Inheritance-Specific Dysregulation of Th1- and Th17-Associated Cytokines in Alopecia Areata.

Autoimmune diseases tend to cluster in families, suggesting genetic predisposition to autoimmunity associated with familial background. We have previously reported similarities in gene expression patterns and PTPN22 polymorphisms between alopecia areata (AA) patients and their healthy relatives, but not unrelated healthy controls. However, the spectrum of disease promoting (or preventing) pathways that may be activated in blood relatives of AA patients remains to be defined. Here, we investigated the extent to which cytokines associated with the Th1 and Th17 pathway are differentially expressed in the blood of patients with AA and its clinical subtypes in comparison to both healthy relatives as well as unrelated healthy controls. A comprehensive set of Th1- and Th17-related cytokines were evaluated by ELISA. We found a significant elevation of the Th17 inducer IL-23, the Th17 product IL-17A, the Th1 hallmark cytokine IFNγ, and TNFα, a Th1 cytokine with relevance to the Th17 pathway in AA patients, regardless of disease subtype, compared to healthy individuals. On further examination, we found that healthy family members grouped together with patients in terms of elevated Th1- and Th17-pathway cytokines in an inheritance-specific manner, distinct from unrelated controls. The elevation of Th17-associated cytokines in healthy controls related to AA patients indicates that Th1 and Th17 dysregulation in AA may be genetically based. Of note, one unrelated control displayed elevated levels of IL-17A and IL-23 similar to those detected in patients. One year after initial blood draw, areas of beard hair loss consistent with the diagnosis of AA were reported by this individual, indicating that the elevation in Th17-related cytokines may have predictive value.

Species redistribution creates unequal outcomes for multispecies fisheries under projected climate change.

Climate change drives species distribution shifts, affecting the availability of resources people rely upon for food and livelihoods. These impacts are complex, manifest at local scales, and have diverse effects across multiple species. However, for wild capture fisheries, current understanding is dominated by predictions for individual species at coarse spatial scales. We show that species-specific responses to localized environmental changes will alter the collection of co-occurring species within established fishing footprints along the U.S. West Coast. We demonstrate that availability of the most economically valuable, primary target species is highly likely to decline coastwide in response to warming and reduced oxygen concentrations, while availability of the most abundant, secondary target species will potentially increase. A spatial reshuffling of primary and secondary target species suggests regionally heterogeneous opportunities for fishers to adapt by changing where or what they fish. Developing foresight into the collective responses of species at local scales will enable more effective and tangible adaptation pathways for fishing communities.

Comparing the Outcomes of Face-to-Face and Synchronous Online Research Mentor Training Using Propensity Score Matching.

In this study, propensity score matching (PSM) was conducted to examine differences in the effectiveness of research mentor training (RMT) implemented using two modes-face-to-face or synchronous online training. This study investigated each training mode and assessed participants' perceived gains in mentoring skills, ability to meet mentees' expectations, and overall quality of mentoring, as well as intention to make changes to their mentoring practices. Additional factors that may contribute to participant outcomes were also examined. In total, 152 mentors trained using a synchronous online platform and 655 mentors trained in in-person workshops were analyzed using the PSM method. Mentors were matched based on similar characteristics, including mentee's career stage, mentor's title, mentor's prior mentoring experience, mentor's race/ethnicity and sex, and mentor's years of experience; results show that both face-to-face and synchronous online modes of RMT are effective. Findings indicated that the training mode did not significantly impact the mentors' perceived training outcomes. Factors associated with the reported training outcomes included dosage (hours of training), facilitator effectiveness, race/ethnicity, and previous mentoring experience. The results of this study demonstrate that mentors' perceived training outcomes are comparable regardless of the training modality used-online versus face-to-face.

Recommendations for quantifying and reducing uncertainty in climate projections of species distributions.

