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Introduction: What is known about male identity or intergenerational relationships between male family members? And how can rural Australian men be engaged in essential health research? Methods: Narrative inquiry is proposed as an ideal means for engaging in the process of uncovering men's storied reflections about their lives, relationships and identity. Results: The article begins with guidance contributed by a group of rural Australian men to narrative researchers who hope to create comfortable environments for men to share personal stories about their intergenerational relationships with male relatives. The men discuss how they see themselves as men in today's Australian rural landscape. Following this, the narrative inquiry literature is discussed. Reflections are provided on male identity as influenced by culture and context, consideration of men and their family relationships, and barriers to men's participation in research, which leads to a focus on rural Australian men. Conclusion: Further research with rural men is called for, in regard to both their participation in research, and their participation in health initiatives. [ABSTRACT FROM AUTHOR]

The need for workers to experience a sense of empowerment in the human service organizations where they are employed is essential, but insufficient. The conceptualization of worker empowerment also needs to extend beyond the organizational context toward a broader context. In this article, the authors review the construct of social worker empowerment, examine conditions which negatively impact the potential for empowerment, and suggest strategies available to administrators and workers for increasing the potential for empowerment both within and beyond the organizational work setting. [ABSTRACT FROM AUTHOR]

The Parent Interview for Autism-Clinical Version (PIA-CV) was developed to measure autism symptom severity across a wide range of behavioral domains. Two studies were conducted to examine the psychometric properties of the PIA-CV for a sample of children under 3 years old. Results of study 1 revealed adequate internal consistency for nine of the 11 PIA-CV dimensions, as well as significant group differences on social-communication domains between 2-year-old children with autism and a developmentally matched sample. Study 2 examined the association between changes in PIA-CV scores and changes in autism symptomatology from age 2 to age 4. Results revealed that changes on PIA-CV dimensions assessing social and communication skills were associated with clinically significant behavioral and diagnostic improvements. These findings support the utility of the PIA-CV for obtaining ecologically valid information from parents and for measuring behavioral change in young children with autism. [ABSTRACT FROM AUTHOR]

Terrestrial crabs (brachyurans and anomurans) have invaded land following a variety of pathways from marine and/or via freshwater environments. This transition from water to land requires physiological, ecological, and behavioral adaptations to allow the exploitation of these new environmental conditions. Arguably, the management of salt and water balance (e.g., osmoregulation) is integral for their survival and success in an environment where predominantly low-salinity aquatic (e.g., freshwater) water sources are found, sometimes in only minimal amounts. This requires a suite of morphological and biochemical modifications, especially at the branchial chamber of semi-terrestrial and terrestrial crabs to allow reprocessing of urine to maximize ion uptake. Using knowledge gained from electrophysiology, biochemistry, and more recent molecular biology techniques, we present summarized updated models for ion transport for all major taxonomic groups of terrestrial crabs. This is an exciting and fast-moving field of research, and we hope that this review will stimulate further study. Terrestrial crabs retain their crown as the ideal model group for studying the evolutionary pathways that facilitated terrestrial invasion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lucu and Turner.)

Introduction: Understanding the patient journey of hepatocellular carcinoma (HCC) may inform future clinical decision-making and enhance the patient experience. The objectives of this study were to explore the patient experience of HCC in relation to treatment options, treatment decision-making and treatment goals throughout the disease journey. This study also aimed to determine the symptoms and impacts of HCC across early, intermediate and advanced HCC., Methods: Semi-structured 60-min interviews were conducted with n = 50 patients with HCC and n = 12 healthcare professionals (HCPs) with experience of treating patients with HCC. Interview data were analyzed using directed content analysis techniques with a hybrid inductive and deductive approach. An assessment of conceptual saturation was conducted for patients' symptom experience., Results: Patients described treatment decisions as mostly HCP-led. In this study, surgery/resection was the most frequently offered treatment option across the HCC journey, and most patients were satisfied with the treatment options presented to them. Overall, patients described extending their overall survival (OS) and preserving quality of life (QoL) as their most important treatment goals, with patients diagnosed with advanced/unresectable HCC prioritizing QoL. HCPs also prioritized OS and progression-free survival (PFS) though reported that QoL became more important as HCC progressed. Patients experienced various symptoms across the HCC journey including fatigue, nausea, appetite loss, diarrhea and pain., Conclusion: Overall, HCPs and patients collaborate throughout the treatment journey regarding treatment decisions and shared treatment goals. OS is critically important to patients and HCPs, though treatment goals may change depending on various clinical factors., (© 2024. The Author(s).)

Behavioral variation abounds in nature. This variation is important for adaptation and speciation, but its molecular basis remains elusive. Here, we use a hybrid zone between two subspecies of songbirds that differ in migration - an ecologically important and taxonomically widespread behavior---to gain insight into this topic. We measure gene expression in five brain regions. Differential expression between migratory states was dominated by circadian genes in all brain regions. The remaining patterns were largely brain-region specific. For example, expression differences between the subspecies that interact with migratory state likely help maintain reproductive isolation in this system and were documented in only three brain regions. Contrary to existing work on regulatory mechanisms underlying species-specific traits, two lines of evidence suggest that trans- (vs. cis) regulatory changes underlie these patterns - no evidence for allele-specific expression in hybrids and minimal associations between genomic differentiation and expression differences. Additional work with hybrids shows expression levels were often distinct (transgressive) from parental forms. Behavioral contrasts and functional enrichment analyses allowed us to connect these patterns to mitonuclear incompatibilities and compensatory responses to stress that could exacerbate selection on hybrids and contribute to speciation., (© 2024. The Author(s).)

