AKT/Protein Kinase B Regulation of BCL Family Members during Oxysterol-induced Apoptosis

Cells of the vasculature, including macrophages, smooth muscle cells, and endothelial cells, exhibit apoptosis in culture upon treatment with oxidized low density lipoprotein, as do vascular cells of atherosclerotic plaque. Several lines of evidence support the hypothesis that the apoptotic component of oxidized low density lipoprotein is one or more oxysterols, which have been shown to induce apoptosis through the mitochondrial pathway. Activation of the mitochondrial pathway of apoptosis is regulated by members of the BCL family of proteins. In this study, we demonstrate that, in the murine macrophage-like cell line P388D1, oxysterols (25-hydroxycholesterol and 7-ketocholesterol) induced the degradation of the prosurvival protein kinase AKT (protein kinase B). This led, in turn, to the activation of the BCL-2 homology-3 domain-only proteins BIM and BAD and down-regulation of the anti-apoptotic multi-BCL homology domain protein BCL-xL. These responses would be expected to activate the pro-apoptotic multi-BCL homology domain proteins BAX and BAK, leading to the previously reported release of cytochrome c observed during oxysterol-induced apoptosis. Somewhat surprisingly, small interfering RNA knockdown of BAX resulted in a complete block of the induction of apoptosis by 25-hydroxycholesterol

NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes

Inflammation in the brain accompanies several high-impact neurological diseases including multiple sclerosis (MS), stroke, and Alzheimer’s disease. Neuroinflammation is sterile, as damage-associated molecular patterns rather than microbial pathogens elicit the response. The inflammasome, which leads to caspase-1 activation, is implicated in neuroinflammation. In this study, we reveal that lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits NLRP3 and NLRC4 inflammasome activation in microglia and astrocytes, which are central players in neuroinflammation. LPC-activated inflammasome also requires ASC (apoptotic speck containing protein with a CARD), caspase-1, cathepsin-mediated degradation, calcium mobilization, and potassium efflux but not caspase-11. To study the physiological relevance, Nlrc4 −/− and Nlrp3 −/− mice are studied in the cuprizone model of neuroinflammation and demyelination. Mice lacking both genes show the most pronounced reduction in astrogliosis and microglial accumulation accompanied by decreased expression of the LPC receptor G2A, whereas MS patient samples show increased G2A. These results reveal that NLRC4 and NLRP3, which normally form distinct inflammasomes, activate an LPC-induced inflammasome and are important in astrogliosis and microgliosis

Determining the Extent of Pioneer Mangrove Acidification on Intertidal Oyster Reefs

The Indian River Lagoon (IRL) stretches 251 kilometers along Florida’s east coast and is one of the most biodiverse estuaries in North America. Mosquito Lagoon, the northernmost portion of the IRL, is home to mangroves and intertidal oyster reefs that provide numerous ecosystem services. These two habitats are overlapping as climate change drives mangroves poleward. Scientists have documented mangrove expansion and the transition of oyster reef habitat to mangrove islands. Past studies have shown large, adult mangrove stands drive soil acidification. The goal of this study was to understand if stand-alone, or pioneer, Rhizophora mangle (red mangroves) and Avicennia germinans (black mangroves) acidify intertidal Crassostrea virginica (eastern oyster) reef sediment. We collected porewater (i.e., water within sediment) and measured pH with a portable pH meter. Porewater pH was sampled from 0 to 1 meter away from pioneer mangroves in 20 cm increments. Closest to the mangrove trunk, reef sediment pH was significantly more acidic (mean pH of 7.18 for R. mangle and 7.02 for A. germinans) compared to oyster reef-only control areas with a mean pH of 7.44 (p-value \u3c 0.001 for both mangrove species). By 1 meter away from the mangrove trunk, the pH for both mangrove species was no longer significantly different from the control areas (p-value = 1.0), indicating mangrove-driven acidification has a localized effect on oyster reef sediments. Acidification weakens oyster shells, and by understanding the extent of mangroves’ acidic effects on oyster reefs, resource managers can use this information to protect declining oyster reef habitat

Why, school, why? Gifted students with academic failure.

