DOCK3 is a dosage-sensitive regulator of skeletal muscle and Duchenne muscular dystrophy-associated pathologies.

DOCK3 is a member of the DOCK family of guanine nucleotide exchange factors that regulate cell migration, fusion and viability. Previously, we identified a dysregulated miR-486/DOCK3 signaling cascade in dystrophin-deficient muscle, which resulted in the overexpression of DOCK3; however, little is known about the role of DOCK3 in muscle. Here, we characterize the functional role of DOCK3 in normal and dystrophic skeletal muscle. Utilizing Dock3 global knockout (Dock3 KO) mice, we found that the haploinsufficiency of Dock3 in Duchenne muscular dystrophy mice improved dystrophic muscle pathologies; however, complete loss of Dock3 worsened muscle function. Adult Dock3 KO mice have impaired muscle function and Dock3 KO myoblasts are defective for myogenic differentiation. Transcriptomic analyses of Dock3 KO muscles reveal a decrease in myogenic factors and pathways involved in muscle differentiation. These studies identify DOCK3 as a novel modulator of muscle health and may yield therapeutic targets for treating dystrophic muscle symptoms.

Indigenous Systems of Management for Culturally and Ecologically Resilient Pacific Salmon (Oncorhynchus spp.) Fisheries.

Pacific salmon (Oncorhynchus spp.) are at the center of social-ecological systems that have supported Indigenous peoples around the North Pacific Rim since time immemorial. Through generations of interdependence with salmon, Indigenous Peoples developed sophisticated systems of management involving cultural and spiritual beliefs, and stewardship practices. Colonization radically altered these social-ecological systems, disrupting Indigenous management, consolidating authority within colonial governments, and moving most harvest into mixed-stock fisheries. We review Indigenous management of salmon, including selective fishing technologies, harvest practices, and governance grounded in multigenerational place-based knowledge. These systems and practices showcase pathways for sustained productivity and resilience in contemporary salmon fisheries. Contrasting Indigenous systems with contemporary management, we document vulnerabilities of colonial governance and harvest management that have contributed to declining salmon fisheries in many locations. We suggest that revitalizing traditional systems of salmon management can improve prospects for sustainable fisheries and healthy fishing communities and identify opportunities for their resurgence.

hnRNP L is essential for myogenic differentiation and modulates myotonic dystrophy pathologies.

INTRODUCTION: RNA-binding proteins (RBPs) play an important role in skeletal muscle development and disease by regulating RNA splicing. In myotonic dystrophy type 1 (DM1), the RBP MBNL1 (muscleblind-like) is sequestered by toxic CUG repeats, leading to missplicing of MBNL1 targets. Mounting evidence from the literature has implicated other factors in the pathogenesis of DM1. Herein we sought to evaluate the functional role of the splicing factor hnRNP L in normal and DM1 muscle cells. METHODS: Co-immunoprecipitation assays using hnRNPL and MBNL1 expression constructs and splicing profiling in normal and DM1 muscle cell lines were performed. Zebrafish morpholinos targeting hnrpl and hnrnpl2 were injected into one-cell zebrafish for developmental and muscle analysis. In human myoblasts downregulation of hnRNP L was achieved with shRNAi. Ascochlorin administration to DM1 myoblasts was performed and expression of the CUG repeats, DM1 splicing biomarkers, and hnRNP L expression levels were evaluated. RESULTS: Using DM1 patient myoblast cell lines we observed the formation of abnormal hnRNP L nuclear foci within and outside the expanded CUG repeats, suggesting a role for this factor in DM1 pathology. We showed that the antiviral and antitumorigenic isoprenoid compound ascochlorin increased MBNL1 and hnRNP L expression levels. Drug treatment of DM1 muscle cells with ascochlorin partially rescued missplicing of established early biomarkers of DM1 and improved the defective myotube formation displayed by DM1 muscle cells. DISCUSSION: Together, these studies revealed that hnRNP L can modulate DM1 pathologies and is a potential therapeutic target.

The SINE Compound KPT-350 Blocks Dystrophic Pathologies in DMD Zebrafish and Mice.

Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease that is caused by the loss of functional dystrophin protein in cardiac and skeletal muscles. DMD patient muscles become weakened, leading to eventual myofiber breakdown and replacement with fibrotic and adipose tissues. Inflammation drives the pathogenic processes through releasing inflammatory cytokines and other factors that promote skeletal muscle degeneration and contributing to the loss of motor function. Selective inhibitors of nuclear export (SINEs) are a class of compounds that function by inhibiting the nuclear export protein exportin 1 (XPO1). The XPO1 protein is an important regulator of key inflammatory and neurological factors that drive inflammation and neurotoxicity in various neurological and neuromuscular diseases. Here, we demonstrate that SINE compound KPT-350 can ameliorate dystrophic-associated pathologies in the muscles of DMD models of zebrafish and mice. Thus, SINE compounds are a promising novel strategy for blocking dystrophic symptoms and could be used in combinatorial treatments for DMD.