Purpose: Obtaining prior authorization (PA) before treatment is becoming increasingly burdensome in oncology, especially in radiation oncology. Here, we describe the impact of a strategic novel operational PA redesign to shorten authorization time and to improve patient access to cancer care at a large United States academic proton therapy center. We ask whether such a redesign may be replicable and adoptable across oncology centers., Materials and Methods: Our PA redesign strategy was based on a 3-tiered approach. Specifically, we (1) held payors accountable to legally backed timelines, (2) leveraged expertise on insurance policies and practices, and (3) updated the submission, appeal writing, and planning procedures for PA. Metrics were compared at the following 3 time points: 6 months before, at phase-in, and at 6 months after intervention., Results: In analyzing the impact of improving PA access to care, the percentage of approvals for commercial proton beam therapy improved by an absolute 30.6% postintervention ( P < .001). The proportion of commercially insured patients treated with proton beam therapy also increased by 6.2%, and the number of new starts rose by 11.7 patients/mo. Overall patient census increased by 13 patients/d. Median authorization time was 1 week, and 90% of surveyed providers reported reduced PA burden and improved patient care., Conclusion: This is the first validated, comprehensive operational strategy to improve access to cancer therapy while reducing the burden of PA. This novel approach may be helpful for addressing barriers to PA in medical and surgical oncology because the redesign is predicated on laws that regulate PA across disciplines., Competing Interests: Conflict of Interest: Nancy P. Mendenhall is the Editor-in-Chief of International Journal of Particle Therapy. All other authors declare no conflict of interest., (©Copyright 2023 The Author(s).)

Introduction: Injectable hyaluronic acid (HA) fillers are commonly used to provide tissue augmentation and combat the effects of facial aging. Ovine and human recombinant formulations of the enzyme hyaluronidase (HAse) are used interchangeably; however, it is unknown if there exists a difference in their ability to degrade HA. Objective: To compare rates at which ovine and human recombinant forms of HAse degrade various HA fillers in vitro. Methods: Increasing amounts of either ovine or human recombinant HAse were added to fixed amounts of nine unique HA filler products. Degradation rates were then analyzed using a colorimetric method by measuring absorbance levels of degraded product. Results: Human recombinant HAse degraded more HA when compared with ovine HAse overall ( p  = 0.014, confidence interval [-0.015 to -0.0018]). Conclusions: Human recombinant HAse was found to be more effective on average in degrading HA fillers when compared with ovine HAse in vitro.

Purpose: We investigated the feasibility of biology-guided radiotherapy (BgRT), a technique that utilizes real-time positron emission imaging to minimize tumor motion uncertainties, to spare nearby organs at risk., Methods: Volumetric modulated arc therapy (VMAT), intensity-modulated proton (IMPT) therapy, and BgRT plans were created for a paratracheal node recurrence (case 1; 60 Gy in 10 fractions) and a primary peripheral left upper lobe adenocarcinoma (case 2; 50 Gy in four fractions)., Results: For case 1, BgRT produced lower bronchus V40 values compared to VMAT and IMPT. For case 2, total lung V20 was lower in the BgRT case compared to VMAT and IMPT., Conclusions: BgRT has the potential to reduce the radiation dose to proximal critical structures but requires further detailed investigation., Competing Interests: JW is a member of the board of advisors and has equity at RefleXion Medical. SM is the founder and CTO of RefleXion Medical. YV is a software architect, RB is a medical physicist, PO is a PET engineer at RefleXion Medical and OO is a clinical scientist at RefleXion Medical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Seyedin, Bassalow, Mawlawi, Turner, Patel, Mazin, Oderinde, Voronenko, Wages, Olcott, Chang, Balter and Welsh.)

Determining the forces that shape diversity in host-associated bacterial communities is critical to understanding the evolution and maintenance of metaorganisms. To gain deeper understanding of the role of host genetics in shaping gut microbial traits, we employed a powerful genetic mapping approach using inbred lines derived from the hybrid zone of two incipient house mouse species. Furthermore, we uniquely performed our analysis on microbial traits measured at the gut mucosal interface, which is in more direct contact with host cells and the immune system. Several mucosa-associated bacterial taxa have high heritability estimates, and interestingly, 16S rRNA transcript-based heritability estimates are positively correlated with cospeciation rate estimates. Genome-wide association mapping identifies 428 loci influencing 120 taxa, with narrow genomic intervals pinpointing promising candidate genes and pathways. Importantly, we identified an enrichment of candidate genes associated with several human diseases, including inflammatory bowel disease, and functional categories including innate immunity and G-protein-coupled receptors. These results highlight key features of the genetic architecture of mammalian host-microbe interactions and how they diverge as new species form., Competing Interests: SD, HF, MR, CC, AK, SI, AF, LT, JB No competing interests declared, (© 2022, Doms et al.)

While gastro-intestinal stromal tumours (GIST) are the most common non-epithelial neoplasms of the gastrointestinal tract, 10% occur externally. Symptomatology is therefore broad, dependent on location. A 42-year-old female presented to the Emergency Department after 12 hours of severe right lower abdominal, preceded by vague pain over two weeks. Imaging revealed a right-sided 7.5 × 5.8 × 5.6 cm ovarian cystic lesion, suspicious for torsion. Laparoscopically, the lesion was densely adherent to small and large bowel, and she was proceeded to resection of an assumed primary ovarian neoplasm. Histopathology revealed an infarcted epithelioid GIST, high-grade with clear margins (stage pT3). There are only 24 cases of GISTs pre-operatively mistaken for gynaecological neoplasms. Additionally, there are reports of GISTs metastasizing to ovaries. Both computed tomography and ultrasound are non-specific, including hypo- and hyperechoic features. In all published cases, imaging was not able to identify presumed gynaecological neoplasms as GISTS. Differential diagnoses for pelvic masses should include non-gynaecological tumours., (Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2021.)

Little is known about the functions of the crustacean gut microbiome, but environmental parameters and habitat are known to affect the composition of the intestinal microbiome, which may in turn affect the physiological status of the host. The mud crab Scylla serrata is an economically important species, and is wild-caught, and farmed across the Indo-Pacific region. In this study, we compared the composition of the gut microbiome (in terms of gut microbial species richness and abundance) of S. serrata collected from wild sites, and farms, from the east and west coast of India, and also tested the effects of the environment on the composition. The water temperature had a statistically significant effect on gut microbiome composition, with microbial biodiversity decreasing with increasing water temperature. This could have negative effects on both wild and farmed mud crabs under future climate change conditions, although further research into the effects of temperature on gut microbiomes is required. By comparison, salinity, crab mass and carapace width, geographical location as well as whether they were farmed or wild-caught crabs did not have a significant impact on gut microbiome composition. The results indicate that farming does not significantly alter the composition of the gut microbiome when compared to wild-caught crabs., (© 2021 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Our laboratories have used genetically engineered mouse models (GEMMs) to assess genetic contributions to skeletal diseases such as osteoporosis and osteoarthritis. Studies on the genetic contributions to OA are often done by assessing how GEMMs respond to surgical methods that induce symptoms modeling OA. Here, we will describe protocols outlining the induction of experimental OA in mice as well as detailed descriptions of methods for analyzing skeletal phenotypes using micro-computerized tomography and skeletal histomorphometry.

