Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been ...termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.
Resident Duty Hours Johns, Michael M. E; Wolman, Dianne Miller; Ulmer, Cheryl
National Academies Press,
04/2009
eBook, Book
Open access
Medical residents in hospitals are often required to be on duty for long hours. In 2003 the organization overseeing graduate medical education adopted common program requirements to restrict resident ...workweeks, including limits to an average of 80 hours over 4 weeks and the longest consecutive period of work to 30 hours in order to protect patients and residents from unsafe conditions resulting from excessive fatigue.
Resident Duty Hours provides a timely examination of how those requirements were implemented and their impact on safety, education, and the training institutions. An in-depth review of the evidence on sleep and human performance indicated a need to increase opportunities for sleep during residency training to prevent acute and chronic sleep deprivation and minimize the risk of fatigue-related errors. In addition to recommending opportunities for on-duty sleep during long duty periods and breaks for sleep of appropriate lengths between work periods, the committee also recommends enhancements of supervision, appropriate workload, and changes in the work environment to improve conditions for safety and learning.
All residents, medical educators, those involved with academic training institutions, specialty societies, professional groups, and consumer/patient safety organizations will find this book useful to advocate for an improved culture of safety.
Long-term use of morphine induces analgesic tolerance, which limits its clinical efficacy. Evidence indicated morphine-evoked neuroinflammation mediated by toll-like receptor 4 (TLR4) - NOD-like ...receptor protein 3 (NLRP3) inflammasome was important for morphine tolerance. In our study, we investigated whether other existing alternative pathways caused morphine-induced activation of TLR4 in microglia. We focused on heat shock protein 70 (HSP70), a damage-associated molecular pattern (DAMP), which was released from various cells upon stimulations under the control of K
channel and bound with TLR4-inducing inflammation. Glibenclamide, a classic K
channel blocker, can improve neuroinflammation by inhibiting the activation of NLRP3 inflammasome. Our present study investigated the effect and possible mechanism of glibenclamide in improving morphine tolerance via its specific inhibition on the release of HSP70 and activation of NLRP3 inflammasome induced by morphine.
CD-1 mice were used for tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 and neural cell line SH-SY5Y were used to investigate the pharmacological effects and the mechanism of glibenclamide on morphine-induced neuroinflammation. The activation of microglia was accessed by immunofluorescence staining. Neuroinflammation-related cytokines were measured by western blot and real-time PCR. The level of HSP70 and related signaling pathway were evaluated by western blot and immunofluorescence staining.
Morphine induced the release of HSP70 from neurons. The released HSP70 activated microglia and triggered TLR4-mediated inflammatory response, leading to the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) p65 and the activation of NLRP3 inflammasome. Moreover, anti-HSP70 neutralizing antibody partly attenuated chronic morphine tolerance. The secretion of HSP70 was under the control of MOR/AKT/K
/ERK signal pathway. Glibenclamide as a classic K
channel blocker markedly inhibited the release of HSP70 induced by morphine and suppressed HSP70-TLR4-NLRP3 inflammasome-mediated neuroinflammation, which consequently attenuated morphine tolerance.
Our study indicated that morphine-induced extracellular HSP70 was an alternative way for the activation of TLR4-NLRP3 in analgesic tolerance. The release of HSP70 was regulated by MOR/AKT/K
/ERK pathway. Our study suggested a promising target, K
channel and a new leading compound, glibenclamide, for treating morphine tolerance.
Multiple rodent models have been used to study diabetic kidney disease (DKD). The purpose of the present study was to compare models of diabetes and obesity-induced metabolic syndrome and determine ...differences in renal outcomes. C57BL/6 male mice were fed either normal chow or high fat diet (HFD). At postnatal week 8, chow-fed mice were randomly assigned to low-dose streptozotocin (STZ, 55 mg/kg/day, five consecutive days) or vehicle control, whereas HFD-fed mice were given either one high-dose of STZ (100 mg/kg) or vehicle control. Intraperitoneal glucose tolerance tests were performed at Week 14, 20 and 30. Urinary albumin to creatinine ratio (ACR) and serum creatinine were measured, and renal structure was assessed using Periodic Acid Schiff (PAS) staining at Week 32. Results showed that chow-fed mice exposed to five doses of STZ resembled type 1 diabetes mellitus with a lean phenotype, hyperglycaemia, microalbuminuria and increased serum creatinine levels. Their kidneys demonstrated moderate tubular injury with evidence of tubular dilatation and glycogenated nuclear inclusion bodies. HFD-fed mice resembled metabolic syndrome as they were obese with dyslipidaemia, insulin resistance, and significantly impaired glucose tolerance. One dose STZ, in addition to HFD, did not worsen metabolic features (including fasting glucose, non esterified fatty acid, and triglyceride levels). There were significant increases in urinary ACR and serum creatinine levels, and renal structural changes were predominantly related to interstitial vacuolation and tubular dilatation in HFD-fed mice.
