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Purpose The purpose of this study was to gain a holistic view of pro-environmental behavior (PEB) among hospitality and tourism consumers through a systematic review of empirical studies. Based on this comprehensive review, this study demonstrates how the literature has been created and has evolved over time, thereby providing proposals for future research agendas. Design/methodology/approach The preferred reporting items for systematic reviews and meta-analyses method was used as a rigorous searching method to provide an updated picture of the research on the PEBs of consumers in hospitality and tourism contexts. A total of 234 empirical studies from both hospitality and nonhospitality publications were selected for the review. Findings The results reveal a growing interest in PEB in the hospitality and tourism context. Focal points, theories and research designs used to explain PEB among hospitality and tourism consumers were identified. In addition, the findings from the cross-tabulation analyses have provided valuable insights for tourism and hospitality research in this area. Research limitations/implications Based on the research findings, this study makes significant contributions to the literature by providing theoretical and practical implications with detailed directions for future researchers and practitioners. Originality/value This study offers one of the first reviews to comprehensively and systematically analyze the empirical research into PEBs among hospitality and tourism consumers. PEB has received significant attention from researchers, practitioners and those policymakers concerned with the sustainability of environments. The findings of this research provide a comprehensive overview of the literature relating to hospitality and tourism through the identification of gaps that require further investigation. Future suggestions to assist practitioners and policymakers in eliciting PEBs are also discussed.

Olfactory epithelium (OE) is capable of lifelong regeneration due to presence of basal progenitor cells that respond to injury or neuronal loss with increased activity. However, this capability diminishes with advancing age and a decrease in odor perception in older individuals is well established. To characterize changes associated with age in the peripheral olfactory system, an in-depth analysis of the OE and its neuronal projections onto the olfactory bulb (OB) as a function of age was performed. Human olfactory tissue autopsy samples from 36 subjects with an average age of 74.1 years were analyzed. Established cell type-specific antibodies were used to identify OE component cells in whole mucosal sheets and epithelial sections as well as glomeruli and periglomerular structures in OB sections. With age, a reduction in OE area occurs across the mucosa progressing in a posterior-dorsal direction. Deterioration of the olfactory system is accompanied with diminution of neuron-containing OE, mature olfactory sensory neurons (OSNs) and OB innervation. On an individual level, the neuronal density within the epithelium appears to predict synapse density within the OB. The innervation of the OB is uneven with higher density at the ventral half that decreases with age as opposed to stable innervation at the dorsal half. Respiratory metaplasia, submucosal cysts, and neuromata, were commonly identified in aged OE. The finding of respiratory metaplasia and aneuronal epithelium with reduction in global basal cells suggests a progression of stem cell quiescence as an underlying pathophysiology of age-related smell loss in humans. KEY POINTS: A gradual loss of olfactory sensory neurons with age in human olfactory epithelium is also reflected in a reduction in glomeruli within the olfactory bulb. This gradual loss of neurons and synaptic connections with age occurs in a specific, spatially inhomogeneous manner. Decreasing mitotically active olfactory epithelium basal cells may contribute to age-related neuronal decline and smell loss in humans.

Purpose This research aims to use meta-analytical structural equation modeling to look into how hospitality employees use technology at work. It further investigates if the relationship between the constructs of the technology acceptance model (TAM) is moderated by job level (supervisory versus non-supervisory) and different cultures (eastern versus western). Design/methodology/approach In total, 140 relationships from 30 empirical studies (N = 6,728) were used in this study’s data analysis in accordance with the preferred reporting items for systematic reviews and meta-analysis. Findings The findings demonstrated that perceived usefulness had a greater influence on “user attitudes” and “acceptance intention” than perceived ease of use. This study also identified that the effect sizes of relationships among TAM constructs appeared to be greater for supervisory employees or in eastern cultures than for those in non-supervisory roles or western cultures. Practical implications The findings provide valuable information for practitioners to increase the adoption of employee technology. Practitioners need to focus on the identification of hospitality employee attitudes, social norms and perceived ease of use. Moreover, hospitality practitioners should be cautious when promoting the adoption of new technologies to employees, as those at different levels may respond differently. Originality/value This is the very first empirical investigation to meta-analyze the predictive power of the TAM in the context of hospitality staff technology adoption at the workplace. The findings also demonstrated differences in the predictive power of TAM constructs according to job level and cultural differences.