Projecting the future distributions of commercially and ecologically important species has become a critical approach for ecosystem managers to strategically anticipate change, but large uncertainties in projections limit climate adaptation planning. Although distribution projections are primarily used to understand the scope of potential change-rather than accurately predict specific outcomes-it is nonetheless essential to understand where and why projections can give implausible results and to identify which processes contribute to uncertainty. Here, we use a series of simulated species distributions, an ensemble of 252 species distribution models, and an ensemble of three regional ocean climate projections, to isolate the influences of uncertainty from earth system model spread and from ecological modeling. The simulations encompass marine species with different functional traits and ecological preferences to more broadly address resource manager and fishery stakeholder needs, and provide a simulated true state with which to evaluate projections. We present our results relative to the degree of environmental extrapolation from historical conditions, which helps facilitate interpretation by ecological modelers working in diverse systems. We found uncertainty associated with species distribution models can exceed uncertainty generated from diverging earth system models (up to 70% of total uncertainty by 2100), and that this result was consistent across species traits. Species distribution model uncertainty increased through time and was primarily related to the degree to which models extrapolated into novel environmental conditions but moderated by how well models captured the underlying dynamics driving species distributions. The predictive power of simulated species distribution models remained relatively high in the first 30 years of projections, in alignment with the time period in which stakeholders make strategic decisions based on climate information. By understanding sources of uncertainty, and how they change at different forecast horizons, we provide recommendations for projecting species distribution models under global climate change.

Toward a conceptual framework for managing and conserving marine habitats: A case study of kelp forests in the Salish Sea.

Kelp forests are in decline across much of their range due to place-specific combinations of local and global stressors. Declines in kelp abundance can lead to cascading losses of biodiversity and productivity with far-reaching ecological and socioeconomic consequences. The Salish Sea is a hotspot of kelp diversity where many species of kelp provide critical habitat and food for commercially, ecologically, and culturally important fish and invertebrate species. However, like other regions, kelp forests in much of the Salish Sea are in rapid decline. Data gaps and limited long-term monitoring have hampered attempts to identify and manage for specific drivers of decline, despite the documented urgency to protect these important habitats. To address these knowledge gaps, we gathered a focus group of experts on kelp in the Salish Sea to identify perceived direct and indirect stressors facing kelp forests. We then conducted a comprehensive literature review of peer-reviewed studies from the Salish Sea and temperate coastal ecosystems worldwide to assess the level of support for the pathways identified by the experts, and we identified knowledge gaps to prioritize future research. Our results revealed major research gaps within the Salish Sea and highlighted the potential to use expert knowledge for making informed decisions in the region. We found high support for the pathways in the global literature, with variable consensus on the relationship between stressors and responses across studies, confirming the influence of local ecological, oceanographic, and anthropogenic contexts and threshold effects on stressor-response relationships. Finally, we prioritized areas for future research in the Salish Sea. This study demonstrates the value expert opinion has to inform management decisions. These methods are readily adaptable to other ecosystem management contexts, and the results of this case study can be immediately applied to kelp management.

Implementing AACN's Healthy Work Environment Framework in an Intensive Care Unit.

BACKGROUND: Bedside nurse turnover in the United States is 15.9%, representing a national challenge that has been attributed to poor work environments. Healthy work environments are associated with improved nurse satisfaction and retention as well as positive patient outcomes; unhealthy work environments have the opposite effects. OBJECTIVES: To implement the American Association of Critical-Care Nurses (AACN) healthy work environment (HWE) framework in an intensive care unit and to evaluate staff satisfaction, turnover, and tenure 2 years later. METHODS: A pre-post study design was used to evaluate implementation of the HWE framework in an intensive care unit in a large academic medical facility. Interventions for each of the 6 HWE standards were performed. The AACN HWE assessment survey was used to measure skilled communication, true collaboration, effective decision-making, appropriate staffing, meaningful recognition, and authentic leadership in 2017 and in 2019. RESULTS: Nurse cohorts (n = 165 in 2017; n = 176 in 2019) had a mean age of 31 (median, 27; range, 23-63) years, were predominantly female (76%), and had a mean of 5 (median, 3) years of intensive care unit nursing experience. Statistically significant improvements were found in all standards except the skilled communication and overall measures. Registered nurse turnover remained stable and tenure increased by 79 days in this 2-year period. CONCLUSIONS: Findings from this study suggest that interventions addressing the HWE standards are associated with improved staff satisfaction, turnover, and average tenure, further demonstrating the value of the HWE framework in improving retention.

