Narrative and its discontents.

This review considers recent challenges to, and changes within, narrative medicine as a paradigm for humanities-based medical education. It suggests that, while narrative medicine has often been criticised for emphasising narrative at the expense of other dimensions of human experience, newer criticism has focused more on its relationship with other areas of medical knowledge. In different ways, recent work has shown greater interest in taking in humanities perspectives on their own terms, rather than (this is the charge against narrative medicine) instrumentalising them as diagnostic tools. The review concludes by considering how these criticisms might make their way into the institutional realities of medical education, as well as what they might learn from narrative medicine's success.

The Landscape of Early Clinical Gene Therapies outside of Oncology.

The field of cell and gene therapy (GT) is expanding rapidly and there is undoubtedly a wave of enthusiasm and anticipation for what these treatments could achieve next. Here we assessed the worldwide landscape of GT assets currently in early clinical development (clinical trial phase 1/2 or about to enter clinical trial). We included all gene therapies, i.e., strategies that modify an individual's protein make-up by introducing exogenous nucleic acid or nucleic acid modifiers, regardless of delivery. Unmodified cell therapies, oncology therapies (reviewed elsewhere), and vaccine programs (distinct therapeutic strategy) were not included. Using a December 31, 2018 cutoff date, we identified 336 gene therapies being developed for 138 different indications covering 165 genetic targets. In all, we found that the early clinical GT landscape comprises a very disparate group of drug candidates in terms of indications, organizations, and delivery methods. We also highlight interesting trends, revealing the evolution of the field toward in vivo therapies and adeno-associated virus vector-based delivery systems. It will be interesting to witness what proportion of this current list effectively translates into new medicines.

Pharmacological and genetic targeting of the PI4KA enzyme reveals its important role in maintaining plasma membrane phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate levels.

Phosphatidylinositol 4-kinase type IIIα (PI4KA) is a host factor essential for hepatitis C virus replication and hence is a target for drug development. PI4KA has also been linked to endoplasmic reticulum exit sites and generation of plasma membrane phosphoinositides. Here, we developed highly specific and potent inhibitors of PI4KA and conditional knock-out mice to study the importance of this enzyme in vitro and in vivo. Our studies showed that PI4KA is essential for the maintenance of plasma membrane phosphatidylinositol 4,5-bisphosphate pools but only during strong stimulation of receptors coupled to phospholipase C activation. Pharmacological blockade of PI4KA in adult animals leads to sudden death closely correlating with the drug's ability to induce phosphatidylinositol 4,5-bisphosphate depletion after agonist stimulation. Genetic inactivation of PI4KA also leads to death; however, the cause in this case is due to severe intestinal necrosis. These studies highlight the risks of targeting PI4KA as an anti-hepatitis C virus strategy and also point to important distinctions between genetic and pharmacological studies when selecting host factors as putative therapeutic targets.

Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes.

The generation of reactive oxygen species (ROS) is inherent to immune responses. ROS are crucially involved in host defense against pathogens by promoting bacterial killing, but also as signaling agents coordinating the production of cytokines. Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca(2+)-permeable channel gated via binding of ADP-ribose, a metabolite formed under conditions of cellular exposure to ROS. Here, we show that TRPM2-deficient mice are extremely susceptible to infection with Listeria monocytogenes (Lm), exhibiting an inefficient innate immune response. In a comparison with IFNγR-deficient mice, TRPM2(-/-) mice shared similar features of uncontrolled bacterial replication and reduced levels of inducible (i)NOS-expressing monocytes, but had intact IFNγ responsiveness. In contrast, we found that levels of cytokines IL-12 and IFNγ were diminished in TRPM2(-/-) mice following Lm infection, which correlated with their reduced innate activation. Moreover, TRPM2(-/-) mice displayed a higher degree of susceptibility than IL-12-unresponsive mice, and supplementation with recombinant IFNγ was sufficient to reverse the unrestrained bacterial growth and ultimately the lethal phenotype of Lm-infected TRPM2(-/-) mice. The severity of listeriosis we observed in TRPM2(-/-) mice has not been reported for any other ion channel. These findings establish an unsuspected role for ADP-ribose and ROS-mediated cation flux for innate immunity, opening up unique possibilities for immunomodulatory intervention through TRPM2.

