Longitudinal studies of patterns of healthcare contacts in those who die by suicide to identify those at risk are scarce.
To examine type and timing of healthcare contacts in those who die by ...suicide.
A population-based electronic case-control study of all who died by suicide in Wales, 2001-2017, linking individuals' electronic healthcare records from general practices, emergency departments and hospitals. We used conditional logistic regression to calculate odds ratios, adjusted for deprivation. We performed a retrospective continuous longitudinal analysis comparing cases' and controls' contacts with health services.
We matched 5130 cases with 25 650 controls (5 per case). A representative cohort of 1721 cases (8605 controls) were eligible for the fully linked analysis. In the week before their death, 31.4% of cases and 15.6% of controls contacted health services. The last point of contact was most commonly associated with mental health and most often occurred in general practices. In the month before their death, 16.6 and 13.0% of cases had an emergency department contact and a hospital admission respectively, compared with 5.5 and 4.2% of controls. At any week in the year before their death, cases were more likely to contact healthcare services than controls. Self-harm, mental health and substance misuse contacts were strongly linked with suicide risk, more so when they occurred in emergency departments or as emergency admissions.
Help-seeking occurs in those at risk of suicide and escalates in the weeks before their death. There is an opportunity to identify and intervene through these contacts.
AbstractExploiting smart cities with digital twins (SCDT) requires the integration of sensing and simulation across diverse infrastructure systems into community management. Community disaster ...management can provide a valuable foundation for SCDT development. The current work proposes and tests a conceptual model of a SCDT for disaster management and describes two threats to SCDT development that can be mitigated by focusing development on disaster management. Information loops, as opposed to individual components, are identified as a critical future focus of SCDT development. Primary contributions include support for SCDT development for disaster management, a conceptual SCDT for disaster management model, and a discussion of issues to be addressed in the development and deployment of SCDT for disaster management.
The fatty acyl composition of phospholipids determines the biophysical character of membranes and impacts the function of membrane proteins. Here, we define a nuclear receptor pathway for the dynamic ...modulation of membrane composition in response to changes in cellular lipid metabolism. Ligand activation of liver X receptors (LXRs) preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids through induction of the remodeling enzyme Lpcat3. Promotion of Lpcat3 activity ameliorates endoplasmic reticulum (ER) stress induced by saturated free fatty acids in vitro or by hepatic lipid accumulation in vivo. Conversely, Lpcat3 knockdown in liver exacerbates ER stress and inflammation. Mechanistically, Lpcat3 modulates inflammation both by regulating inflammatory kinase activation through changes in membrane composition and by affecting substrate availability for inflammatory mediator production. These results outline an endogenous mechanism for the preservation of membrane homeostasis during lipid stress and identify Lpcat3 as an important mediator of LXR effects on metabolism.
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•Induction of Lpcat3 expression by LXRs promotes phospholipid remodeling•LXR-Lpcat3 activation drives unsaturated fatty acid incorporation into phospholipids•Lpcat3 activity in liver modulates lipid-induced ER stress and inflammation•Lpcat3 affects inflammation through regulation of membrane c-Src activity
Christian Wisdom Ford, David F.
06/2007, Letnik:
v.Series Number 16
eBook
What is Christian wisdom for living in the twenty-first century? Where is it to be found? How can it be learnt? In the midst of diverse religions and worldviews and the demands and complexities of ...our world, David Ford explores a Christian way of uniting love of wisdom with wisdom in love. Core elements are the 'discernment of cries', the love of God for God's sake, interpretation of scripture, and the shaping of desire in faith. Case studies deal with inter-faith wisdom among Jews, Christians and Muslims, universities as centres of wisdom as well as knowledge and know-how and the challenge of learning disabilities. Throughout, there is an attempt to do justice to the premodern, modern and postmodern while grappling with scripture, tradition and the cries of the world today. Ford opens up the rich resources of Christianity in engaging with the issues and urgencies of contemporary life.
Regulatory T (Treg) cells induce an immunosuppressive microenvironment that is a major obstacle for successful tumor immunotherapy. Dissecting the regulatory mechanisms between energy metabolism and ...functionality in Treg cells will provide insight toward developing novel immunotherapies against cancer. Here we report that human naturally occurring and tumor-associated Treg cells exhibit distinct metabolic profiles with selectivity for glucose metabolism compared with effector T cells. Treg-mediated accelerated glucose consumption induces cellular senescence and suppression of responder T cells through cross-talk. TLR8 signaling selectively inhibits glucose uptake and glycolysis in human Treg cells, resulting in reversal of Treg suppression. Importantly, TLR8 signaling-mediated reprogramming of glucose metabolism and function in human Treg cells can enhance anti-tumor immunity in vivo in a melanoma adoptive transfer T cell therapy model. Our studies identify mechanistic links between innate signaling and metabolic regulation of human Treg suppression, which may be used as a strategy to advance tumor immunotherapy.