Ex Vivo Expansion of Th2-Polarizing Immunotherapeutic iNKT Cells from Human Peripheral Blood.

iNKT cells, classified as innate lymphocytes with invariant TCRs, have been highlighted as a putative, "off-the-shelf" cellular immunotherapeutic strategy for the treatment of malignant and nonmalignant diseases. However, their paucity in human blood limits their immunotherapeutic applications. Herein we describe a rigorously optimized 21-day ex vivo expansion method to achieve log-fold increases in immunotherapeutic human iNKT cells.

Introduction to effective mentorship for early-career research scientists.

Diversifying the scientific workforce remains a national priority due to the continued lack of representation from underrepresented individuals in STEM fields. Quality mentoring has been identified as a stimulus to enhance not only research success, but also recruitment and retention of underrepresented groups pursuing STEM careers. Utilizing the Entering Mentoring training curriculum framework, this report provides a brief synopsis and key takeaways from the 2019 NIH-ASCB Accomplishing Career Transition (ACT) workshop, "Introduction to Effective Mentorship for Scientists" for 30 senior postdoctoral and early-career faculty researchers from historically underrepresented racial and ethnicity backgrounds. In addition, effective strategies and best practices to enhance STEM mentoring for early-career researchers are provided, which have practical applications for diverse mentoring relationships across disciplines, career stages, and mentee types.

Strong population differentiation in lingcod (Ophiodon elongatus) is driven by a small portion of the genome.

Delimiting intraspecific genetic variation in harvested species is crucial to the assessment of population status for natural resource management and conservation purposes. Here, we evaluated genetic population structure in lingcod (Ophiodon elongatus), a commercially and recreationally important fishery species along the west coast of North America. We used 16,749 restriction site-associated DNA sequencing (RADseq) markers, in 611 individuals collected from across the bulk of the species range from Southeast Alaska to Baja California, Mexico. In contrast to previous population genetic work on this species, we found strong evidence for two distinct genetic clusters. These groups separated latitudinally with a break near Point Reyes off Northern California, and there was a high frequency of admixed individuals in close proximity to the break. F-statistics corroborate this genetic break between northern and southern sampling sites, although most loci are characterized by low FST values, suggesting high gene flow throughout most of the genome. Outlier analyses identified 182 loci putatively under divergent selection, most of which mapped to a single genomic region. When individuals were grouped by cluster assignment (northern, southern, and admixed), 71 loci were fixed between the northern and southern cluster, all of which were identified in the outlier scans. All individuals identified as admixed exhibited near 50:50 assignment to northern and southern clusters and were heterozygous for most fixed loci. Alignments of RADseq loci to a draft lingcod genome assembly and three other teleost genomes with chromosome-level assemblies suggest that outlier and fixed loci are concentrated on a single chromosome. Similar genomic patterns have been attributed to chromosomal inversions in diverse taxonomic groups. Regardless of the evolutionary mechanism, these results represent novel observations of genetic structure in lingcod and designate clear evolutionary units that could be used to inform fisheries management.

Expansion and CD2/CD3/CD28 stimulation enhance Th2 cytokine secretion of human invariant NKT cells with retained anti-tumor cytotoxicity.