The Dobzhansky-Muller (DM) model provides a widely accepted mechanism for the evolution of reproductive isolation: incompatible substitutions disrupt interactions between genes. To date, few candidate incompatibility genes have been identified, leaving the genes driving speciation mostly uncharacterized. The importance of interactions in the DM model suggests that gene coexpression networks provide a powerful framework to understand disrupted pathways associated with postzygotic isolation. Here, we perform weighted gene coexpression network analysis to infer gene interactions in hybrids of two recently diverged European house mouse subspecies, Mus mus domesticus and M. m. musculus, which commonly show hybrid male sterility or subfertility. We use genome-wide testis expression data from 467 hybrid mice from two mapping populations: F2s from a laboratory cross between wild-derived pure subspecies strains and offspring of natural hybrids captured in the Central Europe hybrid zone. This large data set enabled us to build a robust consensus network using hybrid males with fertile phenotypes. We identify several expression modules, or groups of coexpressed genes, that are disrupted in subfertile hybrids, including modules functionally enriched for spermatogenesis, cilium and sperm flagellum organization, chromosome organization, and DNA repair, and including genes expressed in spermatogonia, spermatocytes, and spermatids. Our network-based approach enabled us to hone in on specific hub genes likely to be influencing module-wide gene expression and hence potentially driving large-effect DM incompatibilities. A disproportionate number of hub genes lie within sterility loci identified previously in the hybrid zone mapping population and represent promising candidate barrier genes and targets for future functional analysis., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Regulation of extracellular acid-base balance, while maintaining energy metabolism, is recognised as an important aspect when defining an organism's sensitivity to environmental changes. This study investigated the haemolymph buffering capacity and energy metabolism (oxygen consumption, haemolymph [l-lactate] and [protein]) in early benthic juveniles (carapace length <40 mm) of the European lobster, Homarus gammarus , exposed to elevated temperature and P CO 2 At 13°C, H. gammarus juveniles were able to fully compensate for acid-base disturbances caused by the exposure to elevated seawater P CO 2  at levels associated with ocean acidification and carbon dioxide capture and storage (CCS) leakage scenarios, via haemolymph [HCO 3 - ] regulation. However, metabolic rate remained constant and food consumption decreased under elevated P CO 2 , indicating reduced energy availability. Juveniles at 17°C showed no ability to actively compensate haemolymph pH, resulting in decreased haemolymph pH particularly under CCS conditions. Early benthic juvenile lobsters at 17°C were not able to increase energy intake to offset increased energy demand and therefore appear to be unable to respond to acid-base disturbances due to increased P CO 2   at elevated temperature. Analysis of haemolymph metabolites suggests that, even under control conditions, juveniles were energetically limited. They exhibited high haemolymph [l-lactate], indicating recourse to anaerobic metabolism. Low haemolymph [protein] was linked to minimal non-bicarbonate buffering and reduced oxygen transport capacity. We discuss these results in the context of potential impacts of ongoing ocean change and CCS leakage scenarios on the development of juvenile H. gammarus and future lobster populations and stocks., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Opinion Statement: The treatment of advanced melanoma has undergone a dramatic transformation over the last decade with the advent of targeted and immunomodulatory therapies. This transition from cytotoxic chemotherapy has yielded improvements in both survival and quality of life; yet despite their therapeutic advantages, these treatments have been associated with a diverse range of cutaneous adverse events (AEs). These range from relatively benign eczematous conditions to more severe inflammatory and bullous disorders, and can include induction of second malignancies. AEs can result in serious morbidity and risk of mortality if not recognised and managed early. As a consequence of their novelty, and rapid uptake, these agents have been subject to intense scrutiny and there is a general understanding that cutaneous AEs should be anticipated in treatment plans. Dermatologists should be integrated into management teams to assist in the development of treatment protocols for anticipated common AEs and to provide expert management of more severe, rare or unusual AEs. Our experience has shown a reduction in treatment interruptions, more rapid recognition of unusual AEs and improved management pathways for patients suffering cutaneous AEs.

Coastal ecosystems, including estuaries, are increasingly pressured by expanding hypoxic regions as a result of human activities such as increased release of nutrients and global warming. Hypoxia is often defined as oxygen concentrations below 2 mL O 2 L -1 . However, taxa vary markedly in their sensitivity to hypoxia and can be affected by a broad spectrum of low oxygen levels. To better understand how reduced oxygen availability impacts physiological and molecular processes in invertebrates, we investigated responses of an estuarine amphipod to an ecologically-relevant level of moderate hypoxia (~2.6 mL O 2 L -1 ) or severe hypoxia (~1.3 mL O 2 L -1 ). Moderate hypoxia elicited a reduction in aerobic scope, and widespread changes to gene expression, including upregulation of metabolic genes and stress proteins. Under severe hypoxia, a marked hyperventilatory response associated with maintenance of aerobic performance was accompanied by a muted transcriptional response. This included a return of metabolic genes to baseline levels of expression and downregulation of transcripts involved in protein synthesis, most of which indicate recourse to hypometabolism and/or physiological impairment. We conclude that adverse ecological effects may occur under moderate hypoxia through compromised individual performance and, therefore, even modest declines in future oxygen levels may pose a significant challenge to coastal ecosystems., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Research on the effects of climate change in the marine environment continues to accelerate, yet we know little about the effects of multiple climate drivers in more complex, ecologically relevant settings - especially in sub-tropical and tropical systems. In marine ecosystems, climate change (warming and freshening from land run-off) will increase water column stratification which is favorable for toxin producing dinoflagellates. This can increase the prevalence of toxic microalgal species, leading to bioaccumulation of toxins by filter feeders, such as bivalves, with resultant negative impacts on physiological performance. In this study we manipulated multiple climate drivers (warming, freshening, and acidification), and the availability of toxic microalgae, to determine their impact on the physiological health, and toxin load of the tropical filter-feeding clam, Meretrix meretrix . Using a structural equation modeling (SEM) approach, we found that exposure to projected marine climates resulted in direct negative effects on metabolic and immunological function and, that these effects were often more pronounced in clams exposed to multiple, rather than single climate drivers. Furthermore, our study showed that these physiological responses were modified by indirect effects mediated through the food chain. Specifically, we found that when bivalves were fed with a toxin-producing dinoflagellate ( Alexandrium minutum ) the physiological responses, and toxin load changed differently and in a non-predictable way compared to clams exposed to projected marine climates only. Specifically, oxygen consumption data revealed that these clams did not respond physiologically to climate warming or the combined effects of warming, freshening and acidification. Our results highlight the importance of quantifying both direct and, indirect food chain effects of climate drivers on a key tropical food species, and have important implications for shellfish production and food safety in tropical regions.

