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Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.

In this chapter, we make the case that cooperation is at the center of moral behavior by presenting insights on youth morality from neuroscience, psychology, and evolutionary science. First, we discuss the gaps in the sociological literature concerning youth morality. Instead of studying youth morality explicitly, sociologists often use proxies for morality such as norms, values, and socialization that underplay both youth’s agency in shaping their moral worlds and their innate cooperative abilities. As such, we argue that sociologists’ neglect of youth morality obscures our understanding of the interaction between the socialized and the innate aspects of moral development and behavior. Next, we review existing bio-psychological research that points to the innate aspects of cooperation and why cooperation may have been evolutionarily adaptive. In looking at the moral behaviors of infants, we see that moral judgment, a preference for pro-social versus anti-social others, and the ability to coordinate action, precede norm following and norm enforcing behaviors. We conclude this chapter by discussing the exciting opportunities that could result from interdisciplinary work on the morality of youth, and present some ideas for future directions in the areas of socialization, property and politics, and moral judgment and decision-making.

Regenerative therapeutics for treating peripheral arterial disease are an appealing strategy for creating more durable solutions for limb ischemia. In this work, we performed preclinical testing of an injectable formulation of syndecan-4 proteoliposomes combined with growth factors as treatment for peripheral ischemia delivered in an alginate hydrogel. We tested this therapy in an advanced model of hindlimb ischemia in rabbits with diabetes and hyperlipidemia. Our studies demonstrate enhancement in vascularity and new blood vessel growth with treatment with syndecan-4 proteoliposomes in combination with FGF-2 or FGF-2/PDGF-BB. The effects of the treatments were particularly effective in enhancing vascularity in the lower limb with a 2-4 increase in blood vessels in the treatment group in comparison to the control group. In addition, we demonstrate that the syndecan-4 proteoliposomes have stability for at least 28 days when stored at 4°C to allow transport and use in the hospital environment. In addition, we performed toxicity studies in the mice and found no toxic effects even when injected at high concentration. Overall, our studies support that syndecan-4 proteoliposomes markedly enhance the therapeutic potential of growth factors in the context of disease and may be promising therapeutics for inducing vascular regeneration in peripheral ischemia.

Freedom of speech has long been considered an essential value in democracies. However, its boundaries concerning hate speech continue to be contested across many social and political spheres, including governments, social media websites, and university campuses. Despite the recent growth of so-called free speech communities online and offline, little empirical research has examined how individuals embedded in these communities make moral sense of free speech and its limits. Examining these perspectives is important for understanding the growing involvement and polarization around this issue. Using a digital ethnographic approach, I address this gap by analyzing discussions in a rapidly growing online forum dedicated to free speech (r/FreeSpeech subreddit). I find that most users on the forum understand free speech in an absolutist sense (i.e., it should be free from legal, institutional, material, and even social censorship or consequences), but that users differ in their arguments and justifications concerning hate speech. Some downplay the harms of hate speech, while others acknowledge its harms but either focus on its epistemic subjectivity or on the moral threats of censorship and authoritarianism. Further, the forum appears to have become more polarized and right-wing-dominated over time, rife with ideological tensions between members and between moderators and members. Overall, this study highlights the variation in free speech discourse within online spaces and calls for further research on free speech that focuses on first-hand perspectives.

Introduction and Aims: While much research has sought to identify the factors associated with initiation and cessation of various forms of drug use among vulnerable youth, little is known about relapse into drug use in this population. We sought to characterize relapse into stimulant and opioid use among street-involved youth in Vancouver, Canada. Design and Methods: Data were collected between 2005 and 2017 from the At-Risk Youth Study (ARYS), a prospective cohort study of street-involved youth who use illicit drugs in Vancouver. Multivariable extended Cox regression was utilized to identify factors associated with relapse into harder drug use among youth who had previously ceased using stimulants and/or opioids for six months or longer. Results: Among 246 participants who reported a period of cessation lasting six months or longer, 165 (67.1%) relapsed at some point during study follow-up. Youth who were recently incarcerated (adjusted hazard ratio [AHR]: 1.47), homeless (AHR: 1.40), or had a history of daily stimulant use (AHR: 1.64) were significantly more likely to report relapse, while youth of who identified as white (AHR: 0.78) were significantly less likely to report relapse (all p

Peripheral vascular disease is a widespread clinical problem that affects millions of patients worldwide. A major consequence of peripheral vascular disease is the development of ischemia. In severe cases, patients can develop critical limb ischemia in which they experience constant pain and an increased risk of limb amputation. Current therapies for peripheral ischemia include bypass surgery or percutaneous interventions such as angioplasty with stenting or atherectomy to restore blood flow. However, these treatments often fail to the continued progression of vascular disease or restenosis or are contraindicated due to the overall poor health of the patient. A promising potential approach to treat peripheral ischemia involves the induction of therapeutic neovascularization to allow the patient to develop collateral vasculature. This newly formed network alleviates peripheral ischemia by restoring perfusion to the affected area. The most frequently employed preclinical model for peripheral ischemia utilizes the creation of hind limb ischemia in healthy rabbits through femoral artery ligation. In the past, however, there has been a strong disconnect between the success of preclinical studies and the failure of clinical trials regarding treatments for peripheral ischemia. Healthy animals typically have robust vascular regeneration in response to surgically induced ischemia, in contrast to the reduced vascularity and regeneration in patients with chronic peripheral ischemia. Here, we describe an optimized animal model for peripheral ischemia in rabbits that includes hyperlipidemia and diabetes. This model has reduced collateral formation and blood pressure recovery in comparison to a model with a higher cholesterol diet. Thus, the model may provide better correlation with human patients with compromised angiogenesis from the common co-morbidities that accompany peripheral vascular disease.