Provider Perceptions of Hepatitis C Treatment Adherence and Initiation.

BACKGROUND: Significant disparities in hepatitis C (HCV) treatment existed in the interferon treatment era, such that patients with mental health and substance use disorders were less likely to be treated. We aimed to evaluate whether these perceptions continue to influence HCV treatment decisions. METHODS: We e-mailed HCV providers a survey to assess their perceptions of barriers to HCV treatment adherence and initiation. We assessed the frequency of perceived barriers and willingness to initiate HCV treatment in patients with these barriers. We identified a group of providers more willing to treat patients with perceived barriers to adherence and determined the associated provider characteristics using Spearman's rho and Wilcoxon rank-sum tests. RESULTS: A total of 103 providers (29%) responded to the survey. The most commonly endorsed perceived barriers to adherence were homelessness (65%), ongoing drug (58%), and ongoing alcohol use (33%). However, 90%, 68%, and 90% of providers were still willing to treat patients with these comorbidities, respectively. Ongoing drug use was the most common reason providers were never or rarely willing to initiate HCV treatment. Providers who were less willing to initiate treatment more frequently endorsed patient-related determinants of adherence, while providers who were more willing to initiate treatment more frequently endorsed provider-based barriers to adherence (e.g., communication). CONCLUSIONS: Most responding providers were willing to initiate HCV treatment in all patients, despite the presence of perceived barriers to adherence or previous contraindications to interferon-based treatments. Ongoing substance use remains the most prominent influencer in the decision not to treat.

Determinants of Hepatitis C Treatment Adherence and Treatment Completion Among Veterans in the Direct Acting Antiviral Era.

BACKGROUND: Despite the availability of direct acting antiviral medications (DAAs), there are ongoing concerns about adherence to hepatitis C virus (HCV) treatment. We sought to understand the barriers to and facilitators of DAA adherence in the Veteran population. METHODS: Patients completed semi-structured interviews focused on barriers to and facilitators of HCV treatment adherence both pre- and post-DAA treatment. Adherence was assessed via provider pill count and self-report. Thematic analyses were conducted in the qualitative software program Atlas.ti in order to understand anticipated barriers to and facilitators of treatment adherence and completion. Charts were reviewed for clinical data and sustained virologic response (SVR12). RESULTS: Of 40 patients, 15 had cirrhosis and 10 had prior interferon-based treatment. Pre-treatment interviews revealed anticipated barriers to adherence such as side effects (n = 21) and forgetting pills (n = 11). Most patients (n = 27) reported following provider advice, and others had unique reasons not to (e.g., feeling like a "guinea pig"). Post-treatment interviews uncovered facilitators of treatment including wanting to cure HCV (n = 17), positive results (n = 18), and minimal side effects (n = 15). Three patients (8%) did not complete therapy (whom we further elaborate on) and 6 (15%) missed doses but completed treatment. SVR12 was achieved by all participants who completed therapy (93%). Patients who did not complete therapy or missed doses were all treatment naïve, mostly non-cirrhotic (8 of 9), and often anticipated concerns with forgetting their medications. CONCLUSIONS: This qualitative study uncovered several unanticipated determinants of HCV treatment completion and provides rationale for several targeted interventions such as incorporating structured positive reinforcement.

Searching for responsible and sustainable recreational fisheries in the Anthropocene.

Recreational fisheries that use rod and reel (i.e., angling) operate around the globe in diverse freshwater and marine habitats, targeting many different gamefish species and engaging at least 220 million participants. The motivations for fishing vary extensively; whether anglers engage in catch-and-release or are harvest-oriented, there is strong potential for recreational fisheries to be conducted in a manner that is both responsible and sustainable. There are many examples of recreational fisheries that are well-managed where anglers, the angling industry and managers engage in responsible behaviours that both contribute to long-term sustainability of fish populations and the sector. Yet, recreational fisheries do not operate in a vacuum; fish populations face threats and stressors including harvest from other sectors as well as environmental change, a defining characteristic of the Anthropocene. We argue that the future of recreational fisheries and indeed many wild fish populations and aquatic ecosystems depends on having responsible and sustainable (R&S) recreational fisheries whilst, where possible, addressing, or at least lobbying for increased awareness about the threats to recreational fisheries emanating from outside the sector (e.g., climate change). Here, we first consider how the concepts of R&S intersect in the recreational fishing sector in an increasingly complex socio-cultural context. Next, we explore the role of the angler, angling industry and decision-makers in achieving R&S fisheries. We extend this idea further by considering the consequences of a future without recreational fisheries (either because of failures related to R&S) and explore a pertinent case study situated in Uttarakahand, India. Unlike other fisheries sectors where the number of participants is relatively small, recreational angling participants are numerous and widespread, such that if their actions are responsible, they have the potential to be a key voice for conservation and serve as a major force for good in the Anthropocene. What remains to be seen is whether this will be achieved, or if failure will occur to the point that recreational fisheries face increasing pressure to cease, as a result of external environmental threats, the environmental effects of recreational fishing and emerging ethical concerns about the welfare of angled fish.