Two subspecies of the house mouse, Mus musculus domesticus and Mus musculus musculus, meet in a narrow contact zone across Europe. Mice in the hybrid zone are highly admixed, representing the full range of mixed ancestry from the two subspecies. Given the distinct morphologies of these subspecies, these natural hybrids can be used for genomewide association mapping at sufficiently high resolution to directly infer candidate genes. We focus here on limb bone length differences, which is of special interest for understanding the evolution of developmentally correlated traits. We used 172 first-generation descendants of wild-caught mice from the hybrid zone to measure the length of stylopod (humerus/femur), zeugopod (ulna/tibia) and autopod (metacarpal/metatarsal) elements in skeletal CT scans. We find phenotypic covariation between limb elements in the hybrids similar to patterns previously described in Mus musculus domesticus inbred strains, suggesting that the hybrid genotypes do not influence the covariation pattern in a major way. Mapping was performed using 143,592 SNPs and identified several genomic regions associated with length differences in each bone. Bone length was found to be highly polygenic. None of the candidate regions include the canonical genes known to control embryonic limb development. Instead, we are able to identify candidate genes with known roles in osteoblast differentiation and bone structure determination, as well as recently evolved genes of, as yet, unknown function., (© 2018 John Wiley & Sons Ltd.)

The south west coast of India has been showing a steady increase in shellfish cultivation both for local consumption and fishery export, over recent years. Perna viridis and Crassostrea madrasensis are two species of bivalve molluscs which grow in some selected regions of southern Karnataka, close to the city of Mangalore. In the early 1980s, shellfish consumers in the region were affected by intoxication from Paralytic Shellfish Poison present in local bivalves (clams and oysters) resulting in hospitalisation of many, including one fatality. Since then, there have been no further reports of serious shellfish intoxication and there is little awareness of the risks from natural toxins and no routine monitoring programme in place to protect shellfish consumers. This study presents the findings from the first ever systematic assessment of the presence of marine toxins in mussels and oysters grown in four different shellfish harvesting areas in the region. Shellfish were collected and subjected to analysis for ASP, PSP and lipophilic toxins, as well as a suite of non-EU regulated toxins such as tetrodotoxin and selected cyclic imines. Results revealed the presence of low levels of PSP toxins in oysters throughout the study period. Overall, total toxicities reached a maximum of 10% of the EU regulatory limit of 800 μg STX eq/kg. Toxin profiles were similar to those reported from the 1980 outbreak. No evidence was found for significant levels of ASP and lipophilic toxins, although some cyclic imines were detected, including gymnodimine. The results indicated that the risk to shellfish consumers during this specific study period would have been low. However, with historical evidence for extremely high levels of PSP toxins in molluscs, there is a strong need for routine surveillance of shellfish production areas for marine toxins, in order to mitigate against human health impacts resulting from unexpected harmful algal blooms, with potentially devastating socio-economic consequences., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Numerous loci of large effect have been shown to underlie phenotypic variation between species. However, loci with subtle effects are presumably more frequently involved in microevolutionary processes but have rarely been discovered. We explore the genetic basis of shape variation in the first upper molar of hybrid mice between Mus musculus musculus and M. m. domesticus . We performed the first genome-wide association study for molar shape and used 3D surface morphometrics to quantify subtle variation between individuals. We show that many loci of small effect underlie phenotypic variation, and identify five genomic regions associated with tooth shape; one region contained the gene microphthalmia-associated transcription factor Mitf that has previously been associated with tooth malformations. Using a panel of five mutant laboratory strains, we show the effect of the Mitf gene on tooth shape. This is the first report of a gene causing subtle but consistent variation in tooth shape resembling variation in nature.

Objectives: In addition to the motor and cognitive symptoms that people with Parkinson's disease (PD) typically experience, psychiatric symptoms such as anxiety are also commonly experienced by people with PD. The overall purpose of the current study was to explore driving and driving cessation for people with PD and their families., Methods: A descriptive phenomenological approach was employed using semi-structured interviews and 34 interviews were conducted overall (22 participants with PD and 12 family members)., Results: Experiences of anxiety and worry that had an impact on driving and driving cessation arose from the data, and this article specifically captured the lived experience of anxiety with driving and driving cessation for people with PD and their families., Conclusions: Findings reveal that the experience of anxiety while driving, as well as anticipatory anxiety and/or worry related to driving cessation, affect the driving experiences and wellbeing of people with PD., Clinical Implications: Implications of the study findings are outlined and aim to provide information about the needs to enable future clinical directions to be developed.

