Endogenous lysophosphatidic acid (LPA1) receptor agonists demonstrate ligand bias between calcium and ERK signalling pathways in human lung fibroblasts

Background and Purpose Human lung fibroblasts (HLF) express high levels of the LPA1 receptor, a GPCR that responds to the endogenous lipid mediator, lysophosphatidic acid (LPA). Several molecular species or analogues of LPA exist and have been detected in biological fluids such as serum and plasma. The most widely expressed of the LPA receptor family is the LPA1 receptor, which predominantly couples to Gq/11, Gi/o and G12/13 proteins. This promiscuity of coupling raises the possibility that some of the LPA analogues may bias the LPA1 receptor towards one signalling pathway over another. Experimental Approach Here, we have explored the signalling profiles of a range of LPA analogues in HLF that endogenously express the LPA1 receptor. HLF were treated with LPA analogues and receptor activation monitored via calcium mobilization and ERK phosphorylation. Key Results These analyses demonstrated that the 16:0, 17:0, 18:2 and C18:1 LPA analogues appear to exhibit ligand bias between ERK phosphorylation and calcium mobilization when compared with 18:1 LPA, one of the most abundant forms of LPA that has been found in human plasma. Conclusion and Implications The importance of LPA as a key signalling molecule is shown by its widespread occurrence in biological fluids and its association with disease conditions such as fibrosis and cancer. These findings have important, as yet unexplored, implications for the (patho-) physiological signalling of the LPA1 receptor, as it may be influenced not only by the concentration of endogenous ligand but the isoform as well

Quality of Life and Autonomy in Emerging Adults with Early‐Onset Neuromuscular Disorders

Emerging adulthood is an important period in the development of one’s identity and autonomy. The ways in which identity and autonomy are viewed by emerging adults and how they impact quality of life (QoL) in individuals with early‐onset neuromuscular conditions is not yet known. This study focused on understanding and exploring relationships between self‐perceptions of emerging adulthood, autonomy, and QoL. Five previously validated measures were incorporated into an online survey and distributed to young adults with early‐onset neuromuscular conditions and unaffected controls. Topics explored included individuals’ views regarding their overall QoL, disease‐specific QoL, components of emerging adulthood, and autonomy. We found that a sense of higher disease impact was associated with a lower Overall General QoL. Additionally, perceptions of key autonomy factors “negativity” and “instability” were uniquely associated with Overall General QoL in the case group as compared to controls, whereas “attitudinal autonomy” (attaining the ability to plan and follow through with goals) was important to this age group regardless of health status. The specific factors of emerging adulthood and autonomy that were significantly correlated with Overall General QoL can be used for developing targeted counseling and interventions to improve QoL for individuals and their families.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146967/1/jgc40713.pd

Paper Spray Ionization: Applications and Perspectives

Paper spray ionization has grown to become one of the most successful ambient ionization methods within the past decade. Requiring little to no sample preparation and being remarkably simple to construct, this technique has seen application in a wide number of fields. This review approaches the mechanism of how paper spray works, and seeks to better classify what it is and is not in a rapidly expanding field of ambient techniques. Additionally, many applications of the technique in clinical, forensic, environmental, and reaction monitoring regimes are explored. Finally, perspectives towards the future of how paper spray could be utilized will be expanded upon, including unexplored substrates and possibilities for the 'omics space

Adolescent Brain Cognitive Development (ABCD) Study Linked External Data (LED): Protocol and practices for geocoding and assignment of environmental data

Our brain is constantly shaped by our immediate environments, and while some effects are transient, some have long-term consequences. Therefore, it is critical to identify which environmental risks have evident and long-term impact on brain development. To expand our understanding of the environmental context of each child, the Adolescent Brain Cognitive Development (ABCD) Study® incorporates the use of geospatial location data to capture a range of individual, neighborhood, and state level data based on the child\u27s residential location in order to elucidate the physical environmental contexts in which today\u27s youth are growing up. We review the major considerations and types of geocoded information incorporated by the Linked External Data Environmental (LED) workgroup to expand on the built and natural environmental constructs in the existing and future ABCD Study data releases. Understanding the environmental context of each youth furthers the consortium\u27s mission to understand factors that may influence individual differences in brain development, providing the opportunity to inform public policy and health organization guidelines for child and adolescent health

The Sigma Class glutathione transferase from the liver fluke Fasciola hepatica

BACKGROUND: Liver fluke infection of livestock causes economic losses of over US$ 3 billion worldwide per annum. The disease is increasing in livestock worldwide and is a re-emerging human disease. There are currently no commercial vaccines, and only one drug with significant efficacy against adult worms and juveniles. A liver fluke vaccine is deemed essential as short-lived chemotherapy, which is prone to resistance, is an unsustainable option in both developed and developing countries. Protein superfamilies have provided a number of leading liver fluke vaccine candidates. A new form of glutathione transferase (GST) family, Sigma class GST, closely related to a leading Schistosome vaccine candidate (Sm28), has previously been revealed by proteomics in the liver fluke but not functionally characterised. METHODOLOGY/PRINCIPAL FINDINGS: In this manuscript we show that a purified recombinant form of the F. hepatica Sigma class GST possesses prostaglandin synthase activity and influences activity of host immune cells. Immunocytochemistry and western blotting have shown the protein is present near the surface of the fluke and expressed in eggs and newly excysted juveniles, and present in the excretory/secretory fraction of adults. We have assessed the potential to use F. hepatica Sigma class GST as a vaccine in a goat-based vaccine trial. No significant reduction of worm burden was found but we show significant reduction in the pathology normally associated with liver fluke infection. CONCLUSIONS/SIGNIFICANCE: We have shown that F. hepatica Sigma class GST has likely multi-functional roles in the host-parasite interaction from general detoxification and bile acid sequestration to PGD synthase activity