The effect of hotel employee resilience during COVID-19: The moderation role of perceived risk and challenge stressors.

The effect of hotel employee resilience during major crises lacks sufficient empirical investigation. This research aimed to develop a conceptual model of hotel employee resilience effects on turnover intentions and service quality with belief restoration as mediation and challenge stressors and perceived risk as moderation variables. A questionnaire survey was conducted with 28 star-rated hotels (including two 3-star, fifteen 4-star, and eleven 5-star hotels) in southeastern, northeastern, central, and western China against the background of the COVID-19 pandemic, and with operational (e.g., front office, food and beverage, housekeeping) and administrative (e.g., human resource, sales, finance) departments. A total of 1318 valid questionnaires were collected. The results showed that: (1) employee resilience predicted employee service quality positively and turnover intentions negatively; (2) belief restoration partially mediated the impact of employee resilience on service quality and turnover intentions; and (3) perceived risk and challenge stressors had diverse moderation effects (e.g., U-shaped, linear) in the impacts of resilience, and they were important external and internal situational factors that influenced the impact of employee resilience. This research revealed the effects and situational conditions of hotel employee resilience during a major crisis, which provides a theoretical basis for establishing hotel crisis response strategies.

Self-Identity Matters: An Extended Theory of Planned Behavior to Decode Tourists' Waste Sorting Intentions.

Waste sorting is a practical way of handling the garbage and an effective strategy for facilitating sustainable waste management. This research extended the theory of planned behavior (TPB) with self-identity and moral norms to predict waste sorting intentions in a heritage context of tourism. A total of 403 valid self-administrated questionnaires were achieved at a heritage destination in China. The results indicated that: (1) TPB variables (i.e., attitudes toward the behavior, subjective norms, and perceived behavioral control), self-identity, and moral norms were all directly and positively linked to tourists' waste sorting intentions, respectively; (2) self-identity indirectly influenced tourists' waste sorting intentions through the mediation of moral norms; and (3) the integrated model exhibited better predictive utility than any single model. This research contributes to the literature on waste management in the context of tourism by extending TPB with identity and personal normative constructs. It also provides practical implications for destination managers to leverage tourists' self-identity and moral norms for sustainable management.

Applying a Combination of SEM and fsQCA to Predict Tourist Resource-Saving Behavioral Intentions in Rural Tourism: An Extension of the Theory of Planned Behavior.

How to save resources and protect the environment at destinations is one of the hot issues in tourism. One effective solution is to cultivate tourist resource-saving behavioral intentions (TRSBI). Prior studies mainly use Structural equation modeling (SEM) to explore its antecedents, whereas other potential methods (i.e., fuzzy-set qualitative comparative analysis, fsQCA for short) have been less adopted. This study combines SEM and fsQCA to examine TRSBI in a rural tourism context. Specifically, SEM is executed to investigate how environmental concern influences TRSBI based on the theory of planned behavior (TPB), while fsQCA is applied to uncover the multiple configurations in the TRSBI formation. The findings from SEM indicated that (1) environmental concern positively and directly influenced TRSBI; (2) TPB constructs (i.e., attitudes toward the behavior, subjective norms, and perceived behavioral control) positively and separately mediated the associations of environmental concern with TRSBI. The fsQCA outcomes showed that three configurations result in a high level of TRSBI: (1) high attitudes toward the behavior, subjective norms, and perceived behavioral control, (2) high attitudes toward the behavior, subjective norms, and environmental concern, and (3) high attitudes toward the behavior, perceived behavioral control, and environmental concern. The combined approaches offer a systematic and holistic solution to explore TRSBI in rural tourism.

TRPM2 Ca2+ channel regulates energy balance and glucose metabolism.

