Apoptosis is commonly thought to represent an immunologically silent or even anti-inflammatory mode of cell death, resulting in cell clearance in the absence of explicit activation of the immune ...system. However, here we show that Fas/CD95-induced apoptosis is associated with the production of an array of cytokines and chemokines, including IL-6, IL-8, CXCL1, MCP-1, and GMCSF. Fas-induced production of MCP-1 and IL-8 promoted chemotaxis of phagocytes toward apoptotic cells, suggesting that these factors serve as “find-me” signals in this context. We also show that RIPK1 and IAPs are required for optimal production of cytokines and chemokines in response to Fas receptor stimulation. Consequently, a synthetic IAP antagonist potently suppressed Fas-dependent expression of multiple proinflammatory mediators and inhibited Fas-induced chemotaxis. Thus, in addition to provoking apoptosis, Fas receptor stimulation can trigger the secretion of chemotactic factors and other immunologically active proteins that can influence immune responsiveness toward dying cells.
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► Fas-induced apoptosis is associated with secretion of cytokines and chemokines ► Fas-driven MCP-1 and IL-8 were chemotactic for monocytes and neutrophils, respectively ► IL-8 and MCP-1 can act as “find-me” signals for apoptotic cells ► Apoptotic cells can actively communicate with cells of the immune system
The NLRP3 inflammasome is involved in caspase-1-dependent maturation of IL-1β in many contexts. A two-signal model has emerged for IL-1β maturation, with LPS providing “signal I” and diverse agents ...such as ATP, Nigericin, streptolysin O, uric acid crystals, and alum salts capable of acting as “signal II.” In the absence of signal II, pro-IL-1β is upregulated but typically fails to be processed or released. What unites signal II stimuli has been debated, with the ability to promote K+ efflux suggested as a common factor, but the mechanism of IL-1β release remains unclear. Here, we show that all examined inflammasome signal II agents triggered necrosis, which was highly correlated with their ability to promote IL-1β release. IL-1β secretion occurred in tandem with the release of many additional proteins and was confined to necrotic cells. Thus, signal II agents initiate inflammation by promoting necrosis-driven IL-1β release, suggesting that IL-1β represents an inducible danger signal.
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•Diverse NLRP3 activators promote necrosis•IL-1β release is confined to necrotic cells•“Signal II” represents a necrotic trigger•IL-1β functions as a danger signal
A two-signal model has emerged for NLRP3 inflammasome-dependent IL-1β maturation, but the mechanism of IL-1β release remains unclear. Here, Cullen et al. show that all inflammasome “signal II” agents examined triggered necrosis, with IL-1β secretion confined to necrotic cells, suggesting that IL-1β represents an inducible danger signal.
•Synaptic plasticity modulation is central to antidepressant relief strategies.•Disruptions of bioenergetic signaling directly impact synaptic plasticity.•Cellular stress, inflammation, and ...metabolism extensively influence bioenergetics.•Bioenergetic biomarkers must be identified for improved treatment design.•Biology-based individualized medicine will improve antidepressant treatment outcome.
Disruptions of bioenergetic signaling and neurogenesis are hallmarks of depression physiology and are often the product of dysregulation of the inflammatory, stress-response, and metabolic systems. These systems are extensively interrelated at the physiological level, yet the bulk of the literature to date addresses pathophysiological mechanisms in isolation. A more integrated understanding of the etiology, progression, and treatment response profiles of depression is possible through wider consideration of relevant preclinical and clinical studies that examine the result of disruptions in these systems. Here, we review recent data demonstrating the critical effects of bioenergetic disruption on neuroplasticity and the development and progression of depressive illness. We further highlight the interactive and dynamic nature of the inflammatory and stress response systems and how disruption of these systems influences bioenergetic signaling pathways critical to treatment outcomes. In so doing, we underscore the pressing need to reconsider the implications of treatment resistance and present a framework for developing novel, personalized treatment approaches for depression.
A warm bias in tropical tropopause temperature is found in the Met Office Unified Model (MetUM), in common with most models from phase 5 of CMIP (CMIP5). Key dynamical, microphysical, and radiative ...processes influencing the tropical tropopause temperature and lower-stratospheric water vapor concentrations in climate models are investigated using the MetUM. A series of sensitivity experiments are run to separate the effects of vertical advection, ice optical and microphysical properties, convection, cirrus clouds, and atmospheric composition on simulated tropopause temperature and lower-stratospheric water vapor concentrations in the tropics. The numerical accuracy of the vertical advection, determined in the MetUM by the choice of interpolation and conservation schemes used, is found to be particularly important. Microphysical and radiative processes are found to influence stratospheric water vapor both through modifying the tropical tropopause temperature and through modifying upper-tropospheric water vapor concentrations, allowing more water vapor to be advected into the stratosphere. The representation of any of the processes discussed can act to significantly reduce biases in tropical tropopause temperature and stratospheric water vapor in a physical way, thereby improving climate simulations.
Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low ...statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.
Tobacco use is the leading cause of preventable disease, disability, and death in the United States. Most tobacco product use begins during adolescence. In recent years, tobacco products have evolved ...to include various smoked, smokeless, and electronic products.
2019.