Cellular senescence is a stable form of cell cycle arrest associated with proinflammatory responses. Senescent cells can be cleared by the immune system as a part of normal tissue homeostasis. However, senescent cells can also accumulate in aged and diseased tissues, contributing to inflammation and disease progression. The mechanisms mediating the impaired immune-mediated clearance of senescent cells are poorly understood. Here, we report that senescent cells upregulate the immune checkpoint molecule PD-L1, the ligand for PD-1 on immune cells, which drives immune cell inactivation. The induction of PD-L1 in senescence is dependent on the proinflammatory program. Furthermore, the secreted factors released by senescent cells are sufficient to upregulate PD-L1 in nonsenescent control cells, mediated by the JAK-STAT pathway. In addition, we show that prolongevity intervention rapamycin downregulates PD-L1 in senescent cells. Last, we found that PD-L1 is upregulated in several tissues in naturally aged mice and in the lungs of idiopathic pulmonary fibrosis patients. Together, our results report that senescence and aging are associated with upregulation of a major immune checkpoint molecule, PD-L1. Targeting PD-L1 may offer new therapeutic opportunities in treating senescence and age-associated diseases.

International audience; Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein's amino terminal (N′)-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C∆C0-C1f), displayed dilated cardiomyopathy, underscoring the importance of the N′-region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, likely contributing to normal sarcomere morphology and myoarchitecture. These results led us to hypothesize that restoration of the N′-region of cMyBP-C would return actomyosin interaction to its steady state. Accordingly, we administered recombinant C0-C2 (rC0-C2) to permeabilized cardiomyocytes from transgenic, cMyBP-C null, and human heart failure biopsies, and we found that normal regulation of actomyosin interaction and contractility was restored. Overall, these data provide a unique picture of selective perturbations of the cardiac sarcomere that either lead to injury or adaptation to injury in the myocardium.

Background Therapeutic drug monitoring (TDM) of infliximab (IFX) levels in inflammatory bowel disease (IBD) patients can help to guide dose adjustments or changes to therapy for selected patients in remission or with secondary loss of response (LOR). Aims To determine how IFX TDM is utilised in a real-life clinical setting and to quantify the potential for TDM to reduce the unnecessary use of IFX. Methods Data from all public IBD IFX level testing performed across Australia were prospectively collected from June 2016 to July 2017 to assess physician-reported for testing indications (induction, in remission or LOR) and associated results. The hypothetical influence of IFX TDM was based on an optimal therapeutic range of 6-10 mg/L for mucosal healing. Results Secondary LOR (reactive TDM) was the most common indication for TDM. These patients have consistently lower median IFX levels: 3.02 mg/L (IQR 1.14-6.67 mg/L) versus 5.22 mg/L (IQR 2.70-8.12 mg/L), P = 0.0001 compared with patients in remission (proactive TDM). TDM helped to identify unnecessary use of IFX in 30.6% of the TDM tests performed in luminal Crohn disease and ulcerative colitis patients, with an associated drug cost saving of $531.38 per IFX TDM test episode. Unnecessary IFX use was identified in 38.9% (96/247) of reactive IFX TDM tests performed and in 19.3% (35/181) of proactive testing. Conclusion Use of both reactive and proactive IFX TDM is cost-effective for IBD management as it informs the clinician where unnecessary use of IFX can be stopped.

Hemophilia B is a blood clotting disorder caused by deficient activity of coagulation factor IX (FIX). Multiple recombinant FIX proteins are currently approved to treat hemophilia B, and several gene therapy products are currently being developed. Codon optimization is a frequently used technique in the pharmaceutical industry to improve recombinant protein expression by recoding a coding sequence using multiple synonymous codon substitutions. The underlying assumption of this gene recoding is that synonymous substitutions do not alter protein characteristics because the primary sequence of the protein remains unchanged. However, a critical body of evidence shows that synonymous variants can affect cotranslational folding and protein function. Gene recoding could potentially alter the structure, function, and in vivo immunogenicity of recoded therapeutic proteins. Here, we evaluated multiple recoded variants of F9 designed to further explore the effects of codon usage bias on protein properties. The detailed evaluation of these constructs showed altered conformations, and assessment of translation kinetics by ribosome profiling revealed differences in local translation kinetics. Assessment of wild-type and recoded constructs using a major histocompatibility complex (MHC)-associated peptide proteomics assay showed distinct presentation of FIX-derived peptides bound to MHC class II molecules, suggesting that despite identical amino acid sequence, recoded proteins could exhibit different immunogenicity risks. Posttranslational modification analysis indicated that overexpression from gene recoding results in suboptimal posttranslational processing. Overall, our results highlight potential functional and immunogenicity concerns associated with gene-recoded F9 products. These findings have general applicability and implications for other gene-recoded recombinant proteins.

