The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages.

Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis caused by changes in glucose traffic and metabolism in muscle, liver, and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids.

Dexamethasone impairs the expression of antimicrobial mediators in lipopolysaccharide-activated primary macrophages by inhibiting both expression and function of interferon β.

Glucocorticoids potently inhibit expression of many inflammatory mediators, and have been widely used to treat both acute and chronic inflammatory diseases for more than seventy years. However, they can have several unwanted effects, amongst which immunosuppression is one of the most common. Here we used microarrays and proteomic approaches to characterise the effect of dexamethasone (a synthetic glucocorticoid) on the responses of primary mouse macrophages to a potent pro-inflammatory agonist, lipopolysaccharide (LPS).

Fibroblasts Derived From Vestibular Schwannoma Express Protumorogenic Markers.

Background And Aim: Vestibular schwannomas (VSs), despite being histologically benign, cause significant morbidity because of their challenging intracranial location and the propensity for growth. The role of the stroma and particularly fibroblasts, in the progression of VS, is not completely understood. This study examines the profile of fibroblasts in VS.

Inflammation causes remodeling of mitochondrial cytochrome oxidase mediated by the bifunctional gene .

Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome oxidase (CO), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of CO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript , which orchestrates the substitution of the CO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages.

Evaluation of full-length nanopore 16S sequencing for detection of pathogens in microbial keratitis.

Background: Microbial keratitis is a leading cause of preventable blindness worldwide. Conventional sampling and culture techniques are time-consuming, with over 40% of cases being culture-negative. Nanopore sequencing technology is portable and capable of generating long sequencing reads in real-time.

The Epstein-Barr Virus-Encoded EBNA1 Protein Activates the Bone Morphogenic Protein (BMP) Signalling Pathway to Promote Carcinoma Cell Migration.

The Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) protein is expressed in all virus-associated malignancies, where it performs an essential role in the maintenance, replication and transcription of the EBV genome. In recent years, it has become apparent that EBNA1 can also influence cellular gene transcription. Here, we demonstrate that EBNA1 is able to stimulate the expression of the Transforming growth factor-beta (TGFβ) superfamily member, bone morphogenic protein 2 (BMP2), with consequential activation of the BMP signalling pathway in carcinoma cell lines.

Underutilized and undertheorized: the use of hospitalization for ambulatory care sensitive conditions for assessing the extent to which primary healthcare services are meeting needs in British Columbia First Nation communities.

Background: Since the 1960s, the federal government has been providing or funding a selection of community-based primary healthcare (PHC) programs on First Nations reserves. A key question is whether local access to PHC can help address health inequities in First Nations on-reserve communities in British Columbia (BC).

Objectives: This paper examines whether hospitalization for Ambulatory Care Sensitive Conditions (1) can be used as a proxy measure for the organization of PHC in First Nations reserve areas; and (2) is associated with premature mortality rates.

Hospitalization for mental health related ambulatory care sensitive conditions: what are the trends for First Nations in British Columbia?

Background: Indigenous peoples globally experience a disproportionate burden of mental illness due to forced policies and practices of colonization and cultural disruption. The objective of this study was to provide a baseline profile of hospitalization rates for mental health-related Ambulatory Care Sensitive Conditions among First-Nations living both on and off reserve in British Columbia, Canada, and explore the relationship between local access to health services and mental health-related hospitalization rates.

Methods: A population-based time trend analysis of mental health-related Ambulatory Care Sensitive Conditions hospitalizations was conducted using de-identified administrative health data.

Macrophage responses to lipopolysaccharide are modulated by a feedback loop involving prostaglandin E, dual specificity phosphatase 1 and tristetraprolin.

In many different cell types, pro-inflammatory agonists induce the expression of cyclooxygenase 2 (COX-2), an enzyme that catalyzes rate-limiting steps in the conversion of arachidonic acid to a variety of lipid signaling molecules, including prostaglandin E (PGE). PGE has key roles in many early inflammatory events, such as the changes of vascular function that promote or facilitate leukocyte recruitment to sites of inflammation. Depending on context, it also exerts many important anti-inflammatory effects, for example increasing the expression of the anti-inflammatory cytokine interleukin 10 (IL-10), and decreasing that of the pro-inflammatory cytokine tumor necrosis factor (TNF).

The RNA-binding protein Tristetraprolin (TTP) is a critical negative regulator of the NLRP3 inflammasome.