Fatalistic Cancer Beliefs and Information Seeking in Formerly Incarcerated African-American and Hispanic Men: Implications for Cancer Health Communication and Research.

African-American and Hispanic men are disproportionately affected by cancer experiencing higher rates of cancer-related morbidity and mortality for many cancers (but not all). These challenges may be magnified for a subpopulation of African-American and Hispanic men who have been incarcerated. A survey assessing demographics, incarceration experience, psychosocial, behavioral, and cancer health information seeking was administered to 230 previously incarcerated men aged 35 years and older. Data analysis was performed to assess the association between fatalism, perceived susceptibility, and health information seeking in this population. This study revealed the following: the majority of the participants (68.7%) held the fatalistic belief: "When I think of cancer, I automatically think of death." Second, the fatalistic belief, "There's not much you can do to lower your chances of getting cancer," is more prevalent among those who perceived a higher risk of developing cancer. Third, older participants (those between 55 and 70 years old) and widowed are less likely to think of death when they think of cancer. In addition, those who use the Internet to look for health or medical information (i.e., engaging in health information seeking) are less likely to agree with the fatalistic belief: "It seems like everything causes cancer." Given the high incidence of certain cancers among African-American and Hispanic men and the vulnerability of those involved in the criminal justice system, our findings highlight the importance of understanding perceived susceptibility to cancer, fatalistic beliefs about cancer, and information seeking in formerly incarcerated men.

Primary Care and Hepatology Provider-Perceived Barriers to and Facilitators of Hepatitis C Treatment Candidacy and Adherence.

BACKGROUND: Provider perceptions regarding barriers to and facilitators of hepatitis C (HCV) treatment initiation and adherence have not been fully evaluated in the interferon-free treatment era. New treatments have provided opportunities for non-specialists to treat HCV, underscoring the importance of understanding primary care provider (PCP) and specialist perspectives. METHODS: Based on qualitative sampling principles, 12 PCPs and 12 hepatology providers (HPs) from the VA Pittsburgh Healthcare System completed audio-recorded semi-structured interviews. Qualitative analysts coded perceived barriers and facilitators from the interviews with 100% double coding. Codes were thematized and analyzed using Atlas.ti. RESULTS: Key barriers to treatment described by HPs and PCPs included patients' substance use disorders, mental health, transportation availability, history of non-adherence, and concern about side effects. PCPs also focused on medication cost as a system-based barrier. The main facilitators of treatment initiation and adherence described by both HPs and PCPs were provider education and encouragement. HPs focused almost exclusively on provider-based facilitators, while PCPs noted patient-based facilitators including past adherence, media exposure to information about HCV medications, a desire to clear the virus, and positive feedback regarding treatment response. CONCLUSIONS: Providers generally focused on perceived patient-level barriers to HCV treatment initiation and adherence, as well as provider-level facilitators; PCPs additionally noted patient preferences and system-level issues that guide decision making regarding treatment initiation. While HPs focused almost exclusively on provider-level facilitators, PCPs additionally focused on patient-level facilitators of treatment. These data provide novel insights and suggest focusing on patient, provider, and system-level strategies to further improve HCV treatment initiation and adherence.

Macronutrient balancing affects patch departure by guerezas (Colobus guereza).