Glucose is an important metabolic fuel and circulating levels are tightly regulated in most mammals, but can drop when body fuel reserves become critically low. Glucose is mobilized rapidly from liver and muscle during stress in response to increased circulating cortisol. Blood glucose levels can thus be of value in conservation as an indicator of nutritional status and may be a useful, rapid assessment marker for acute or chronic stress. However, seals show unusual glucose regulation: circulating levels are high and insulin sensitivity is limited. Accurate blood glucose measurement is therefore vital to enable meaningful health and physiological assessments in captive, wild or rehabilitated seals and to explore its utility as a marker of conservation relevance in these animals. Point-of-care devices are simple, portable, relatively cheap and use less blood compared with traditional sampling approaches, making them useful in conservation-related monitoring. We investigated the accuracy of a hand-held glucometer for 'instant' field measurement of blood glucose, compared with blood drawing followed by laboratory testing, in wild grey seals ( Halichoerus grypus ), a species used as an indicator for Good Environmental Status in European waters. The glucometer showed high precision, but low accuracy, relative to laboratory measurements, and was least accurate at extreme values. It did not provide a reliable alternative to plasma analysis. Poor correlation between methods may be due to suboptimal field conditions, greater and more variable haematocrit, faster erythrocyte settling rate and/or lipaemia in seals. Glucometers must therefore be rigorously tested before use in new species and demographic groups. Sampling, processing and glucose determination methods have major implications for conclusions regarding glucose regulation, and health assessment in seals generally, which is important in species of conservation concern and in development of circulating glucose as a marker of stress or nutritional state for use in management and monitoring.

Physiological responses to temperature are known to be a major determinant of species distributions and can dictate the sensitivity of populations to global warming. In contrast, little is known about how other major global change drivers, such as ocean acidification (OA), will shape species distributions in the future. Here, by integrating population genetics with experimental data for growth and mineralization, physiology and metabolomics, we demonstrate that the sensitivity of populations of the gastropod Littorina littorea to future OA is shaped by regional adaptation. Individuals from populations towards the edges of the natural latitudinal range in the Northeast Atlantic exhibit greater shell dissolution and the inability to upregulate their metabolism when exposed to low pH, thus appearing most sensitive to low seawater pH. Our results suggest that future levels of OA could mediate temperature-driven shifts in species distributions, thereby influencing future biogeography and the functioning of marine ecosystems.

Purpose: We prospectively compared computed tomography (CT)- and magnetic resonance imaging (MRI)-based high-risk clinical target volume (HR-CTV) contours at the time of brachytherapy for cervical cancer in an effort to identify patients who might benefit most from MRI-based planning., Methods and Materials: Thirty-seven patients who had undergone a pretreatment diagnostic MRI scan were included in the analysis. We delineated the HR-CTV on the brachytherapy CT and brachytherapy MRI scans independently for each patient. We then calculated the absolute volumes for each HR-CTV and the Dice coefficient of similarity (DC, a measure of spatial agreement) for the HR-CTV contours. We identified the clinical and tumor factors associated with (1) a discrepancy in volume between the CT HR-CTV and MRI HR-CTV contours; and (2) DC. The mean values were compared using 1-way analysis of variance or paired or unpaired t tests, as appropriate. Simple and multivariable linear regression analyses were used to model the effects of covariates on the outcomes., Results: Patients with International Federation of Gynecology and Obstetrics stage IB to IVA cervical cancer were treated with intracavitary brachytherapy using tandem and ovoid (n=33) or tandem and cylinder (n=4) applicators. The mean CT HR-CTV volume (44.1 cm 3 ) was larger than the mean MRI HR-CTV volume (35.1 cm 3 ; P<.0001, paired t test). On multivariable analysis, a higher body mass index (BMI) and tumor size ≥5 cm with parametrial invasion on the MRI scan at diagnosis were associated with an increased discrepancy in volume between the HR-CTV contours (P<.02 for both). In addition, the spatial agreement (as measured by DC) between the HR-CTV contours decreased with an increasing BMI (P=.013)., Conclusions: We recommend MRI-based brachytherapy planning for patients with tumors >5 cm and parametrial invasion on MRI at diagnosis and for those with a high BMI., (Copyright © 2016. Published by Elsevier Inc.)

There is growing evidence that climate change will increase the prevalence of toxic algae and harmful bacteria, which can accumulate in marine bivalves. However, we know little about any possible interactions between exposure to these microorganisms and the effects of climate change on bivalve health, or about how this may affect the bivalve toxin-pathogen load. In mesocosm experiments, mussels, Perna viridis, were subjected to simulated climate change (warming and/or hyposalinity) and exposed to harmful bacteria and/or toxin-producing dinoflagellates. We found significant interactions between climate change and these microbes on metabolic and/or immunobiological function and toxin-pathogen load in mussels. Surprisingly, however, these effects were virtually eliminated when mussels were exposed to both harmful microorganisms simultaneously. This study is the first to examine the effects of climate change on determining mussel toxin-pathogen load in an ecologically relevant, multi-trophic context. The results may have considerable implications for seafood safety.

Background: Huntington's disease (HD) causes progressive atrophy to the striatum, a critical node in frontostriatal circuitry. Maintenance of motor function is dependent on functional connectivity of these premotor, motor, and dorsolateral frontostriatal circuits, and structural integrity of the striatum itself. We aimed to investigate whether size and shape of the striatum as a measure of frontostriatal circuit structural integrity was correlated with functional frontostriatal electrophysiological neural premotor processing (contingent negative variation, CNV), to better understand motoric structure-function relationships in early HD., Methods: Magnetic resonance imaging (MRI) scans and electrophysiological (EEG) measures of premotor processing were obtained from a combined HD group (12 presymptomatic, 7 symptomatic). Manual segmentation of caudate and putamen was conducted with subsequent shape analysis. Separate correlational analyses (volume and shape) included covariates of age, gender, intracranial volume, and time between EEG and MRI., Results: Right caudate volume correlated with early CNV latency over frontocentral regions and late CNV frontally, whereas right caudate shape correlated with early CNV latency centrally. Left caudate volume correlated with early CNV latency over centroparietal regions and late CNV frontally. Right and left putamen volumes correlated with early CNV latency frontally, and right and left putamen shape/volume correlated with parietal CNV slope., Conclusions: Timing (latency) and pattern (slope) of frontostriatal circuit-mediated premotor functional activation across scalp regions were correlated with abnormalities in structural integrity of the key frontostriatal circuit component, the striatum (size and shape). This was accompanied by normal reaction times, suggesting it may be undetected in regular tasks due to preserved motor "performance." Such differences in functional activation may reflect atrophy-based frontostriatal circuitry despecialization and/or compensatory recruitment of additional brain regions.