BACKGROUND: Emerging evidence suggests that non-medical prescription opioid (NMPO) use may be a risk factor for initiating heroin use; however, pathways from PO to heroin use among youth remain underexplored. We sought to examine the association between NMPO use and heroin initiation. METHODS: Between September 2005 and June 2017 data were derived from an open prospective cohort of street-involved youth aged 14–28 who use illegal drugs in Vancouver, Canada. The study included 526 youth who had never used non-injection heroin, and 652 youth who had never used injection heroin at baseline. We used Cox proportional hazards regressions to examine the association between NMPO use – in addition to other substance use patterns – and subsequent initiation into non-injection and injection heroin use. RESULTS: Among those who had never used non-injection heroin at baseline, 133 (25.3%) initiated non-injection heroin use during the study period. Among those who had never injected heroin at baseline, 137 (21.0%) initiated heroin injection during the study period. In multivariable analyses, NMPO use, crack use, and crystal methamphetamine use predicted non-injection heroin initiation (all p < 0.05). In separate multivariable analyses, non-injection heroin and crystal methamphetamine predicted heroin injection initiation (all p < 0.05). CONCLUSIONS: Among street-involved youth in this setting, NMPO use predicted initiation into non-injection heroin use but not initiation into heroin injection. Interestingly, crack cocaine and crystal methamphetamine use were stronger predictors of heroin initiation than NMPO use was, suggesting that stimulant use may carry greater risks for heroin initiation than NMPO use.

ObjectiveFood insufficiency, defined by the experience of hunger, is known to be prevalent and a source of health-related harm among-street involved youth, but little is known about its relationship with depression in this population. Therefore, we sought to assess the association between food insufficiency and symptoms of depression among a cohort of street-involved youth.DesignMultivariable logistic regression was used to assess the relationship between food insufficiency, defined as being hungry but not having enough money to buy food, and depression as measured by the Center for Epidemiological Studies Depression (CES-D) scale.SettingData from April 2006 to November 2013 were derived from the At-Risk Youth Study (ARYS), a prospective cohort of street-involved youth who use illicit drugs in Vancouver, Canada.SubjectsThere were 1066 street-involved youth enrolled in the study, including 340 (31·9 %) females.ResultsOf 1066 youth enrolled in the study, 724 (67·9 %) reported some food insufficiency and 565 (53·0 %) met criteria for depression. Compared with youth who did not report food insufficiency, those who reported often experiencing food insufficiency had a higher likelihood of reporting depression (adjusted OR=2·52; 95 % CI 1·74, 3·67), as did those who reported sometimes experiencing food insufficiency (adjusted OR=1·99; 95 % CI 1·47, 2·70).ConclusionsFood insufficiency was prevalent and associated in a dose-dependent trend with symptoms of depression among street-involved youth in our setting. Findings highlight the need to address the nutritional and mental health needs of youth and identify pathways by which food insufficiency may contribute to depression among vulnerable populations.

Background: The distribution of take-home naloxone (THN) kits has been an important strategy in reducing overdose fatalities among people who use drugs. However, little is known about the use of THN among youth who are street-involved. The present study explores knowledge and possession of THN among street-involved youth in a Canadian setting. Methods: Data were derived from the At-Risk Youth Study (ARYS), a prospective cohort of street-involved youth age 14–28 at enrollment in Vancouver, Canada. Participants completed a standardized questionnaire, which included items related to knowledge and possession of THN, sociodemographic characteristics, and substance use-related factors. Multivariable logistic regression models were used to identify factors independently associated with knowledge and possession of THN. Results: Between December 2014 and November 2016, 177 youth were interviewed, including 68 females (38.4%). While 126 (71.2%) participants reported knowledge of THN, only 40 (22.6%) possessed a THN kit. Caucasian/white ethnicity was found to be positively associated with both knowledge and possession of THN (both p

Mental health issues are increasingly prevalent among North American post-secondary students and often impede academic progress. However, students appear reluctant to seek help and access mental health services due to stigma associated with mental health issues. Our study explored university students’ perspectives on and experiences of mental illness stigma on campus with the ultimate aim of working towards building more inclusive communities. Drawing on a participatory action research approach, we recruited 24 Canadian university students and conducted 13 semi-structured interviews, three focus groups, and three Photovoice sessions. Thematic analysis of the transcribed narratives and discussions derived from the data-collection process generated three themes. First, students identified academic pressure, the concealed nature of mental illness, and mistreatment of people with mental illness as sources of stigma. Second, stigma threatened three aspects of student life: being, doing, and belonging. Third, enhancing awareness of students’ mental health issues and improving mental health service delivery were indicated as critical to addressing stigma. The university's ability-focused culture appeared to contribute to reinforcing stigma and to students being threatened with losing or damaging their academic competence status. Universities should initiate dialogue with students and faculty to communicate the relationship between students’ mental health and academic success.