Foraging strategies are central in shaping social structure and grouping patterns in primates. We address Colobus guereza foraging strategies by investigating their patch departure decisions in relation to diet composition and nutrition. We examine whether guerezas are constrained in their intake of food in patches and thereby forage according to a fixed amount strategy that dictates patch departure. Additionally, we assess whether guereza employ a fixed time strategy or attempt to balance nutrients when foraging. We measured food patch occupancy time, intake rates, and analyzed foods for macronutrients, fiber, and condensed tannins. We determined that guerezas do not employ a fixed time foraging strategy; patch residence time varied widely between 1 and 290 min. They also did not depart patches or stop eating when they reached a specific intake of dry mass, macronutrients, or condensed tannins. However, guerezas maintained a macronutrient balance when feeding across patches, and the balance of protein to non-protein energy (fats and carbohydrates) in patches is the best indicator of time adult guerezas spent feeding in patches. Previous studies have shown that the protein-to-fiber ratio is important in predicting food selection for folivores and their biomass; however, we found that guerezas did not maximize protein and minimize fiber intake while foraging in patches, nor did they stay longer in patches with the highest ratio of protein to fiber concentrations. This study raises questions about the nutritional and social implications of patch depletion as a foraging strategy in folivorous monkeys where food limitation predicts competitive and social regimes. Am. J. Primatol. 79:e22495, 2017. © 2015 Wiley Periodicals, Inc.

Ophthalmic diagnostic testing and examination findings in a colony of captive brown pelicans (Pelecanus occidentalis).

OBJECTIVE: To establish reference values and report ophthalmic examination findings in a colony of captive brown pelicans (Pelecanus occidentalis). DESIGN: Descriptive study. ANIMALS STUDIED: Sixty-three captive brown pelicans in Florida were examined. PROCEDURES: A complete ophthalmic examination including Schirmer tear test (STT), applanation tonometry, fluorescein stain, biomicroscopy, and direct and indirect ophthalmoscopy was performed. A-scan ultrasonography was performed to measure axial globe length (AGL), anterior chamber depth (ACD), lens thickness, and vitreal chamber length. Fifty-two adults and 11 juvenile pelicans with an age range of 4 months to 38 years were evaluated. RESULTS: Twenty-nine pelicans (46%) had a normal ocular examination. Mean STT in normal pelicans was 5.45 ± 1.88 mm/min. Mean intraocular pressure (IOP) in normal pelicans was 10.86 ± 1.61 mmHg. One pelican was fluorescein positive unilaterally. Mean AGL was 20.70 ± 0.62 mm. Mean ACD was 3.38 ± 0.19 mm. Mean axial lens diameter (ALD) was 5.19 ± 0.23 mm. Mean vitreal chamber depth (VCD) was 12.15 ± 0.53 mm. Twenty-three pelicans (36.51%) had cataracts, 17 pelicans (26.98%) had vitreal degeneration, 18 pelicans (28.57%) had corneal disease, and seven pelicans (11.11%) had evidence of significant ocular trauma, which included collapsed anterior chamber or lens luxation. CONCLUSIONS AND CLINICAL RELEVANCE: To the author's knowledge, this is the first report of normal ophthalmic parameters and the incidence and type of ocular disease in a captive flock of brown pelicans. This information may aid in the diagnosis and treatment of brown pelicans with ocular disease.

High genetic diversity and population structure in the endangered Canarian endemic Ruta oreojasme (Rutaceae).

Insular species are expected to have low genetic diversity, for their populations are often small and isolated, and characterized by restricted gene flow and increased incidence of inbreeding. However, empirical results do not always match this expectation. For example, population genetic analyses of several Canarian endemics, based mainly on allozymes, show levels of genetic diversity exceptionally high for insular species. To investigate whether genetic variation in rare species endemic to Canary Islands is low, as predicted by theoretical expectations, or high, as documented in some previous studies, we analysed genetic diversity of the endangered Ruta oreojasme, a rare endemic of the island of Gran Canaria, using microsatellite markers, which are more variable than allozymes. Our analyses identified very high levels of genetic diversity (A = 7.625, P = 0.984, H o = 0.558, H e = 0.687) for R. oreojasme. Even though the distribution of the species is restricted to the South of Gran Canaria, only one population shows low genetic diversity, isolation and signs of a recent bottleneck/founder event. Some intrinsic characteristics of R. oreojasme (hermaphroditism, proterandry and polyploidy), the relative climatic stability of the Canarian archipelago during Quaternary glacials/interglacials, the size of most populations (thousands of individuals), its age, and the relative proximity of the archipelago to the mainland might have contributed to the high diversity that characterises this endemic. As expected, given the marked topographic complexity of Gran Canaria, we found marked genetic structure in R. oreojasme populations. Our results support the observation that Canarian endemics are characterised by unexpectedly high genetic diversity and provides important insights for potential applications to the conservation of R. oreojasme.