La tolérance est une vertu cardinale dans les sociétés occidentales, et son histoire est souvent écrite comme un progrès linéaire jusqu’à son éclosion complète à l’époque moderne. Dans une telle ...perspective, des périodes antérieures comme l’Antiquité tardive apparaissent fortement comme des temps d’intolérance et de violence religieuse. Mais fait-on droit à des sociétés du passé en les étudiant à partir d’une conception moderne de la tolérance ? Ce livre montre comment, à partir de la pensée classique, l’Antiquité tardive développa des conceptions originales de la tolérance et de ses limites, qui étaient enracinées dans les idées antiques sur l’homme, la raison et la société. Il cherche ainsi à interroger notre propre conception de la tolérance qui, au lieu d’être l’aboutissement parfait d’une longue histoire, est aussi une conception spécifique et historique - avec ses propres limites.
Plants are exposed to a variety of abiotic stresses in nature and exhibit unique and complex responses to these stresses depending on their degree of plasticity involving many morphological, ...cellular, anatomical, and physiological changes. Phytohormones are known to play vital roles in the ability of plants to acclimatize to varying environments, by mediating growth, development, source/sink transitions and nutrient allocation. These signal molecules are produced within the plant, and also referred as plant growth regulators. Although plant response to salinity depends on several factors; nevertheless, phytohormones are thought to be the most important endogenous substances that are critical in modulating physiological responses that eventually lead to adaptation to salinity. Response usually involves fluctuations in the levels of several phytohormones, which relates with changes in expression of genes involved in their biosynthesis and the responses they regulate. Present review described the potential role of different phytohormones and their balances against salinity stress and summarized the research progress regarding plant responses towards salinity at physiological and molecular levels. We emphasized the role of abscisic acid, indole acetic acid, cytokinins, gibberellic acid, salicylic acid, brassinosteroids, jasmonates, ethylene and triazoles in mediating plant responses and discussed their crosstalk at various baseline pathways transduced by these phytohormones under salinity. Current progress is exemplified by the identification and validation of several significant genes that enhanced crops tolerance to salinity, while missing links on different aspects of phytohormone related salinity tolerance are pointed out. Deciphering mechanisms by which plant perceives salinity and trigger the signal transduction cascades via phytohormones is vital to devise salinity related breeding and transgenic approaches.
The salinization of irrigated lands is increasingly detrimental to plant biomass production and agricultural productivity, as most plant species are sensitive to high concentrations of sodium (Na
+), ...which causes combined Na
+ toxicity and osmotic stress. Plants have multiple Na
+-transport systems to circumvent Na
+ toxicity. Essential physiological functions of major Na
+ transporters and their mechanisms mediating salinity resistance have been identified in
Arabidopsis , including the AtSOS1, AtNHX and AtHKT1;1 transporters. As we discuss here, recent studies have demonstrated that a class of xylem–parenchyma-expressed Na
+-permeable plant HKT transporters represent a primary mechanism mediating salt tolerance and Na
+ exclusion from leaves in
Arabidopsis, and that major salt-tolerance quantitative trait loci in monocot crop plants are also based on this HKT-mediated mechanism.
Mitogen-activated protein kinase cascades are important signaling modules that convert environmental stimuli into cellular responses. We show that MPK3, MPK4, and MPK6 are rapidly activated after ...cold treatment. The mpk3 and mpk6 mutants display increased expression of CBF genes and enhanced freezing tolerance, whereas constitutive activation of the MKK4/5-MPK3/6 cascade in plants causes reduced expression of CBF genes and hypersensitivity to freezing, suggesting that the MKK4/5-MPK3/6 cascade negatively regulates the cold response. MPK3 and MPK6 can phosphorylate ICE1, a basic-helix-loop-helix transcription factor that regulates the expression of CBF genes, and the phosphorylation promotes the degradation of ICE1. Interestingly, the MEKK1-MKK2-MPK4 pathway constitutively suppresses MPK3 and MPK6 activities and has a positive role in the cold response. Furthermore, the MAPKKK YDA and two calcium/calmodulin-regulated receptor-like kinases, CRLK1 and CRLK2, negatively modulate the cold activation of MPK3/6. Our results uncover important roles of MAPK cascades in the regulation of plant cold response.
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•The MKK4/5-MPK3/6 cascade negatively regulates freezing tolerance•The MEKK1-MKK2-MPK4 cascade positively regulates freezing tolerance•MPK3/6-mediated phosphorylation of ICE1 promotes ICE1 degradation•CRLK1 and CRLK2 suppress the cold activation of MPK3/6
ICE1 is a central regulator of the plant cold response, and its levels are tightly controlled. Zhao et al. show that cold-activated MPK3 and MPK6 phosphorylate ICE1 and promote its degradation, thus negatively regulating the cold response, whereas MPK4 positively regulates the cold response by constitutively suppressing MPK3 and MPK6 activity.
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