Introduction: Alpha actinin-2 (ACTN2) is a major cytoskeletal protein that plays a critical role in maintaining the structural and functional integrity of the sarcomere. ACTN2 mutations, although rare, have been shown to be associated with various types of cardiomyopathy. Using genome-wide association and multi-omic approaches, we recently identified non-coding variants that showed a strong association with heart failure (HF). Two of the variants are within an evolutionary conserved transcriptional enhancer region that regulates the ACTN2 gene in human stem cell derived cardiomyocytes (hPSC-CMs). However, the role of cardiac enhancers in the development of HF remains unknown, therefore we used engineered heart tissues (EHT) from hPSC-CMs to investigate the effects of the ACTN2 enhancer. Methods: We used hPSC-CMs and performed morphologic and functional analyses by immunostaining, calcium transient measurements and quantitative assays such as western blotting, proteomics, qPCR and single cell transcriptomics. Next, we utilized CRISPR interference (CRISPRi) and chromatin immunoprecipitation (ChIP) to analyze the transcriptional regulation of the ACTN2 enhancer. Finally, we measured force generation using EHTs. Results: We first engineered hPSC-CMs carrying an ACTN2 enhancer deletion. This resulted in decreased ACTN2 gene and protein expression, and cardiomyocytes developed myofibrillar disarray, hypertrophy, lower beating rates and suppressed calcium transients. Moreover, EHTs demonstrated reduced mechanical force. Using CRISPRi and ChIP we found that the transcription factor MEF2c binds a short DNA sequence containing an enhancer variant to regulate ACTN2 expression. Single cell RNA-Seq analysis of hPSC-CMs treated with isoproterenol to model the hyperadrenergic state observed in HF, revealed the induction of pathways involved in protein quality control, actin fragmentation and apoptosis. We have also recently developed a mouse model to address the effect of the enhancer in vivo . Conclusions: Our study confirms that a conserved and clinically relevant enhancer region can effectively regulate ACTN2 , and variants within that region can have detrimental consequences on CMs which can contribute to HF.

Synonymous codons occur with different frequencies in different organisms, a phenomenon termed codon usage bias. Codon optimization, a common term for a variety of approaches used widely by the biopharmaceutical industry, involves synonymous substitutions to increase protein expression. It had long been presumed that synonymous variants, which, by definition, do not alter the primary amino acid sequence, have no effect on protein structure and function. However, a critical mass of reports suggests that synonymous codon variations may impact protein conformation. To investigate the impact of synonymous codons usage on protein expression and function, we designed an optimized coagulation factor IX (FIX) variant and used multiple methods to compare its properties to the wild-type FIX upon expression in HEK293T cells. We found that the two variants differ in their conformation, even when controlling for the difference in expression levels. Using ribosome profiling, we identified robust changes in the translational kinetics of the two variants and were able to identify a region in the gene that may have a role in altering the conformation of the protein. Our data have direct implications for codon optimization strategies, for production of recombinant proteins and gene therapies.

Analysis of The Cancer Genome Atlas and other published data of head and neck squamous cell carcinoma (HNSCC) reveals somatic alterations of the Hippo-YAP pathway in approximately 50% of HNSCC. Better strategies to target the YAP1 transcriptional complex are sought. Here, we show that FAT1, an upstream inhibitor of YAP1, is mutated either by missense or by truncating mutation in 29% of HNSCC. Comprehensive proteomic and drug-screening studies across pan-cancer models confirm that FAT1-mutant HNSCC exhibits selective and higher sensitivity to BRD4 inhibition by JQ1. Epigenomic analysis reveals an active chromatin state in FAT1-mutant HNSCC cells that is driven by the YAP/TAZ transcriptional complex through recruitment of BRD4 to deposit active histone marks, thereby maintaining an oncogenic transcriptional state. This study reveals a detailed cooperative mechanism between YAP1 and BRD4 in HNSCC and suggests a specific therapeutic opportunity for the treatment of this subset of head and neck cancer patients.