The NLRP3 inflammasome is a central regulator of inflammation in many common diseases, including atherosclerosis and type 2 diabetes, driving the production of pro-inflammatory mediators such as IL-1β and IL-18. Due to its function as an inflammatory gatekeeper, expression and activation of NLRP3 need to be tightly regulated. In this study, we highlight novel post-transcriptional mechanisms that can modulate NLRP3 expression.

Gain-of-Function Mutation of Tristetraprolin Impairs Negative Feedback Control of Macrophages yet Has Overwhelmingly Anti-Inflammatory Consequences .

The mRNA-destabilizing factor tristetraprolin (TTP) binds in a sequence-specific manner to the 3' untranslated regions of many proinflammatory mRNAs and recruits complexes of nucleases to promote rapid mRNA turnover. Mice lacking TTP develop a severe, spontaneous inflammatory syndrome characterized by the overexpression of tumor necrosis factor and other inflammatory mediators. However, TTP also employs the same mechanism to inhibit the expression of the potent anti-inflammatory cytokine interleukin 10 (IL-10).

Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not dermal fibroblasts.

Background: It has been hypothesized that chronic inflammatory diseases such as rheumatoid arthritis (RA) may be caused by a failure of negative feedback mechanisms. This study sought to examine negative feedback mechanisms in fibroblast-like synoviocytes (FLS), one of the most abundant cell types in the joint. We hypothesized that prior exposure of healthy FLS to an inflammatory stimulus would attenuate their responses to a second inflammatory stimulus, in the same way that negative feedback mechanisms desensitize macrophages to repeated stimulation by lipopolysaccharide.

Tissue-specific roles for sonic hedgehog signaling in establishing thymus and parathyroid organ fate.

The thymus and parathyroids develop from third pharyngeal pouch (3rd pp) endoderm. Our previous studies show that Shh null mice have smaller, aparathyroid primordia in which thymus fate specification extends into the pharynx. SHH signaling is active in both dorsal pouch endoderm and neighboring neural crest (NC) mesenchyme.

Managing Matajoosh: determinants of first Nations' cancer care decisions.

Background: Accessing cancer treatment requires First Nation peoples living in rural and remote communities to either commute to care, or to relocate to an urban centre for the length or part of the treatment. While Canadians living in rural and remote communities must often make difficult decisions following a cancer diagnosis, such decisions are further complicated by the unique policy and socio-historical contexts affecting many First Nation peoples in Canada. These contexts often intersect with negative healthcare experiences which can be related to jurisdictional confusion encountered when seeking care.

Dominant Suppression of Inflammation via Targeted Mutation of the mRNA Destabilizing Protein Tristetraprolin.

In myeloid cells, the mRNA-destabilizing protein tristetraprolin (TTP) is induced and extensively phosphorylated in response to LPS. To investigate the role of two specific phosphorylations, at serines 52 and 178, we created a mouse strain in which those residues were replaced by nonphosphorylatable alanine residues. The mutant form of TTP was constitutively degraded by the proteasome and therefore expressed at low levels, yet it functioned as a potent mRNA destabilizing factor and inhibitor of the expression of many inflammatory mediators.

Functional astrocyte-neuron lactate shuttle in a human stem cell-derived neuronal network.

The NT2.D1 cell line is one of the most well-documented embryocarcinoma cell lines, and can be differentiated into neurons and astrocytes. Great focus has also been placed on defining the electrophysiological properties of the neuronal cells, and more recently we have investigated the functional properties of their associated astrocytes.

Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development.

Mood stabilising drugs such as lithium (LiCl) and valproic acid (VPA) are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neurosphere-based in vitro model to characterise the pharmacological and toxicological effects of LiCl and VPA using gene expression changes linked to phenotypic alterations in cells.

A preliminary investigation into the impact of a pesticide combination on human neuronal and glial cell lines in vitro.

Many pesticides are used increasingly in combinations during crop protection and their stability ensures the presence of such combinations in foodstuffs. The effects of three fungicides, pyrimethanil, cyprodinil and fludioxonil, were investigated together and separately on U251 and SH-SY5Y cells, which can be representative of human CNS glial and neuronal cells respectively. Over 48h, all three agents showed significant reductions in cellular ATP, at concentrations that were more than tenfold lower than those which significantly impaired cellular viability.

Is it worthwhile to invest in home care?