Craniofacial shape differences between taxa have often been linked to environmental adaptation, e.g., new food sources, or have been studied in the context of domestication. Evidence for the genetic basis of such phenotypic differences to date suggests that between-species as well as between-population variation has an oligogenic basis, i.e., few loci of large effect explain most of the variation. In mice, it has been shown that within-population craniofacial variation has a highly polygenic basis, but there are no data regarding the genetic basis of between-species differences in natural populations. Here, we address this question using a phenotype-focused approach. Using 3D geometric morphometrics, we phenotyped a panel of mice derived from a natural hybrid zone between Mus musculus domesticus and Mus mus musculus and quantify the transition of craniofacial shape along the hybridization gradient. We find a continuous shape transition along the hybridization gradient and unaltered developmental stability associated with hybridization. This suggests that the morphospace between the two subspecies is continuous despite reproductive isolation and strong barriers to gene flow. We show that quantitative changes in overall genome composition generate quantitative changes in craniofacial shape; this supports a highly polygenic basis for between-species craniofacial differences in the house mouse. We discuss our findings in the context of oligogenic versus polygenic models of the genetic architecture of morphological traits.

Selective BRAF inhibitors (BRAFi) yield objective responses in 50% of patients with metastatic BRAF V600E mutant melanoma. Adding an MEK inhibitor increases this response rate to 70%. Limited data are available on the outcomes of unresectable stage III patients, and it remains unclear whether BRAF-targeted therapy can be utilized as a neoadjuvant strategy. Data on patients with advanced locoregional BRAF V600E mutant melanoma treated with BRAF-targeted therapy at Moffitt Cancer Center were analyzed to determine response rates, subsequent resection rates after tumor downsizing, pathologic responses, and patient survival. Fifteen patients with locoregional disease treated with BRAF-targeted therapy, either BRAFi alone (vemurafenib; 11 patients) or a combination of BRAFi and an MEK inhibitor (dabrafenib plus trametinib or placebo; four patients), were identified. The median age was 50 years; the median follow-up was 25.4 months. The median BRAF-targeted therapy treatment duration was 6.0 months (range 1.2-29.4 months). Response Evaluation Criteria In Solid Tumors-based evaluation demonstrated objective response in 11 patients (73.3%). Six patients underwent resection of the remaining disease after therapy. Pathological analysis showed complete pathologic response (n=2), partial pathologic response (n=2), or no pathologic response (n=2). Four of six patients undergoing surgery have been alive for more than 2 years, including three patients currently free from active disease. No complications attributable to BRAF-targeted therapy were observed in the perioperative period. Dose reduction or discontinuation because of toxicities occurred in 10/15 patients. Neoadjuvant BRAF-targeted therapy may be effective in advanced locoregional BRAF V600E mutant melanoma patients in increasing resectability, yielding pathological responses, and achieving prolonged survival.

We are starting to understand the relationship between metabolic rate responses and species' ability to respond to exposure to high p CO 2 . However, most of our knowledge has come from investigations of single species. The examination of metabolic responses of closely related species with differing distributions around natural elevated CO 2 areas may be useful to inform our understanding of their adaptive significance. Furthermore, little is known about the physiological responses of marine invertebrate juveniles to high p CO 2 , despite the fact they are known to be sensitive to other stressors, often acting as bottlenecks for future species success. We conducted an in situ transplant experiment using juveniles of isopods found living inside and around a high p CO 2 vent (Ischia, Italy): the CO 2 'tolerant' Dynamene bifida and 'sensitive' Cymodoce truncata and Dynamene torelliae . This allowed us to test for any generality of the hypothesis that p CO 2 sensitive marine invertebrates may be those that experience trade-offs between energy metabolism and cellular homoeostasis under high p CO 2 conditions. Both sensitive species were able to maintain their energy metabolism under high p CO 2 conditions, but in C. truncata this may occur at the expense of [carbonic anhydrase], confirming our hypothesis. By comparison, the tolerant D. bifida appeared metabolically well adapted to high p CO 2 , being able to upregulate ATP production without recourse to anaerobiosis. These isopods are important keystone species; however, given they differ in their metabolic responses to future p CO 2 , shifts in the structure of the marine ecosystems they inhabit may be expected under future ocean acidification conditions., Competing Interests: All authors declare they have no conflict of interest. Ethical approval All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Background: Huntington's disease (HD) causes progressive motor dysfunction through characteristic atrophy. Changes to neural structure begin in premanifest stages yet individuals are able to maintain a high degree of function, suggesting involvement of supportive processing during motor performance. Electroencephalography (EEG) enables the investigation of subtle impairments at the neuronal level, and possible compensatory strategies, by examining differential activation patterns. We aimed to use EEG to investigate neural motor processing (via the Readiness Potential; RP), premotor processing and sensorimotor integration (Contingent Negative Variation; CNV) during simple motor performance in HD., Methods: We assessed neural activity associated with motor preparation and processing in 20 premanifest (pre-HD), 14 symptomatic HD (symp-HD), and 17 healthy controls. Participants performed sequential tapping within two experimental paradigms (simple tapping; Go/No-Go). RP and CNV potentials were calculated separately for each group., Results: Motor components and behavioural measures did not distinguish pre-HD from controls. Compared to controls and pre-HD, symp-HD demonstrated significantly reduced relative amplitude and latency of the RP, whereas controls and pre-HD did not differ. However, early CNV was found to significantly differ between control and pre-HD groups, due to enhanced early CNV in pre-HD., Conclusions: For the first time, we provide evidence of atypical activation during preparatory processing in pre-HD. The increased activation during this early stage of the disease may reflect ancillary processing in the form of recruitment of additional neural resources for adequate motor preparation, despite atrophic disruption to structure and circuitry. We propose an early adaptive compensation mechanism in pre-HD during motor preparation.