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•Human Tregs exhibit distinct metabolic profiles compared with effector T cells•Activated Tregs uniquely accelerate glucose consumption for their suppression•TLR8 signaling selectively inhibits glucose uptake and glycolysis in human Tregs•TLR8-mediated reprogramming of Treg glucose metabolism enhances anti-tumor immunity
Treg-mediated immunosuppression is a significant obstacle for tumor immunotherapy. Li et al. show that human Treg cells heighten glucose consumption and subsequently trigger cellular senescence and suppression of effector T cells. With TLR8 signaling, they selectively inhibit glucose uptake and glycolysis in human Treg cells, resulting in Treg function reversal and enhanced anti-tumor immunity.
The lipid biology of sepsis Amunugama, Kaushalya; Pike, Daniel P.; Ford, David A.
Journal of lipid research,
01/2021, Letnik:
62
Journal Article
Recenzirano
Odprti dostop
Sepsis, defined as the dysregulated immune response to an infection leading to organ dysfunction, is one of the leading causes of mortality around the globe. Despite the significant progress in ...delineating the underlying mechanisms of sepsis pathogenesis, there are currently no effective treatments or specific diagnostic biomarkers in the clinical setting. The perturbation of cell signaling mechanisms, inadequate inflammation resolution, and energy imbalance, all of which are altered during sepsis, are also known to lead to defective lipid metabolism. The use of lipids as biomarkers with high specificity and sensitivity may aid in early diagnosis and guide clinical decision making. In addition, identifying the link between specific lipid signatures and their role in sepsis pathology may lead to novel therapeutics. In this review, we discuss the recent evidence on dysregulated lipid metabolism both in experimental and human sepsis focused on bioactive lipids, fatty acids, and cholesterol as well as the enzymes regulating their levels during sepsis. We highlight not only their potential roles in sepsis pathogenesis but also the possibility of using these respective lipid compounds as diagnostic and prognostic biomarkers of sepsis.
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Previous studies have revealed that membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) is involved in the development of insulin resistance in type 2 ...diabetes. In this study, we aimed to investigate the therapeutic potential of targeting Lpcat3 in the treatment of insulin resistance in diabetic mouse models. Lpcat3 expression was suppressed in the whole body by antisense oligonucleotides (ASO) injection or in the liver by adeno‐associated virus (AAV)‐encoded Cre in high‐fat diet (HFD)‐induced and genetic ob/ob type 2 diabetic mouse models. Glucose tolerance test (GTT), insulin tolerance test (ITT), fasting blood glucose, and insulin levels were used to assess insulin sensitivity. Lipid levels in the liver and serum were measured. The expression of genes involved in de novo lipogenesis was analyzed by real‐time RT‐PCR. Metabolic rates were measured by indirect calorimetry using the Comprehensive Lab Animal Monitoring System (CLAMS). Our data demonstrate that acute knockout of hepatic Lpcat3 by AAV‐Cre improves both hyperglycemia and hypertriglyceridemia in HFD‐fed mice. Similarly, whole‐body ablation of Lpcat3 by ASO administration improves obesity and insulin resistance in both HFD‐fed and ob/ob mice. These findings demonstrate that targeting LPCAT3 could be a novel therapy for insulin resistance.
Deletion of Lpcat3 in the liver or whole‐body suppression of Lpcat3 expression through antisense oligonucleotides (ASO) treatment improves obesity and insulin sensitivity in both high‐fat diet‐induced and genetic ob/ob mouse models.
Transfer of Functional Cargo in Exomeres Zhang, Qin; Higginbotham, James N.; Jeppesen, Dennis K. ...
Cell reports (Cambridge),
04/2019, Letnik:
27, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Exomeres are a recently discovered type of extracellular nanoparticle with no known biological function. Herein, we describe a simple ultracentrifugation-based method for separation of exomeres from ...exosomes. Exomeres are enriched in Argonaute 1–3 and amyloid precursor protein. We identify distinct functions of exomeres mediated by two of their cargo, the β-galactoside α2,6-sialyltransferase 1 (ST6Gal-I) that α2,6- sialylates N-glycans, and the EGFR ligand, amphiregulin (AREG). Functional ST6Gal-I in exomeres can be transferred to cells, resulting in hypersialylation of recipient cell-surface proteins including β1-integrin. AREG-containing exomeres elicit prolonged EGFR and downstream signaling in recipient cells, modulate EGFR trafficking in normal intestinal organoids, and dramatically enhance the growth of colonic tumor organoids. This study provides a simplified method of exomere isolation and demonstrates that exomeres contain and can transfer functional cargo. These findings underscore the heterogeneity of nanoparticles and should accelerate advances in determining the composition and biological functions of exomeres.
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•Exomeres can be isolated using a simplified ultracentrifugation method•Exomeres are enriched for Argonaute proteins and APP•ST6Gal-I in exomeres sialylates recipient cell-surface targets including β1-integrin•AREG in exomeres modulates EGFR trafficking and increases tumor organoid growth
Exomeres are nanoparticles recently identified by asymmetric flow field-flow fractionation. Zhang et al. develop a simplified method for exomere isolation and confirm that exomeres have unique protein and lipid profiles. They show that two exomere cargos, ST6Gal-I and AREG, are biologically active in recipient cells.
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