the GAD-7 consistent with current anxiety. The majority of participants (76.2%) experienced pain, which was significantly associated with prior mental health diagnoses (p < 0.05). A total of 34% reported either a prior diagnosis of depression or scored 10 or greater on the PHQ-8, and 31% reported either a prior diagnosis of anxiety or scored 10 or greater on the GAD-7. CONCLUSIONS: This study identified a substantial percentage of individuals with mental health concerns as well as pain in the adult skeletal dysplasia population. Further research is warranted to investigate barriers to service or treatment of mental health disorders as well as pain management.

PCNT point mutations and familial intracranial aneurysms.

OBJECTIVE: To identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing. METHODS: We performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants. RESULTS: We identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases. CONCLUSION: The PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt -/-) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.

Ecology can inform genetics: Disassortative mating contributes to MHC polymorphism in Leach's storm-petrels (Oceanodroma leucorhoa).

Studies of MHC-based mate choice in wild populations often test hypotheses on species exhibiting female choice and male-male competition, which reflects the general prevalence of females as the choosy sex in natural systems. Here, we examined mutual mate-choice patterns in a small burrow-nesting seabird, the Leach's storm-petrel (Oceanodroma leucorhoa), using the major histocompatibility complex (MHC). The life history and ecology of this species are extreme: both partners work together to fledge a single chick during the breeding season, a task that requires regularly travelling hundreds of kilometres to and from foraging grounds over a 6- to 8-week provisioning period. Using a 5-year data set unprecedented for this species (n = 1078 adults and 925 chicks), we found a positive relationship between variation in the likelihood of female reproductive success and heterozygosity at Ocle-DAB2, a MHC class IIB locus. Contrary to previous reports rejecting disassortative mating as a mechanism for maintaining genetic polymorphism in this species, here we show that males make significant disassortative mate-choice decisions. Variability in female reproductive success suggests that the most common homozygous females (Ocle-DAB2*01/Ocle-DAB2*01) may be physiologically disadvantaged and, therefore, less preferred as lifelong partners for choosy males. The results from this study support the role of mate choice in maintaining high levels of MHC variability in a wild seabird species and highlight the need to incorporate a broader ecological framework and sufficient sample sizes into studies of MHC-based mating patterns in wild populations in general.

Morphological and genetic factors shape the microbiome of a seabird species (Oceanodroma leucorhoa) more than environmental and social factors.

BACKGROUND: The microbiome provides multiple benefits to animal hosts that can profoundly impact health and behavior. Microbiomes are well-characterized in humans and other animals in controlled settings, yet assessments of wild bird microbial communities remain vastly understudied. This is particularly true for pelagic seabirds with unique life histories that differ from terrestrial bird species. This study was designed to examine how morphological, genetic, environmental, and social factors affect the microbiome of a burrow-nesting seabird species, Leach's storm petrel (Oceanodroma leucorhoa). These seabirds are highly olfactory and may rely on microbiome-mediated odor cues during mate selection. Composition and structure of bacterial communities associated with the uropygial gland and brood patch were assessed using 16S rRNA amplicon-based Illumina Mi-Seq analysis and compared to burrow-associated bacterial communities. This is the first study to examine microbial diversity associated with multiple body sites on a seabird species. RESULTS: Results indicate that sex and skin site contribute most to bacterial community variation in Leach's storm petrels and that major histocompatibility complex (MHC) genotype may impact the composition of bacterial assemblages in males. In contrast to terrestrial birds and other animals, environmental and social interactions do not significantly influence storm petrel-associated bacterial assemblages. Thus, individual morphological and genetic influences outweighed environmental and social factors on microbiome composition. CONCLUSIONS: Contrary to observations of terrestrial birds, microbiomes of Leach's storm petrels vary most by the sex of the bird and by the body site sampled, rather than environmental surroundings or social behavior.

Biodiversity redistribution under climate change: Impacts on ecosystems and human well-being.

Distributions of Earth's species are changing at accelerating rates, increasingly driven by human-mediated climate change. Such changes are already altering the composition of ecological communities, but beyond conservation of natural systems, how and why does this matter? We review evidence that climate-driven species redistribution at regional to global scales affects ecosystem functioning, human well-being, and the dynamics of climate change itself. Production of natural resources required for food security, patterns of disease transmission, and processes of carbon sequestration are all altered by changes in species distribution. Consideration of these effects of biodiversity redistribution is critical yet lacking in most mitigation and adaptation strategies, including the United Nation's Sustainable Development Goals.