BACKGROUND AIMS: Key obstacles in human iNKT cell translational research and immunotherapy include the lack of robust protocols for dependable expansion of human iNKT cells and the paucity of data on phenotypes in post-expanded cells. METHODS: We delineate expansion methods using interleukin (IL)-2, IL-7 and allogeneic feeder cells and anti-CD2/CD3/CD28 stimulation by which to dependably augment Th2 polarization and direct cytotoxicity of human peripheral blood CD3+Vα24+Vß11+ iNKT cells. RESULTS: Gene and protein expression profiling demonstrated augmented Th2 cytokine secretion (IL-4, IL-5, IL-13) in expanded iNKT cells stimulated with anti-CD2/CD3/CD28 antibodies. Cytotoxic effector molecules including granzyme B were increased in expanded iNKT cells after CD2/CD3/CD28 stimulation. Direct cytotoxicity assays using unstimulated expanded iNKT cell effectors revealed α-galactosyl ceramide (α-GalCer)-dependent killing of the T-ALL cell line Jurkat. Moreover, CD2/CD3/CD28 stimulation of expanded iNKT cells augmented their (α-GalCer-independent) killing of Jurkat cells. Co-culture of expanded iNKT cells with stimulated responder cells confirmed contact-dependent inhibition of activated CD4+ and CD8+ responder T cells. DISCUSSION: These data establish a robust protocol to expand and novel pathways to enhance Th2 cytokine secretion and direct cytotoxicity in human iNKT cells, findings with direct implications for autoimmunity, vaccine augmentation and anti-infective immunity, cancer immunotherapy and transplantation.

If you build it, they will come: Reaching across the "IL" with Neo-2/15.

A computationally designed mimic of interleukin-2 (IL-2) selectively expands cytotoxic CD8+ T cells over regulatory T cells and supports antitumor immunity.

From the predictable to the unexpected: kelp forest and benthic invertebrate community dynamics following decades of sea otter expansion.

The recovery of predators has the potential to restore ecosystems and fundamentally alter the services they provide. One iconic example of this is keystone predation by sea otters in the Northeast Pacific. Here, we combine spatial time series of sea otter abundance, canopy kelp area, and benthic invertebrate abundance from Washington State, USA, to examine the shifting consequences of sea otter reintroduction for kelp and kelp forest communities. We leverage the spatial variation in sea otter recovery to understand connections between sea otters and the kelp forest community. Sea otter increases created a pronounced decline in sea otter prey-particularly kelp-grazing sea urchins-and led to an expansion of canopy kelps from the late 1980s until roughly 2000. However, while sea otter and kelp population growth rates were positively correlated prior to 2002, this association disappeared over the last two decades. This disconnect occurred despite surveys showing that sea otter prey have continued to decline. Kelp area trends are decoupled from both sea otter and benthic invertebrate abundance at current densities. Variability in kelp abundance has declined in the most recent 15 years, as it has the synchrony in kelp abundance among sites. Together, these findings suggest that initial nearshore community responses to sea otter population expansion follow predictably from trophic cascade theory, but now, other factors may be as or more important in influencing community dynamics. Thus, the utility of sea otter predation in ecosystem restoration must be considered within the context of complex and shifting environmental conditions.

When are they old enough to drink? Outcomes of an Australian social marketing intervention targeting alcohol initiation.

INTRODUCTION AND AIMS: This paper reports on the evaluation of an Australian whole-of-community social marketing intervention targeting social norms, which aimed to reduce inflated perceptions of the prevalence of underage drinking and increase the age at which alcohol initiation is considered acceptable. DESIGN AND METHODS: A community-wide intervention was delivered in a single community over a period of 2 years, targeting adolescents, parents and community members. Pre-and post-intervention computer-assisted telephone interview surveys were conducted in the intervention and a matched comparison (control) community. A total of 417 respondents completed both surveys (215 in the intervention community and 202 in the control community). RESULTS: The intervention community saw an increase of 6 months in the average age at which it is perceived to be acceptable for young people to have a sip/taste of alcohol and 5 months in the average age at which it is perceived to be acceptable to have weak/watered down alcohol. Furthermore, there was a reduction in the perception of the prevalence of alcohol consumption by young people to a level consistent with actual underage drinking rates. In comparison, the control community saw no change in any of these variables. DISCUSSION AND CONCLUSIONS: This study provides preliminary evidence that a whole-of-community social marketing intervention can change perceptions of the prevalence, and acceptability, of underage drinking. Given the central role of social norms in decisions regarding alcohol consumption, these changes have the potential to reduce parental supply and thus underage drinking.