TRPM2 Ca(2+)-permeable cation channel is widely expressed and activated by markers of cellular stress. Since inflammation and stress play a major role in insulin resistance, we examined the role of TRPM2 Ca(2+) channel in glucose metabolism. A 2-h hyperinsulinemic euglycemic clamp was performed in TRPM2-deficient (KO) and wild-type mice to assess insulin sensitivity. To examine the effects of diet-induced obesity, mice were fed a high-fat diet for 4-10 mo, and metabolic cage and clamp studies were conducted in conscious mice. TRPM2-KO mice were more insulin sensitive partly because of increased glucose metabolism in peripheral organs. After 4 mo of high-fat feeding, TRPM2-KO mice were resistant to diet-induced obesity, and this was associated with increased energy expenditure and elevated expressions of PGC-1α, PGC-1ß, PPARα, ERRα, TFAM, and MCAD in white adipose tissue. Hyperinsulinemic euglycemic clamps showed that TRPM2-KO mice were more insulin sensitive, with increased Akt and GSK-3ß phosphorylation in heart. Obesity-mediated inflammation in adipose tissue and liver was attenuated in TRPM2-KO mice. Overall, TRPM2 deletion protected mice from developing diet-induced obesity and insulin resistance. Our findings identify a novel role of TRPM2 Ca(2+) channel in the regulation of energy expenditure, inflammation, and insulin resistance.

The Role of Social Capital in Predicting Tourists' Waste Sorting Intentions in Rural Destinations: Extending the Theory of Planned Behavior.

Improper waste disposal of tourists has detrimental impacts on the environment, economy, and people in rural destinations. Separating at the source is an effective means to mitigate these adverse impacts on rural destinations. Hence, identifying factors influencing tourists' waste sorting intentions in rural destinations is critical to the sustainability of rural tourism and rural land. However, few studies focus on tourists' waste sorting intentions. Drawing on the theory of planned behavior (TPB) and social capital, this research examined the determinants of tourists' waste sorting intentions in rural destinations. A total of 395 valid questionnaires were collected from a rural destination in Huzhou, China. The results indicated that: (1) all TPB variables, i.e., attitude toward the behavior, subjective norms, and perceived behavioral control, positively and directly affect tourists' waste sorting intentions; (2) interpersonal trust directly and positively influences tourists' waste sorting intentions; (3) subjective norms, perceived behavioral control, interpersonal trust, and emotional bonding indirectly influence tourists' waste sorting intentions through the mediation of attitude toward the behavior; (4) emotional bonding does not directly affect tourists' waste sorting intentions, but the link is established through the mediation of attitude toward the behavior. This research expands the body of knowledge by integrating individuals' psychological elements with their social contexts. The findings offer some theoretical and managerial implications for understanding how tourists' social contexts facilitate tourists' waste sorting intentions.

Linking Perceived Environmental CSR to Residents' Environmental Citizenship Behavior in Rural Tourism: The Mediating Role of Resident-Environment Relationship Quality.

Residents' environmental citizenship behavior is essential to the environmental protection and sustainable development of rural destinations. However, previous research with regards to environmental citizenship behavior has focused on an employee perspective, rather than a resident one. Through the theoretical lens of the Stimulus-Organism-Response (SOR) model, our research examined how perceived environmental CSR (ECSR) contributes to residents' environmental citizenship behavior, with resident-environment relationship quality acting as the organism. Data collected from a Chinese rural destination were analyzed with a structural equation modeling approach. Results indicate that: (1) perceived ECSR directly and positively influences residents' environmental citizenship behavior; (2) relationship quality variables (i.e., environmental identification and environmental commitment) directly and positively affect residents' environmental citizenship behavior; (3) environmental identification directly and positively affects environmental commitment; (4) relationship quality variables positively mediate the effect of perceived ECSR on residents' environmental citizenship behavior. The current research complements existing tourism literature on environmental citizenship behavior with a focus on perceived ECSR and relationship quality from the aspect of residents in rural destinations. The findings also provide some practical implications that potentially facilitate the adoption of environmental citizenship behavior among residents for sustainable destination management.

The dynamic linkages among outbound tourism, economic growth, and international trade: empirical evidence from China.