Species distributions and ecology can often be explained by their physiological sensitivity to environmental conditions. Whilst we have a relatively good understanding of how these are shaped by temperature, for other emerging drivers, such as PCO2  we know relatively little. The marine polychaete Sabella spallanzanii increases its metabolic rate when exposed to high PCO2  conditions and remains absent from the CO2 vent of Ischia. To understand new possible pathways of sensitivity to CO2 in marine ectotherms, we examined the metabolic plasticity of S. spallanzanii exposed in situ to elevated PCO2  by measuring fundamental metabolite and carbonic anhydrase concentrations. We show that whilst this species can survive elevated PCO2  conditions in the short term, and exhibits an increase in energy metabolism, this is accompanied by a significant decrease in carbonic anhydrase concentration. These homeostatic changes are unlikely to be sustainable in the longer term, indicating S. spallanzanii may struggle with future high PCO2  conditions., (© 2015. Published by The Company of Biologists Ltd.)

Recent evidence suggests that natural selection operating on hosts to maintain their microbiome contributes to the emergence of new species, that is, the 'hologenomic basis of speciation'. Here we analyse the gut microbiota of two house mice subspecies, Mus musculus musculus and M. m. domesticus, across their Central European hybrid zone, in addition to hybrids generated in the lab. Hybrid mice display widespread transgressive phenotypes (that is, exceed or fall short of parental values) in a variety of measures of bacterial community structure, which reveals the importance of stabilizing selection operating on the intestinal microbiome within species. Further genetic and immunological analyses reveal genetic incompatibilities, aberrant immune gene expression and increased intestinal pathology associated with altered community structure among hybrids. These results provide unique insight into the consequences of evolutionary divergence in a vertebrate 'hologenome', which may be an unrecognized contributing factor to reproductive isolation in this taxonomic group.

Mapping hybrid defects in contact zones between incipient species can identify genomic regions contributing to reproductive isolation and reveal genetic mechanisms of speciation. The house mouse features a rare combination of sophisticated genetic tools and natural hybrid zones between subspecies. Male hybrids often show reduced fertility, a common reproductive barrier between incipient species. Laboratory crosses have identified sterility loci, but each encompasses hundreds of genes. We map genetic determinants of testis weight and testis gene expression using offspring of mice captured in a hybrid zone between M. musculus musculus and M. m. domesticus. Many generations of admixture enables high-resolution mapping of loci contributing to these sterility-related phenotypes. We identify complex interactions among sterility loci, suggesting multiple, non-independent genetic incompatibilities contribute to barriers to gene flow in the hybrid zone.

The identification of the genes involved in morphological variation in nature is still a major challenge. Here, we explore a new approach: we combine 178 samples from a natural hybrid zone between two subspecies of the house mouse (Mus musculus domesticus and Mus musculus musculus), and high coverage of the genome (~ 145K SNPs) to identify loci underlying craniofacial shape variation. Due to the long history of recombination in the hybrid zone, high mapping resolution is anticipated. The combination of genomes from subspecies allows the mapping of both, variation within subspecies and inter-subspecific differences, thereby increasing the overall amount of causal genetic variation that can be detected. Skull and mandible shape were measured using 3D landmarks and geometric morphometrics. Using principal component axes as phenotypes, and a linear mixed model accounting for genetic relatedness in the mapping populations, we identified nine genomic regions associated with skull shape and 10 with mandible shape. High mapping resolution (median size of significant regions = 148 kb) enabled identification of single or few candidate genes in most cases. Some of the genes act as regulators or modifiers of signalling pathways relevant for morphological development and bone formation, including several with known craniofacial phenotypes in mice and humans. The significant associations combined explain 13% and 7% of the skull and mandible shape variation, respectively. In addition, a positive correlation was found between chromosomal length and proportion of variation explained. Our results suggest a complex genetic architecture for shape traits and support a polygenic model., (© 2014 The Authors. Molecular Ecology Published by John Wiley & Sons Ltd.)

Hybrid dysfunction, a common feature of reproductive barriers between species, is often caused by negative epistasis between loci ("Dobzhansky-Muller incompatibilities"). The nature and complexity of hybrid incompatibilities remain poorly understood because identifying interacting loci that affect complex phenotypes is difficult. With subspecies in the early stages of speciation, an array of genetic tools, and detailed knowledge of reproductive biology, house mice (Mus musculus) provide a model system for dissecting hybrid incompatibilities. Male hybrids between M. musculus subspecies often show reduced fertility. Previous studies identified loci and several X chromosome-autosome interactions that contribute to sterility. To characterize the genetic basis of hybrid sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven 'hotspots,' seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL-but not cis eQTL-were substantially lower when mapping was restricted to a 'fertile' subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility. The integrated mapping approach we employed is applicable in a broad range of organisms and we advocate for widespread adoption of a network-centered approach in speciation genetics.

Animal models have historically informed veterinary and human pathophysiology. Next-generation genomic sequencing and molecular analyses using analytes derived from tissue require integrative approaches to determine macroanalyte integrity as well as morphology for imaging algorithms that can extend translational applications. The field of biospecimen science and biobanking will play critical roles in tissue sample collection and processing to ensure the integrity of macromolecules, aid experimental design, and provide more accurate and reproducible downstream genomic data. Herein, we employ animal experiments to combine protein expression analysis by microscopy with RNA integrity number and quantitative measures of morphologic changes of autolysis. These analyses can be used to predict the effect of preanalytic variables and provide the basis for standardized methods in tissue sample collection and processing. We also discuss the application of digital imaging with quantitative RNA and tissue-based protein measurements to show that genomic methods augment traditional in vivo imaging to support biospecimen science. To make these observations, we have established a time course experiment of murine kidney tissues that predicts conventional measures of RNA integrity by RIN analysis and provides reliable and accurate measures of biospecimen integrity and fitness, in particular for time points less than 3 hours post-tissue resection.