Combining Social Norms and Social Marketing to Address Underage Drinking: Development and Process Evaluation of a Whole-of-Community Intervention.

Youth alcohol consumption has been steadily declining in Australia, as in other countries; fewer young people are drinking and the age of initiation is increasing. However, young people, their parents and others in their communities continue to believe that adolescent (excessive) drinking is the norm. This perception, and the concurrent misperception that the majority of parents are happy to provide their underage children with alcohol, creates a perceived culture of acceptance of youth alcohol consumption. Young people believe that it is accepted, and even expected, that they will drink; and parents perceive that not providing their adolescent children with alcohol will lead to social exclusion. There is evidence that shifting social norms can have an immediate and lasting effect adolescents' (and adults') alcohol related attitudes and behaviors. This paper reports on a novel, community based social marketing intervention designed to correct misperceptions of alcohol related social norms in an Australian community. The project utilized a social marketing approach, informed by the full complement of Andreasen's social marketing benchmarking criteria, and concurrently targeted adolescents, parents of adolescents and the broader community. Using extensive formative research and multiple evaluation techniques, the study demonstrates that shifts in community social norms are possible and suggests that this approach could be used more widely to support the positive trends in youth alcohol consumption and parental supply.

What is 'binge drinking'? Perceptions of Australian adolescents and adults, and implications for mass media campaigns.

OBJECTIVE: While the term 'binge drinking' has no definitive definition, it is commonly used in lay conversation and mass media communication campaigns. It is important to understand how the general population interprets the term, and their positive and negative perceptions of this behaviour. METHODS: A convenience sample of 549 participants from two Australian towns completed a survey on perceptions of binge drinking; 221 adolescents, 104 parents of adolescents and 224 adult community members. RESULTS: Across all three groups, binge drinking was defined using broad descriptors; few respondents referred to specific consumption levels and those who did varied widely in the quantities specified. The majority of respondents described binge drinking negatively and, in most cases, more negatively for adolescents than adults. However, both adult groups perceived binge drinking to be more enjoyable and pleasant for adolescents than for adults, and more enjoyable and pleasant than adolescents did themselves. CONCLUSIONS AND IMPLICATIONS: There is a need for shared understanding of terms to ensure that educational interventions and communication campaigns are using the same definitions as their target audiences. There is also a need to ensure adults are not providing young people with mixed messages about excessive alcohol consumption.

Lost in translation: a focus group study of parents' and adolescents' interpretations of underage drinking and parental supply.

BACKGROUND: Reductions in underage drinking will only come about from changes in the social and cultural environment. Despite decades of messages discouraging parental supply, parents perceive social norms supportive of allowing children to consume alcohol in 'safe' environments. METHODS: Twelve focus groups conducted in a regional community in NSW, Australia; four with parents of teenagers (n = 27; 70 % female) and eight with adolescents (n = 47; 55 % female). Participants were recruited using local media. Groups explored knowledge and attitudes and around alcohol consumption by, and parental supply of alcohol to, underage teenagers; and discussed materials from previous campaigns targeting adolescents and parents. RESULTS: Parents and adolescents perceived teen drinking to be a common behaviour within the community, but applied moral judgements to these behaviours. Younger adolescents expressed more negative views of teen drinkers and parents who supply alcohol than older adolescents. Adolescents and parents perceived those who 'provide alcohol' (other families) as bad parents, and those who 'teach responsible drinking' (themselves) as good people. Both groups expressed a preference for high-fear, victim-blaming messages that targeted 'those people' whose behaviours are problematic. CONCLUSIONS: In developing and testing interventions to address underage drinking, it is essential to ensure the target audience perceive themselves to be the target audience. If we do not have a shared understanding of underage 'drinking' and parental 'provision', such messages will continue to be perceived by parents who are trying to do the 'right' thing as targeting a different behaviour and tacitly supporting their decision to provide their children with alcohol.