FXR agonists as therapeutic agents for non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and a risk factor for both cardiovascular and hepatic related morbidity and mortality. The increasing prevalence of this disease requires novel therapeutic approaches to prevent disease progression. Farnesoid X receptors are bile acid receptors with roles in lipid, glucose, and energy homeostasis. Synthetic farnesoid X receptor (FXR) agonists have been developed to specifically target these receptors for therapeutic use in NAFLD patients. Here, we present a review of bile acid physiology and how agonism of FXR receptors has been examined in pre-clinical and clinical NAFLD. Early evidence suggests a potential role for synthetic FXR agonists in the management of NAFLD; however, additional studies are needed to clarify their effects on lipid and glucose parameters in humans.

The smoking behaviors and cancer-related disparities among urban middle aged and older men involved in the criminal justice system.

This study examined cancer knowledge, mental health, and tobacco use in formerly incarcerated men. The Cancer-Health Research Study with Formerly Incarcerated Men in New York City used a cross-sectional research design to examine cancer knowledge and prevention (CKP) outcomes among 259 justice-involved males, ages 35-67. CKP was assessed using items from the National Cancer Institute's Health Information National Trends Survey. Psychological symptoms were examined using the Brief Symptom Inventory. Of the 259 men who completed the survey, 76% of the respondents self-reported as current smokers. Current smokers smoked between 1 and 40 cigarettes per day. The mean number of cigarettes smoked per day was 10.37 (SD = 6.76). Sixty-five percent (n = 165) of the respondents underwent cancer-screening tests. CKP scores ranged from 2 to 28; the mean was 15.05 (SD = 5.49), indicating that the men scored very low in terms of CKP. CKP scores were negatively associated with the number of cigarettes smoked per day, τ = -.13, p = .01. These results have important implications for enhancing access to cancer-health education programs in justice-involved settings.

Goals, challenges, and next steps in transdisciplinary fisheries research: perspectives and experiences from early-career researchers.

Fisheries are highly complex social-ecological systems that often face 'wicked' problems from unsustainable resource management to climate change. Addressing these challenges requires transdisciplinary approaches that integrate perspectives across scientific disciplines and knowledge systems. Despite widespread calls for transdisciplinary fisheries research (TFR), there are still limitations in personal and institutional capacity to conduct and support this work to the highest potential. The viewpoints of early career researchers (ECRs) in this field can illuminate challenges and promote systemic change within fisheries research. This paper presents the perspectives of ECRs from across the globe, gathered through a virtual workshop held during the 2021 World Fisheries Congress, on goals, challenges, and future potential for TFR. Big picture goals for TFR were guided by principles of co-production and included (i) integrating transdisciplinary thinking at all stages of the research process, (ii) ensuring that research is inclusive and equitable, (iii) co-creating knowledge that is credible, relevant, actionable, and impactful, and (iv) consistently communicating with partners. Institutional inertia, lack of recognition of the extra time and labour required for TFR, and lack of skill development opportunities were identified as three key barriers in conducting TFR. Several critical actions were identified to help ECRs, established researchers, and institutions reach these goals. We encourage ECRs to form peer-mentorship networks to guide each other along the way. We suggest that established researchers ensure consistent mentorship while also giving space to ECR voices. Actions for institutions include retooling education programs, developing and implementing new metrics of impact, and critically examining individualism and privilege in academia. We suggest that the opportunities and actions identified here, if widely embraced now, can enable research that addresses complex challenges facing fishery systems contributing to a healthier future for fish and humans alike.

"When the Wild Roses Bloom": Indigenous Knowledge and Environmental Change in Northwestern North America.

Indigenous Peoples in Northwestern North America have always worked with predictable cycles of day and night, tides, moon phases, seasons, and species growth and reproduction, including such phenological indicators as the blooming of flowers and the songs of birds. Negotiating variability has been constant in people's lives. Long-term monitoring and detailed knowledge of other lifeforms and landscapes of people's home territories have assisted in responding and adapting to change. Aspects of cultural knowledge and practice that have helped Indigenous Peoples navigate nature's cycles at different scales of time and space include kin ties and social relationships, experiential learning, language, storytelling and timing of ceremonies such as "First Foods" celebrations. Working with ecological processes, Indigenous Peoples have been able to maintain optimal conditions for preferred species, reducing variability and uncertainty through taking care of productive habitats, leaving ecosystems intact, and allowing other species to change in their own cycles. Since the onset of colonization, however, Indigenous Peoples' lifeways have been changed drastically, culminating with the current impacts of global climate change and biodiversity loss. This paper, based on contributions of numerous Indigenous Knowledge holders from across Northwestern North America, outlines some of the key ways in which Indigenous Peoples have embraced predictability and change in their environments and lifeways, and addresses the particular threat of climate change: its recognition, ways of adapting to it, and, ultimately, how it might be reversed through developing more careful, respectful relationships with and responsibilities for the other-than-human world.