Este trabalho é uma reflexão acerca da arte-educação e das histórias de tradição oral em suas relações com os conceitos de experiência e aprendizagem. O ponto de partida é a experiência da Escola de Arte Granada, localizada no interior do estado do Rio de Janeiro, na qual o trabalho é realizado a partir da integração de diversas linguagens artísticas com a arte de contar histórias. As questões trazidas pelos autores que tratam da arte-educação propiciam uma reflexão sobre o que compreendemos pelas duas palavras que compõem o termo \'arte-educação\'. A observação da Escola Granada, a partir de entrevistas com as educadoras da escola, revela o uso dos contos de tradição oral como material educativo que continua sempre atual e pode ser usado pelo ser humano em seu processo de desenvolvimento. A reflexão sobre os contos conduz ao estudo da tradição oral e ao conceito de educação na cultura tradicional. Tal concepção é relacionada a certas propostas visionárias sobre as mudanças necessárias na educação para o século XXI. This work is a reflection about art-education and stories from the oral tradition, in their connection to the concepts of experience and learning. The starting point is the experience of Escola de Arte Granada, located in the countryside of Rio de Janeiro, where the work is developed starting from the integration of various artistic languages with the art of storytelling. The questions brought about by the authors who consider arteducation provide us with a reflection about what we understand by the two words that compose the term \'art-education\'. The observation of Escola Granada, arising from the interviews with the school\'s educators, reveals the usage of traditional tales as an educative material, which is always up-to-date and can be used by the human being in the process of development. The reflection about these tales leads us to the study of oral tradition and the concept of education in traditional cultures. This conception is related to certain visionary proposals regarding the necessary changes for 21st century education.

The engulfment of apoptotic cells is required for normal metazoan development and tissue remodeling. In Caenorhabditis elegans, two parallel and partially redundant conserved pathways act in cell-corpse engulfment. One pathway includes the adaptor protein CED-2 CrkII and the small GTPase CED-10 Rac, and acts to rearrange the cytoskeleton of the engulfing cell. The other pathway includes the receptor tyrosine kinase CED-1 and might recruit membranes to extend the surface of the engulfing cell. Although many components required for engulfment have been identified, little is known about inhibition of engulfment. The tyrosine kinase Abl regulates the actin cytoskeleton in mammals and Drosophila in multiple ways. For example, Abl inhibits cell migration via phosphorylation of CrkII. We tested whether ABL-1, the C. elegans ortholog of Abl, inhibits the CED-2 CrkII-dependent engulfment of apoptotic cells. Our genetic studies indicate that ABL-1 inhibits apoptotic cell engulfment, but not through CED-2 CrkII, and instead acts in parallel to the two known engulfment pathways. The CED-10 Rac pathway is also required for proper migration of the distal tip cells (DTCs) during the development of the C. elegans gonad. The loss of ABL-1 function partially restores normal DTC migration in the CED-10 Rac pathway mutants. We found that ABI-1 the C. elegans homolog of mammalian Abi (Abl interactor) proteins, is required for engulfment of apoptotic cells and proper DTC migration. Like Abl, Abi proteins are cytoskeletal regulators. ABI-1 acts in parallel to the two known engulfment pathways, likely downstream of ABL-1. ABL-1 and ABI-1 interact physically in vitro. We propose that ABL-1 opposes the engulfment of apoptotic cells by inhibiting ABI-1 via a pathway that is distinct from the two known engulfment pathways., Author Summary Cell death or apoptosis is a normal part of animal development, as is the engulfment and removal of dead cells by other cells. In the nematode Caenorhabditis elegans, ten highly conserved proteins have been characterized previously for their roles in engulfment and in cell migration, both of which involve the formation of cellular extensions. Little is known, however, about how engulfment is inhibited. In mammals, the tyrosine kinase Abl, which regulates the actin cytoskeleton and which when misexpressed causes two types of leukemia, prevents the CrkII protein from facilitating cell migration. CrkII functions in engulfment in C. elegans and mammals. We tested whether the C. elegans homolog of Abl, ABL-1, could inhibit engulfment. We found that ABL-1 functions as an inhibitor of apoptotic cell engulfment and cell migration. However, our analysis further showed that ABL-1 does not function by inhibiting other known engulfment proteins, including C. elegans CrkII. Our data indicate that ABL-1 blocks ABI-1, the C. elegans homolog of the mammalian and Drosophila Abl-interactor (Abi) cytoskeletal-regulatory proteins. We propose that ABL-1 acts via ABI-1 to inhibit a newly identified pathway during cell corpse engulfment and cell migration., We show thatC. elegans Abl (ABL-1) inhibits the engulfment of apoptotic cells via a newly defined pathway that includes theC. elegans homolog of the cytoskeletal regulator Abl-interactor.