Training and caring for primates.

Ms. Andrews-Kelly recounts the experiences and inspirations that have guided her career in providing care, enrichment and training for non-human primates.

Chronic hypersensitivity pneumonitis caused by Saccharopolyspora rectivirgula is not associated with a switch to a Th2 response.

Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease that develops following repeated exposure to inhaled environmental antigens. The disease results in alveolitis and granuloma formation and may progress to a chronic form associated with fibrosis; a greater understanding of the immunopathogenic mechanisms leading to chronic HP is needed. We used the Saccharopolyspora rectivirgula (SR) mouse model of HP to determine the extent to which a switch to a Th2-type immune response is associated with chronic HP. Exposure of wild-type (WT) and tlr2/9(-/-) mice to SR for 14 wk resulted in neutrophilic and lymphocytic alveolitis that was not dependent on Toll-like receptors (TLRs) 2 and 9. Long-term exposure of WT mice to SR resulted in a significant increase in collagen deposition, protein leakage, and IL-1α accompanied by a decrease in quasistatic compliance and total lung capacity compared with unexposed mice. This was associated with an increase in IL-17 but not IL-4 production or recruitment of Th2 cells. tlr2/9(-/-) mice exhibited an increase in protein leakage but less IL-1α and collagen deposition in the lungs compared with WT mice, yet they still displayed a decrease in quasistatic compliance, although total lung capacity was not affected. These mice exhibited an increase in both IL-13 and IL-17, which suggests that IL-13 may ameliorate some of the lung damage caused by long-term SR exposure. Our results suggest that lung pathology following long-term SR exposure in WT mice is associated with the IL-17 response and that TLRs 2 and 9 may inhibit the development of the IL-13/Th2 response.

17ß-estradiol replacement in ovariectomized female rats slows set 1 dorsolateral striatial-dependent learning and enhances learning of set 2 in an extradimensional set-shifting paradigm.

The role of estrogen in extradimensional set-shifting was evaluated with replacement of 17ß-estradiol (E2) in ovariectomized (OVX) female rats. Rats were reinforced with food when they entered an arm of a plus-maze that was distinguished by visual and/or tactile cues (Set 1). In Set 2, reinforcement was shifted to construct a new association between food and visual/tactile cues that were different from Set 1. The purpose of using this extradimensional set-shifting task was to differentiate the effect of acute or continuous E2 on the dorsolateral (DLS) versus dorsomedial (DMS) striatum and medial prefrontal cortex (mPFC), because Set 1 and 2 learning, respectively, are associated with these particular brain regions. Results showed that compared to controls, acute E2-replaced female rats required more training trials to reach criterion in Set 1. Moreover, E2-replaced females showed a significant delay in the rate of acquisition of Set 1 learning compared to controls. In Set 2 there were no group differences in perseverative errors, which are reduced by mPFC activation, or when learning took place in a previously reinforced arm, a DMS-mediated effect. Despite this, control females required more training trials to learn Set 2 compared to Set 1, suggesting that prior learning in Set 1 interfered with Set 2 performance in non-E-replaced rats. In contrast, E2 groups learned Set 2 in fewer training trials than Set 1. These data suggest that E2 facilitates set shifting, apart from any apparent enhancement of DMS or mPFC function, perhaps by interfering with DLS-mediated Set 1 learning.

Adolescent drinking, social identity, and parenting for safety: Perspectives from Australian adolescents and parents.

We explored young people and parents' views on adolescent drinking and safety in the locations where drinking may occur. Focus groups with adolescents and parents showed that many believed adolescent drinking and drunkenness is normative. Younger adolescents had more negative views of adolescent drinkers than their older peers. Adolescent drinking occurred in private settings and parents made decisions about allowing their adolescent children to attend social events based on the level of safety attributed to the location. If adolescent drinking was likely then home was the preferred location as it provided scope for risk minimisation. Positive portrayals of non-drinking adolescents and information to assist parents' decision-making are needed.