The objective of this study was to estimate the impact of the First Nations and Inuit Home and Community Care Program (FNIHCCP) on the rates of hospitalization for ambulatory care sensitive conditions (ACSCs) in the province of Manitoba. A population-based time trend analysis was conducted using the de-identified administrative data housed at the Manitoba Centre for Health Policy, including data from 1984/85 to 2004/05. Findings show a significant decline in the rates of hospitalization (all conditions) following the introduction of the FNIHCCP in communities served by health offices (p<0.

Epstein-Barr virus-encoded EBNA1 enhances RNA polymerase III-dependent EBER expression through induction of EBER-associated cellular transcription factors.

Background: Epstein-Barr Virus (EBV)-encoded RNAs (EBERs) are non-polyadenylated RNA molecules transcribed from the EBV genome by RNA polymerase III (pol III). EBERs are the most abundant viral latent gene products, although the precise mechanisms by which EBV is able to achieve such high levels of EBER expression are not fully understood. Previously EBV has been demonstrated to induce transcription factors associated with EBER expression, including pol III transcription factors and ATF-2.

Have investments in on-reserve health services and initiatives promoting community control improved First Nations' health in Manitoba?

The objective of this study was to document the relationship between First Nation's community characteristics and the rates of hospitalization for Ambulatory Care Sensitive Conditions (ACSC) in the province of Manitoba, Canada. A population-based time trend analysis of selected ACSC was conducted using the de-identified administrative data housed at the Manitoba Centre for Health Policy, including vital statistics and health information. The study population included all Manitoba residents eligible under the universal Manitoba Health Services Insurance Plan and living on First Nation reserves between 1984/85 and 2004/05.

Epstein-Barr virus-encoded EBNA1 inhibits the canonical NF-kappaB pathway in carcinoma cells by inhibiting IKK phosphorylation.

Background: The Epstein-Barr virus (EBV)-encoded EBNA1 protein is expressed in all EBV-associated tumours, including undifferentiated nasopharyngeal carcinoma (NPC), where it is indispensable for viral replication, genome maintenance and viral gene expression. EBNA1's transcription factor-like functions also extend to influencing the expression of cellular genes involved in pathways commonly dysregulated during oncogenesis, including elevation of AP-1 activity in NPC cell lines resulting in enhancement of angiogenesis in vitro. In this study we sought to extend these observations by examining the role of EBNA1 upon another pathway commonly deregulated during carcinogenesis; namely NF-kappaB.

Epstein-Barr virus-encoded EBNA1 modulates the AP-1 transcription factor pathway in nasopharyngeal carcinoma cells and enhances angiogenesis in vitro.

The Epstein-Barr virus (EBV)-encoded EBNA1 protein is expressed in all virus-associated tumours, including nasopharyngeal carcinoma (NPC), where it plays an essential role in EBV genome maintenance, replication and transcription. Previous studies suggest that EBNA1 may have additional effects relevant to oncogenesis, including enhancement of cell survival, raising the possibility that EBNA1 may influence cellular gene expression. We have recently demonstrated by gene expression microarray profiling in an NPC cell model that EBNA1 influences the expression of a range of cellular genes, including those involved in transcription, translation and cell signalling.

Epstein-Barr virus-encoded LMP1 induces a hyperproliferative and inflammatory gene expression programme in cultured keratinocytes.

SCC12F cells are a line of keratinocytes that retain the capacity for terminal differentiation in vitro. We showed previously that the Epstein-Barr virus (EBV)-encoded oncogene latent membrane protein 1 (LMP1) altered SCC12F morphology in vitro, downregulated cell-cell-adhesion molecule expression and promoted cell motility. In organotypic raft culture, LMP1-expressing cells failed to stratify and formed poorly organized structures which displayed impaired terminal differentiation.

Identifying indigenous peoples for health research in a global context: a review of perspectives and challenges.

Objectives: Identifying Indigenous Peoples globally is complex and contested despite there being an estimated 370 million living in 70 countries. The specific context and use of locally relevant and clear definitions or characterizations of Indigenous Peoples is important for recognizing unique health risks Indigenous Peoples face, for understanding local Indigenous health aspirations and for reflecting on the need for culturally disaggregated data to plan meaningful research and health improvement programs. This paper explores perspectives on defining Indigenous Peoples and reflects on challenges in identifying Indigenous Peoples.