Neste estudo de caso, de caráter descritivo-interpretativo, pretende-se identificar fatores de desenvolvimento e (in)sucesso escolar de jovens com características de sobredotação, na escolaridade obrigatória (12 a 16 anos). As narrativas apresentadas pelos investigadores revelam as relações entre características individuais e orientações escolares nem sempre aceites. A análise clarifica o tédio, frustração e fracasso que enfrentam estes alunos no cotidiano, tomada de decisão de alheamento, confronto ou ‘crise de identidade’ para a homogeneização e cumprimento de tarefas rotineiras que a escola oferece. Revelam ainda o relevo dos papéis do professor na diferenciação curricular e, em certos casos, no sucesso escolar dos estudantes.In this case study of a descriptive and interpretive nature it is intended to identify developmental factors and the success/failure at school of gifted youngsters (aged 12 to 16 years old) in compulsory education. The narratives presented by researchers show that the relationships between individual characteristics and school guidance are not always accepted. The analysis clarifies the boredom, frustration and failure facing these students in their everyday life, absent-minded decision-making, opposition or ‘identity crisis’ related to their standardization and compliance with routine tasks that the school requires today. They also reveal the importance of the role of the teacher in terms of curriculum differentiation and, in some cases, the academic success of the students.CIEC - Centro de Investigação em Estudos da Criança, IE, UMinho (UI 317 da FCT), Portugal. Fundos Nacionais através da FCT (Fundação para a Ciência e a Tecnologia) e cofinanciado pelo Fundo Europeu de Desenvolvimento Regional (FEDER) através do COMPETE 2020 – Programa Operacional Competitividade e Internacionalização (POCI) com a referência POCI-01-0145-FEDER-007562info:eu-repo/semantics/publishedVersio

Fatal neurologic disease and abortion in mare infected with lineage 1 West Nile virus, South Africa

In 2010, lineage 1 West Nile virus was detected in South Africa in the brain of a pregnant mare that succumbed to neurologic disease and in her aborted fetus, suggesting an association with abortion in horses. All West Nile virus strains previously detected in horses and humans in South Africa were lineage 2.This study was funded by the National Research Foundation of South Africa.http://www.cdc.gov/ei

Glycogen synthase kinase 3 (GSK-3) inactivation compensates for the lack of CD28 in the priming of CD8+ cytotoxic T-cells: implications for anti-PD-1 immunotherapy

The rescue of exhausted CD8+ cytolytic T-cells (CTLs) by anti-PD-1 blockade has been found to require CD28 expression. At the same time, we have shown that the inactivation of the serine/threonine kinase GSK‐3α/β with small interfering RNAs (siRNAs) and small molecule inhibitors (SMIs) specifically down-regulate PD-1 expression for enhanced CD8+ CTL function and clearance of tumours and viral infections.  Despite this, it has been unclear whether the GSK‐3α/β pathway accounts for CD28 co‐stimulation of CD8+ CTL function.  In this paper, we show that inactivation of GSK‐3α/β through siRNA or by SMIs during priming can substitute CD28 stimulation in the potentiation of cytotoxic CD8+ CTL function. This increased response was observed in the blockade of CD28 co-receptor by CTLA-4-IgG in OT-1 T-cells responding to OVA peptide as presented by the lymphoma cell line EL4. The effect was seen using several GSK-3 SMIs, and was accompanied by an increase in Lamp-1 and GZMB expression. Conversely, CD28 crosslinking obviated the need for GSK‐3α/β inhibition in its enhancement of CTL function.  Our findings support a model where GSK‐3 is the central co-signal for CD28 priming of CD8+ CTLs in anti-PD-1 immunotherapy

Novel study design to assess the utility of the copd assessment test in a primary care setting

The quality of a consultation provided by a physician can have a profound impact on the quality of care and patient engagement in treatment decisions. When the COPD Assessment Test (CAT) was developed, one of its aims was to aid the communication between physician and patient about the impact of COPD. We developed a novel study design to assess this in a primary care consultation. Primary care physicians across five countries in Europe conducted videoed consultations with six standardised COPD patients (played by trained actors) which had patient-specific issues that the physician needed to identify through questioning. Half the physicians saw the patients with the completed CAT, and half without. Independent assessors scored the physicians on their ability to identify and address the patient-specific issues, review standard COPD aspects, their understanding of the case and their overall performance. This novel study design presented many challenges which needed to be addressed to achieve an acceptable level of robustness to assess the utility of the CAT. This paper discusses these challenges and the measures adopted to eliminate or minimise their impact on the study results

Checks and Balances in Autoimmune Vasculitis

Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune checkpoint molecules, is crucial in fine-tuning the immune response and preventing autoimmunity. The activation of specific inhibitory signaling pathways allows cancer cells to evade recognition and destruction by the host immune system. The use of immune checkpoint inhibitors (ICIs) to treat cancer has proven to be effective producing durable antitumor responses in multiple cancer types. However, one of the disadvantages derived from the use of these agents is the appearance of inflammatory manifestations termed immune-related adverse events (irAEs). These irAEs are often relatively mild, but more severe irAEs have been reported as well including several forms of vasculitis. In this article, we argue that age-related changes in expression and function of immune checkpoint molecules lead to an unstable immune system, which is prone to tolerance failure and autoimmune vasculitis development. The topic is introduced by a case report from our hospital describing a melanoma patient treated with ICIs and who subsequently developed biopsy-proven giant cell arteritis. Following this case report, we present an in-depth review on the role of immune checkpoint pathways in the development and progression of autoimmune vasculitis and its relation with an aging immune system