The aim of this research was to examine the long- and short-run relationships among real expenditures on outbound tourism from China, economic growth and international trade for the period of 1995 to 2018, applying a newly developed cointegration test-the Bootstrap Autoregressive Distributed Lag framework. Evidence of cointegration was found when expenditures on outbound tourism served as the dependent variable, and economic growth and international trade were important factors affecting outbound tourism from China. For the short-run, a two-way Granger causality relationship was detected between economic growth and outbound tourism expenditures, and the feedback was confirmed between outbound tourism expenditures and international trade. The findings have important policy implications for the growth of the outbound tourism market. Large volumes of outbound tourists result in economic losses for China and outbound tourism reduces the growth of tourism-driven international trade.

Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling.

The mammalian nicotinamide-adenine dinucleotide (NAD)-dependent deacetylase Sirt1 impacts different processes involved in the maintenance of brain integrity and in the pathogenic pathways associated with several neurodegenerative disorders, including Alzheimer's disease. Here we used human Sirt1 transgenic mice to demonstrate that neuron-specific Sirt1 overexpression promoted neurite outgrowth and improved cell viability under normal and nutrient-limiting conditions in primary culture systems and that Sirt1-overexpressing neurons exhibited higher tolerance to cell death or degeneration induced by amyloid-ß1-42 oligomers. Coincidentally, we found that enhanced Sirt1 expression in neurons downregulated the mammalian target of rapamycin (mTOR) protein levels and its phosphorylation without changes in its mRNA levels, which was accompanied by concomitant inhibition of the mTOR downstream signaling activity as revealed by decreased p70S6 kinase (p70S6K) phosphorylation at Thr389. Consistently with this, using a Sirt1 siRNA transfection approach, we observed that reduction of endogenous mouse Sirt1 led to increased levels of mTOR and phosphorylation of itself and p70S6K as well as impaired cell survival and neurite outgrowth in wild-type mouse primary neurons, corroborating a suppressing effect of mTOR by Sirt1. Correspondingly, the mTOR inhibitor rapamycin markedly improved neuronal cell survival in response to nutrient deprivation and significantly enhanced neurite outgrowth in wild-type mouse neurons. The protective effect of rapamycin was extended to neurons even with Sirt1 siRNA knockdown that displayed developmental abnormalities compared with siRNA control-treated cells. Collectively, our findings suggest that Sirt1 may act to promote growth and survival of neurons in the central nervous system via its negative modulation of mTOR signaling.

Impacts of Environmental Regulations on Tourism Carbon Emissions.

This research analyzed the impact of environmental regulations and their power in suppressing tourism carbon emissions. The results showed that: (1) four types of environmental regulations had significant inhibiting effects on tourism carbon emissions, but different types of regulations had varying effects; and (2) environmental regulations had a significant time lag effect on tourism carbon emissions. The decay rates of the environmental regulation effects were dissimilar for supervisory management, market incentives, command and control, and public participation; and (3) environmental regulations had dissimilar influences on tourism carbon emissions at the regional level. Government agencies should choose differentiated environmental regulation tools, attach great importance to the time-lag effect of environmental regulations on tourism carbon emissions, and establish systems and mechanisms of public participation in environmental matters.

Medical, Health and Wellness Tourism Research-A Review of the Literature (1970-2020) and Research Agenda.

Medical, health and wellness tourism and travel represent a dynamic and rapidly growing multi-disciplinary economic activity and field of knowledge. This research responds to earlier calls to integrate research on travel medicine and tourism. It critically reviews the literature published on these topics over a 50-year period (1970 to 2020) using CiteSpace software. Some 802 articles were gathered and analyzed from major databases including the Web of Science and Scopus. Markets (demand and behavior), destinations (development and promotion), and development environments (policies and impacts) emerged as the main three research themes in medical-health-wellness tourism. Medical-health-wellness tourism will integrate with other care sectors and become more embedded in policy-making related to sustainable development, especially with regards to quality of life initiatives. A future research agenda for medical-health-tourism is discussed.

Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice.