The injection of anthropogenically-produced CO2 into the atmosphere will lead to an increase in temperature and a decrease in pH at the surface of the oceans by 2100. Marine intertidal organisms possess the ability to cope in the short term with environmental fluctuations exceeding predicted values. However, how they will cope with chronic exposure to elevated temperature and pCO2 is virtually unknown. In addition, individuals from the same species/population often show remarkable levels of variation in their responses to complex climatic changes: in particular, variation in metabolic rates often is linked to differences in individuals' performances and fitness. Despite its ecological and evolutionary importance, inter-individual variation has rarely been investigated within the context of climatic changes, and most investigations have typically employed orthogonal experimental designs paired to analyses of independent samples. Although this is undoubtedly a powerful and useful approach, it may not be the most appropriate for understanding all alterations of biological functions in response to environmental changes. An individual approach arguably should be favored when trying to describe organisms' responses to climatic change. Consequently, to test which approach had the greater power to discriminate the intensity and direction of an organism's response to complex climatic changes, we investigated the extracellular osmo/iono-regulatory abilities, upper thermal tolerances (UTTs), and metabolic rates of individual adults of an intertidal amphipod, Echinogammarus marinus, exposed for 15 days to combined elevated temperature and pCO2. The individual approach led to stronger and different predictions on how ectotherms will likely respond to ongoing complex climatic change, compared with the independent approaches. Consequently, this may call into question the relevance, or even the validity, of some of the predictions made to date. Finally, we argue that treating individual differences as biologically meaningful can lead to a better understanding of the physiological responses themselves and the selective processes that will occur with complex climatic changes; selection will likely play a crucial role in defining species' responses to future environmental changes. Individuals with higher metabolic rates were also characterized by greater extracellular osmo/iono-regulative abilities and higher UTTs, and thus there appeared to be no evolutionary trade-offs between these functions. However, as individuals with greater metabolic rates also have greater costs for maintenance and repair, and likely a lower fraction of energy available for growth and reproduction, trade-offs between life-history and physiological performance may still arise.

Assessing genetic variation underlying ecologically important traits is increasingly of interest and importance in population and conservation genetics. For some groups generally useful markers exist for examining the relative role of selection and drift in shaping genetic diversity e.g. the major histocompatibility complex in vertebrates and self-incompatibility loci in plants. For invertebrates there is no such generally useful locus. However, phosphoglucose isomerase (Pgi) has been proposed as a useful functional marker in the conservation genetics of invertebrates. Where thermal microclimate varies, balanced polymorphisms may be maintained due to trade-offs between thermally stable and kinetically advantageous allelic forms. We here report very low levels of Pgi variation in bumblebees rendering this locus to be of little use as an adaptive marker in a conservation genetics context in this group. Potential explanations for this lack of variation are considered.

There is a growing body of evidence implicating the involvement of crustacean hyperglycaemic hormone (CHH) in ionic homeostasis in decapod crustaceans. However, little is known regarding hormonally influenced osmoregulatory processes in terrestrial decapods. As many terrestrial decapods experience opposing seasonal demands upon ionoregulatory physiologies, we reasoned that these would make interesting models in which to study the effect of CHH upon these phenomena. In particular, those (tropical) species that also undergo seasonal migrations might be especially informative, as we know relatively little regarding the nature of CHHs in terrestrial decapods, and hormonally mediated responses to seasonal changes in metabolic demands might also be superimposed or otherwise integrated with those associated with ionic homeostasis. Using Discoplax celeste as a model crab that experiences seasonal extremes in water availability, and exhibits diurnal and migratory activity patterns, we identified two CHHs in the sinus gland. We biochemically characterised (cDNA cloning) one CHH and functionally characterised (in terms of dose-dependent hyperglycaemic responses and glucose-dependent negative feedback loops) both CHHs. Whole-animal in situ branchial chamber (22)NaCl perfusion experiments showed that injection of both CHHs increased gill Na(+) uptake in a seasonally dependent manner, and (51)Cr-EDTA clearance experiments demonstrated that CHH increased urine production by the antennal gland. Seasonal and salinity-dependent differences in haemolymph CHH titre further implicated CHH in osmoregulatory processes. Intriguingly, CHH appeared to have no effect on gill Na(+)/K(+)-ATPase or V-ATPase activity, suggesting unknown mechanisms of this hormone's action on Na(+) transport across gill epithelia.

In response to on-going biodiversity loss, conservation genetics has established itself as an important branch of biology. Historically concentrating on assessing stochastic processes using neutral loci, there has been a recent surge of interest in understanding and quantifying variation at loci underlying ecologically important traits. To this end, patterns of selection and polymorphism at these loci must be characterized. Loci underlying immunity make good candidates in this context: they are expected to be important for population persistence and may exhibit diversifying or divergent selection. Predictions regarding the pattern of selection expected at immune system loci have been based on their interactions with pathogens, however, published studies report mixed results as to whether these are borne out or not. Here, polymorphism and selection is examined for three innate immune system loci in bumblebees: a peptidoglycan recognition protein, a putative alpha-macroglobulin, and scavenger receptor. Both intra- and inter-specific sequence variation is quantified. Very little polymorphism was encountered, precluding robust tests of selection. However, the lack of inter-specific polymorphisms suggests a lack of positive selection for the regions sequenced. Results are discussed with respect to population genetic predictions and generation of a specific immune response in insects. Alternative loci and methods for studying adaptive genetic variation in a conservation context are considered.

Barriers to gene flow between naturally hybridizing taxa reveal the initial stages of speciation. Reduced hybrid fertility is a common feature of reproductive barriers separating recently diverged species. In house mice (Mus musculus), hybrid male sterility has been studied extensively using experimental crosses between subspecies. Here, we present the first detailed picture of hybrid male fertility in the European M. m. domesticus-M. m. musculus hybrid zone. Complete sterility appears rare or absent in natural hybrids but a large proportion of males (~30%) have sperm count or relative testis weight below the range in pure subspecies, and likely suffer reduced fertility. Comparison of a suite of traits related to fertility among subfertile males indicates reduced hybrid fertility in the contact zone is highly variable among individuals and ancestry groups in the type, number, and severity of spermatogenesis defects present. Taken together, these results suggest multiple underlying genetic incompatibilities are segregating in the hybrid zone, which likely contribute to reproductive isolation between subspecies., (© 2011 The Author(s). Evolution© 2011 The Society for the Study of Evolution.)