PROTOCOL: In‐person interventions to reduce social isolation and loneliness: An evidence and gap map

Abstract This is the protocol for an evidence and gap map. The objectives are as follows: This EGM aims to map available evidence on the effects of in‐person interventions to reduce social isolation and/or loneliness across all age groups in all settings

Integrating multisector molecular characterization into personalized peptide vaccine design for patients with newly diagnosed glioblastoma

PURPOSE: Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. PATIENTS AND METHODS: In this study, we report the findings of four patients enrolled onto the NeoVax clinical trial (NCT0342209). RESULTS: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells pre- and post-NeoVax for patients 1 to 3 using IFNγ-ELISPOT assay. A statistically significant increase in IFNγ producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from patient 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. CONCLUSIONS: Collectively, our findings suggest that NeoVax stimulated the expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in patients with GBM

Loss of Myotubularin Function Results in T-Tubule Disorganization in Zebrafish and Human Myotubular Myopathy

Myotubularin is a lipid phosphatase implicated in endosomal trafficking in vitro, but with an unknown function in vivo. Mutations in myotubularin cause myotubular myopathy, a devastating congenital myopathy with unclear pathogenesis and no current therapies. Myotubular myopathy was the first described of a growing list of conditions caused by mutations in proteins implicated in membrane trafficking. To advance the understanding of myotubularin function and disease pathogenesis, we have created a zebrafish model of myotubular myopathy using morpholino antisense technology. Zebrafish with reduced levels of myotubularin have significantly impaired motor function and obvious histopathologic changes in their muscle. These changes include abnormally shaped and positioned nuclei and myofiber hypotrophy. These findings are consistent with those observed in the human disease. We demonstrate for the first time that myotubularin functions to regulate PI3P levels in a vertebrate in vivo, and that homologous myotubularin-related proteins can functionally compensate for the loss of myotubularin. Finally, we identify abnormalities in the tubulo-reticular network in muscle from myotubularin zebrafish morphants and correlate these changes with abnormalities in T-tubule organization in biopsies from patients with myotubular myopathy. In all, we have generated a new model of myotubular myopathy and employed this model to uncover a novel function for myotubularin and a new pathomechanism for the human disease that may explain the weakness associated with the condition (defective excitation–contraction coupling). In addition, our findings of tubuloreticular abnormalities and defective excitation-contraction coupling mechanistically link myotubular myopathy with several other inherited muscle diseases, most notably those due to ryanodine receptor mutations. Based on our findings, we speculate that congenital myopathies, usually considered entities with similar clinical features but very disparate pathomechanisms, may at their root be disorders of calcium homeostasis

A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells

SummaryGlioblastoma harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs) that can propagate tumors in vivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC) drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model in vivo. CDC20-APC control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-APC/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-APC-targeted strategies in the treatment of glioblastoma

In‐person interventions to reduce social isolation and loneliness: An evidence and gap map

BackgroundSocial isolation and loneliness can occur in all age groups, and they are linked to increased mortality and poorer health outcomes. There is a growing body of research indicating inconsistent findings on the effectiveness of interventions aiming to alleviate social isolation and loneliness. Hence the need to facilitate the discoverability of research on these interventions.ObjectivesTo map available evidence on the effects of in-person interventions aimed at mitigating social isolation and/or loneliness across all age groups and settings.Search MethodsThe following databases were searched from inception up to 17 February 2022 with no language restrictions: Ovid MEDLINE, Embase, EBM Reviews—Cochrane Central Register of Controlled Trials, APA PsycInfo via Ovid, CINAHL via EBSCO, EBSCO (all databases except CINAHL), Global Index Medicus, ProQuest (all databases), ProQuest ERIC, Web of Science, Korean Citation Index, Russian Science Citation Index, and SciELO Citation Index via Clarivate, and Elsevier Scopus.Selection CriteriaTitles, abstracts, and full texts of potentially eligible articles identified were screened independently by two reviewers for inclusion following the outlined eligibility criteria.Data Collection and AnalysisWe developed and pilot tested a data extraction code set in Eppi-Reviewer. Data was individually extracted and coded. We used the AMSTAR2 tool to assess the quality of reviews. However, the quality of the primary studies was not assessed.Main ResultsA total of 513 articles (421 primary studies and 92 systematic reviews) were included in this evidence and gap map which assessed the effectiveness of in-person interventions to reduce social isolation and loneliness. Most (68%) of the reviews were classified as critically low quality, while less than 5% were classified as high or moderate quality. Most reviews looked at interpersonal delivery and community-based delivery interventions, especially interventions for changing cognition led by a health professional and group activities, respectively. Loneliness, wellbeing, and depression/anxiety were the most assessed outcomes. Most research was conducted in high-income countries, concentrated in the United States, United Kingdom, and Australia, with none from low-income countries. Major gaps were identified in societal level and community-based delivery interventions that address policies and community structures, respectively. Less than 5% of included reviews assessed process indicators or implementation outcomes. Similar patterns of evidence and gaps were found in primary studies. All age groups were represented but more reviews and primary studies focused on older adults (≥60 years, 63%) compared to young people (≤24 years, 34%). Two thirds described how at-risk populations were identified and even fewer assessed differences in effect across equity factors for populations experiencing inequities