The serine protease HtrA2/Omi is released from the mitochondrial intermembrane space following apoptotic stimuli. Once in the cytosol, HtrA2/Omi has been implicated in promoting cell death by binding to inhibitor of apoptosis proteins (IAPs) via its amino-terminal Reaper-related motif, thus inducing caspase activity, and also in mediating caspase-independent death through its own protease activity. We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25. These animals, or cells derived from them, show no evidence of reduced rates of cell death but on the contrary suffer loss of a population of neurons in the striatum, resulting in a neurodegenerative disorder with a parkinsonian phenotype that leads to death of the mice around 30 days after birth. The phenotype of these mice suggests that it is the protease function of this protein and not its IAP binding motif that is critical. This conclusion is reinforced by the finding that simultaneous deletion of the other major IAP binding protein, Smac/DIABLO, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them. Mammalian HtrA2/Omi is therefore likely to function in vivo in a manner similar to that of its bacterial homologues DegS and DegP, which are involved in protection against cell stress, and not like the proapoptotic Reaper family proteins in Drosophila melanogaster.

Alcohol use and generational masculinity: An interdisciplinary approach.

INTRODUCTION: Alcohol ranks as a major risk factor for health-related harm and mortality. Older males who encounter alcohol problems late in life are an under-studied part of the affected population. This article seeks to broaden our understanding of this group by combining empirical data with humanistic cultural analysis. Specifically, it seeks to show how the desire to cope alone can be linked to generationally specific constructions of hegemonic masculinity. METHOD: Clinical empirical methods are fused here with those of literary analysis. The subjects which the clinical researcher chooses for scrutiny are different from those most natural to literary study, yet the interpretive approaches of qualitative phenomenological investigation and literary close reading are in fact quite similar, and we argue that new knowledge can be generated by evaluating cultural texts alongside the testimony of phenomenological research subjects. FINDINGS AND DISCUSSION: Our findings illustrate a thematic connection between subject testimony and literary texts from the relevant historical period. In the sources we compared - a qualitative study conducted in Denmark and a British novel, Kingsley Amis's 1954 Lucky Jim - we found a strong link between the values of masculinity and the values of independence. Older men's resistance of institutional treatment for alcohol problems has motivations which go beyond the desire not to rely on outside aid, a desire which may apply to any illness. As Lucky Jim helps us show, alcohol use functions for men of a certain generation as a symbol of rebellion against institutions, and having institutions play a dominant role in their alcohol cessation may create resistance in these men.

Dysregulation of Specialized Delay/Interference-Dependent Working Memory Following Loss of Dysbindin-1A in Schizophrenia-Related Phenotypes.

Dysbindin-1, a protein that regulates aspects of early and late brain development, has been implicated in the pathobiology of schizophrenia. As the functional roles of the three major isoforms of dysbindin-1, (A, B, and C) remain unknown, we generated a novel mutant mouse, dys-1A-/-, with selective loss of dysbindin-1A and investigated schizophrenia-related phenotypes in both males and females. Loss of dysbindin-1A resulted in heightened initial exploration and disruption in subsequent habituation to a novel environment, together with heightened anxiety-related behavior in a stressful environment. Loss of dysbindin-1A was not associated with disruption of either long-term (olfactory) memory or spontaneous alternation behavior. However, dys-1A-/- showed enhancement in delay-dependent working memory under high levels of interference relative to controls, ie, impairment in sensitivity to the disruptive effect of such interference. These findings in dys-1A-/- provide the first evidence for differential functional roles for dysbindin-1A vs dysbindin-1C isoforms among phenotypes relevant to the pathobiology of schizophrenia. Future studies should investigate putative sex differences in these phenotypic effects.

Functional studies of signaling pathways in peri-implantation development of the mouse embryo by RNAi.