Chronic elevation of free fatty acids (FFA) in obesity may cause ß-cell dysfunction leading to type 2 diabetes (T2D). Recent studies have focused on innate immunity receptors due to evidence implicating inflammation in obesity-induced T2D. While several of these receptors have been implicated in FFA-induced ß-cell dysfunction, the nucleotide-binding oligomerization domain (NOD) receptors have not been investigated. Our previous work showed that whole-body NOD1-null mice were protected from palmitate-induced ß-cell dysfunction in vivo. This may be due to lack of NOD1 in ß-cells and/or macrophages infiltrating islets. Also, islets of whole-body NOD1-null and JNK1-null mice were protected from ß-cell dysfunction induced by palmitate but not oleate in vitro, suggesting NOD1 activation is likely in ß-cells, is specific to saturated FFA and may cause ß-cell dysfunction via JNK1. Thus, we hypothesized that ß-cell NOD1 mediates palmitate-induced ß-cell dysfunction in vivo, and that JNK1 is downstream of NOD1 activation. Addition of an ethyl group on palmitate reduces toxicity of unbound palmitate, thus ethylpalmitate (EtPAL) was used. Ethyl esterases in mouse plasma hydrolyze EtPAL into palmitate and ethanol. ß-cell specific NOD1-null (ßKO) mice (using Ins1- and RIP-Cre) and their controls were infused with EtPAL or ethanol vehicle (Veh) for 48 hours, followed by a hyperglycemic clamp to evaluate ß-cell function in vivo from the disposition index (DI). Islets of JNK1-null and wildtype (WT) mice were isolated and treated with a NOD1 activator to investigate the NOD1-JNK1 axis. As expected, EtPAL infusion elevated plasma FFA. EtPAL decreased DI in control mice, while EtPAL-infused ßKO mice had similar DI to Veh-infused mice. Further, the NOD1 activator reduced insulin secretion in WT islets but not in JNK1-null islets. These data implicate ß-cell NOD1-JNK1 axis in palmitate-induced ß-cell dysfunction and reveal a novel pathway that could be targeted for manipulation in order to preserve ß-cell function. Disclosure J. Yung: None. A. Ivovic: None. I. Clark: None. F. Li: None. B. Lin: None. Y. Tan: None. A. Giacca: None. Funding Canadian Institutes of Health Research (CIHR50748)

Telehealth has become an increasingly important part of health care delivery, with a dramatic rise in telehealth visits during the COVID-19 pandemic. Telehealth visits will continue to be a part of care delivery after the pandemic subsides, and it is important that medical students receive training in telehealth skills to meet emerging telehealth competencies. This paper describes strategies for successfully integrating medical students into telehealth visits in the ambulatory setting based on existing literature and the extensive experience of the authors teaching and learning in the telehealth environment.

SummaryCOVID-19 has caused over 1 million deaths globally, yet the cellular mechanisms underlying severe disease remain poorly understood. By analyzing several thousand plasma proteins in 306 COVID-19 patients and 78 symptomatic controls over serial timepoints using two complementary approaches, we uncover COVID-19 host immune and non-immune proteins not previously linked to this disease. Integration of plasma proteomics with nine published scRNAseq datasets shows that SARS-CoV-2 infection upregulates monocyte/macrophage, plasmablast, and T cell effector proteins. By comparing patients who died to severely ill patients who survived, we identify dynamic immunomodulatory and tissue-associated proteins associated with survival, providing insights into which host responses are beneficial and which are detrimental to survival. We identify intracellular death signatures from specific tissues and cell types, and by associating these with angiotensin converting enzyme 2 (ACE2) expression, we map tissue damage associated with severe disease and propose which damage results from direct viral infection rather than from indirect effects of illness. We find that disease severity in lung tissue is driven by myeloid cell phenotypes and cell-cell interactions with lung epithelial cells and T cells. Based on these results, we propose a model of immune and epithelial cell interactions that drive cell-type specific and tissue-specific damage in severe COVID-19.

Muscle contraction, which is initiated by Ca2+, results in precise sliding of myosin-based thick and actin-based thin filament contractile proteins. The interactions between myosin and actin are finely tuned by three isoforms of myosin binding protein-C (MyBP-C): slow-skeletal, fast-skeletal, and cardiac (ssMyBP-C, fsMyBP-C and cMyBP-C, respectively), each with distinct N-terminal regulatory regions. The skeletal MyBP-C isoforms are conditionally coexpressed in cardiac muscle, but little is known about their function. Therefore, to characterize the functional differences and regulatory mechanisms among these three isoforms, we expressed recombinant N-terminal fragments and examined their effect on contractile properties in biophysical assays. Addition of the fragments to in vitro motility assays demonstrated that ssMyBP-C and cMyBP-C activate thin filament sliding at low Ca2+. Corresponding 3D electron microscopy reconstructions of native thin filaments suggest that graded shifts of tropomyosin on actin are responsible for this activation (cardiac > slow-skeletal > fast-skeletal). Conversely, at higher Ca2+, addition of fsMyBP-C and cMyBP-C fragments reduced sliding velocities in the in vitro motility assays and increased force production in cardiac muscle fibers. We conclude that due to the high frequency of Ca2+ cycling in cardiac muscle, cardiac MyBP-C may play dual roles at both low and high Ca2+. However, skeletal MyBP-C isoforms may be tuned to meet the needs of specific skeletal muscles.