BACKGROUND: Studies of gene function in the mouse have relied mainly on gene targeting via homologous recombination. However, this approach is difficult to apply in specific windows of time, and to simultaneously knock-down multiple genes. Here we report an efficient method for dsRNA-mediated gene silencing in late cleavage-stage mouse embryos that permits examination of phenotypes at post-implantation stages. RESULTS: We show that introduction of Bmp4 dsRNA into intact blastocysts by electroporation recapitulates the genetic Bmp4 null phenotype at gastrulation. It also reveals a novel role for Bmp4 in the regulation the anterior visceral endoderm specific gene expression and its positioning. We also show that RNAi can be used to simultaneously target several genes. When applied to the three murine isoforms of Dishevelled, it leads to earlier defects than previously observed in double knock-outs. These include severe delays in post-implantation development and defects in the anterior midline and neural folds at headfold stages. CONCLUSION: Our results indicate that the BMP4 signalling pathway contributes to the development of the anterior visceral endoderm, and reveal an early functional redundancy between the products of the murine Dishevelled genes. The proposed approach constitutes a powerful tool to screen the functions of genes that govern the development of the mouse embryo.

Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3beta on a muscle-specific promoter.

Glycogen synthase kinase-3 (GSK-3) protein levels and activity are elevated in skeletal muscle in type 2 diabetes, and inversely correlated with both glycogen synthase activity and insulin-stimulated glucose disposal. To explore this relationship, we have produced transgenic mice that overexpress human GSK-3beta in skeletal muscle. GSK-3beta transgenic mice were heavier, by up to 20% (P < .001), than their age-matched controls due to an increase in fat mass. The male GSK-3beta transgenic mice had significantly raised plasma insulin levels and by 24 weeks of age became glucose-intolerant as determined by a 50% increase in the area under their oral glucose tolerance curve (P < .001). They were also hyperlipidemic with significantly raised serum cholesterol (+90%), nonesterified fatty acids (NEFAs) (+55%), and triglycerides (+170%). At 29 weeks of age, GSK-3beta protein levels were 5-fold higher, and glycogen synthase activation (-27%), glycogen levels (-58%) and insulin receptor substrate-1 (IRS-1) protein levels (-67%) were significantly reduced in skeletal muscle. Hepatic glycogen levels were significantly increased 4-fold. Female GSK-3beta transgenic mice did not develop glucose intolerance despite 7-fold overexpression of GSK-3beta protein and a 20% reduction in glycogen synthase activation in skeletal muscle. However, plasma NEFAs and muscle IRS-1 protein levels were unchanged in females. We conclude that overexpression of human GSK-3beta in skeletal muscle of male mice resulted in impaired glucose tolerance despite raised insulin levels, consistent with the possibility that elevated levels of GSK-3 in type 2 diabetes are partly responsible for insulin resistance.

Adenoviral-mediated Cre expression effectively suppresses GlyT1 binding in the thalamic area of GlyT1 conditional knock-out mice.

To properly understand the function of genes of neurological interest, in vivo manipulation in the adult is essential, particularly when the target gene is involved in brain development. Moreover, since the physiological effects of target protein may be region-specific, targeting a distinct brain region could be required to dissect these effects in specific brain locations. Infection of somatic tissues of transgenic mice bearing loxP-flanked gene sequences with a viral vector expressing Cre recombinase provides a means of allowing flexible spatio-temporal control of target gene expression. Viral vector-mediated Cre expression could be used to mediate localized gene modulation in a specific brain region. In the present study this technology was applied to the glycine transporter type-1 (GlyT1) protein which is responsible for the uptake of synaptic glycine in the forebrain and has been implicated as a therapeutic target for the treatment of schizophrenia. Since GlyT1 is widely expressed in glial cells, we employed an adenoviral-based vector (Ad5) to deliver Cre protein, due to the preferentially transduction of glial cells by adenoviral vectors in rodent brain. We show significant reduced GlyT1 binding specifically in the thalamic area of conditional GlyT1 (GlyT1c) transgenic mice injected with Ad5-Cre virus, as measured by GlyT1 autoradiography. In conclusion, we demonstrated the validity of viral vector-mediated delivery of Cre to loxP targeted transgenic mice as a novel strategy to investigate target gene function in selected subregions of the adult brain, which provides a valuable technique to investigate gene function both in normal physiology and in disease models.