Wire + arc additive manufacturing (WAAM), a promising technology to produce complex parts, was used to produce steel components with a custom-designed cored-metal wire. The chosen chemical composition of the cored wire is known to produced advance high-strength steel. The as-printed microstructure consists of martensite, retained austenite, and different morphological phases of ferrite, including quasi-polygonal, acicular, and Widmanstatten. Nanoindentation shows the highest hardness value for martensite, followed by acicular ferrite and then quasi-polygonal ferrite. However, a considerable spatial microstructural heterogeneity was observed in as-printed samples due to thermal cycling and chemical segregation. A higher fraction of harder martensite phase was observed at the bottom of the printed coupon, and the phase fraction of martensite decreased due to heat accumulation along the deposition height. Microstructural heterogeneity is reflected in the inhomogeneous distribution of nanohardness. Tempering of the printed sample results in carbide precipitation in martensite phases, leading to a decrease in the martensite hardness, but the heterogeneity is conserved. Both quench hardening and quenching and partitioning (Q&P) treatment were found to homogenize the microstructures. The quench-hardened samples' microstructure was comprised of lath martensite, while the Q&P treatment led to formation of tempered martensite and retained austenite.

Striated cardiac and skeletal muscles play very different roles in the body, but they are similar at the molecular level. In particular, contraction, regardless of the type of muscle, is a precise and complex process involving the integral protein myofilaments and their associated regulatory components. The smallest functional unit of muscle contraction is the sarcomere. Within the sarcomere can be found a sophisticated ensemble of proteins associated with the thick filaments (myosin, myosin binding protein-C, titin, and obscurin) and thin myofilaments (actin, troponin, tropomyosin, nebulin, and nebulette). These parallel thick and thin filaments slide across one another, pulling the two ends of the sarcomere together to regulate contraction. More specifically, the regulation of both timing and force of contraction is accomplished through an intricate network of intra- and interfilament interactions belonging to each myofilament. This review introduces the sarcomere proteins involved in striated muscle contraction and places greater emphasis on the more recently identified and less well-characterized myofilaments: cardiac myosin binding protein-C, titin, nebulin, and obscurin. © 2017 American Physiological Society. Compr Physiol 7:675-692, 2017.

The Open Science Grid (OSG) provides a common service for resource providers and scientific institutions, and supports sciences such as High Energy Physics, Structural Biology, and other community sciences. As scientific frontiers expand, so does the need for resources to analyze new data. For example, high energy physics (LHC) sciences foresee an exponential growth in the amount of data collected, which comes with corresponding growth in the need for computing resources. Allowing resource providers an easy way to share their resources is paramount to ensure the grow of resources available to scientists. In this context, the OSG Hosted CE initiative provides site administrator a way to reduce the effort needed to install and maintain a Compute Element (CE), and represents a solution for sites who do not have the effort and expertise to run their own Grid middleware. An HTCondor Compute Element is installed on a remote VM at UChicago for each site that joins the Hosted CE initiative. The hardware/software stack is maintained by OSG Operations staff in a homogeneus and automated way, providing a reduction in the overall operational effort needed to maintain the CEs: one single organization does it in an uniform way, instead of each single resource provider doing it in their own way. Currently, more than 20 institutions joined the Hosted CE initiative. This contribution discusses the technical details behind a Hosted CE installation, highlighting key strenghts and common pitfalls, and outlining future plans to further reduce operational experience.

Synonymous variants within coding regions may influence protein expression and function. We have previously reported increased protein expression levels ex vivo (~120% in comparison to wild-type) from a synonymous polymorphism variant, c.354G>A [p.P118P], of the ADAMTS13 gene, encoding a plasma protease responsible for von Willebrand Factor (VWF) degradation. In the current study, we investigated the potential mechanism(s) behind the increased protein expression levels from this variant and its effect on ADAMTS13 physico-chemical properties. Cell-free assays showed enhanced translation of the c.354G>A variant and the analysis of codon usage characteristics suggested that introduction of the frequently used codon/codon pair(s) may have been potentially responsible for this effect. Limited proteolysis, however, showed no substantial influence of altered translation on protein conformation. Analysis of post-translational modifications also showed no notable differences but identified three previously unreported glycosylation markers. Despite these similarities, p.P118P variant unexpectedly showed higher specific activity. Structural analysis using modeled interactions indicated that subtle conformational changes arising from altered translation kinetics could affect interactions between an exosite of ADAMTS13 and VWF resulting in altered specific activity. This report highlights how a single synonymous nucleotide variation can impact cellular expression and specific activity in the absence of measurable impact on protein structure.