The National Youth Tobacco Survey (NYTS) is an annual, cross-sectional, school-based, self-administered survey of U.S. middle school (grades 6-8) and high school (grades 9-12) students. A three-stage cluster sampling procedure is used to generate a nationally representative sample of U.S. students attending public and private schools. NYTS is the only nationally representative survey of U.S. middle and high school students that focuses exclusively on tobacco use patterns and associated factors. NYTS is designed to provide national data on tobacco product use and has been conducted periodically during 1999-2009 and annually since 2011. Data from NYTS are used to support the design, implementation, and evaluation of comprehensive tobacco use prevention and control programs and to inform tobacco regulatory activities. Since its inception in 1999 through 2018, NYTS had been conducted via paper and pencil questionnaires. In 2019, NYTS for the first time was administered in schools using electronic data collection methods. CDC's Office on Smoking and Health, in collaboration with the U.S. Food and Drug Administration's (FDA's) Center for Tobacco Products, analyzed data from the 2019 NYTS to assess tobacco product use patterns and associated factors among U.S. middle and high school students. Overall, 19,018 questionnaires were completed and weighted to represent approximately 27.0 million students. On the basis of self-reported grade level, this included 8,837 middle school questionnaires (11.9 million students) and 10,097 high school questionnaires (15.0 million students); 84 questionnaires with missing information on grade level were excluded from school-level analyses.
In 2019, an estimated 53.3% of high school students (8.0 million) and 24.3% of middle school students (2.9 million) reported having ever tried a tobacco product. Current (past 30-day) use of a tobacco product (i.e., electronic cigarettes e-cigarettes, cigarettes, cigars, smokeless tobacco, hookahs, pipe tobacco, and bidis small brown cigarettes wrapped in a leaf) was reported by 31.2% of high school students (4.7 million) and 12.5% of middle school students (1.5 million). E-cigarettes were the most commonly cited tobacco product currently used by 27.5% of high school students (4.1 million) and 10.5% of middle school students (1.2 million), followed in order by cigars, cigarettes, smokeless tobacco, hookahs, and pipe tobacco. Tobacco product use also varied by sex and race/ethnicity. Among current users of each tobacco product, the prevalence of frequent tobacco product use (on ≥20 days of the preceding 30 days) ranged from 16.8% of cigar smokers to 34.1% of smokeless tobacco product users. Among current users of each individual tobacco product, e-cigarettes were the most commonly used flavored tobacco product (68.8% of current e-cigarette users). Among students who reported ever having tried e-cigarettes, the three most commonly selected reasons for use were "I was curious about them" (55.3%), "friend or family member used them" (30.8%), and "they are available in flavors, such as mint, candy, fruit, or chocolate" (22.4%). Among never users of each individual tobacco product, curiosity and susceptibility (a construct that can help to identify future tobacco product experimentation or use) was highest for e-cigarettes (39.1% and 45.0%, respectively) and cigarettes (37.0% and 45.9%, respectively). Overall, 86.3% of students who reported contact with an assessed potential source of tobacco product advertisements or promotions (going to a convenience store, supermarket, or gas station; using the Internet; watching television or streaming services or going to the movies; or reading newspapers or magazines) reported exposure to marketing for any tobacco product; 69.3% reported exposure to e-cigarette marketing and 81.7% reported exposure to marketing for cigarettes or other tobacco products. Among all students, perceiving no harm or little harm from intermittent tobacco product use (use on some days but not every day) was 28.2% for e-cigarettes, 16.4% for hookahs, 11.5% for smokeless tobacco products, and 9.5% for cigarettes. Among current users of any tobacco product, 24.7% reported experiencing cravings to use tobacco products during the past 30 days and 13.7% reported wanting to use a tobacco product within 30 minutes of waking. Moreover, 57.8% of current tobacco product users reported they were seriously thinking about quitting the use of all tobacco products and 57.5% reported they had stopped using all tobacco products for ≥1 day because they were trying to quit.
In 2019, approximately one in four youths (23.0%) had used a tobacco product during the past 30 days. By school level, this represented approximately three in 10 high school students (31.2%) and approximately one in eight middle school students (12.5%). Since 2014, e-cigarettes have been the most commonly used tobacco product among youths. Importantly, more than half of current youth tobacco product users reported seriously thinking about quitting all tobacco products in 2019. However, established factors of use and initiation, including the availability of flavors, exposure to tobacco product marketing, curiosity and susceptibility, and misperceptions about harm from tobacco product use, remained prevalent in 2019 and continue to promote tobacco product use among youths.
The continued monitoring of all forms of youth tobacco product use and associated factors through surveillance efforts including NYTS is important to the development of public health policy and action at national, state, and community levels. Everyone, including public health professionals, health care providers, policymakers, educators, parents, and others who influence youths, can help protect youths from the harms of all tobacco products. In addition, the comprehensive and sustained implementation of evidence-based tobacco control strategies, combined with FDA's regulation of tobacco products, is important for reducing all forms of tobacco product use among U.S. youths.
In previous studies, the Totaled Health Risks in Vascular Events (THRIVE) score has shown broad utility, allowing prediction of clinical outcome, death, and risk of hemorrhage after tissue-type ...plasminogen activator (tPA) treatment, irrespective of the type of acute stroke therapy applied to the patient.
We used data from the Virtual International Stroke Trials Archive to further validate the THRIVE score in a large cohort of patients receiving tPA or no acute treatment, to confirm the relationship between THRIVE and hemorrhage after tPA, and to compare the THRIVE score with several other available outcome prediction scores.
The THRIVE score strongly predicts clinical outcome (odds ratio, 0.55 for good outcome 95% CI, 0.53-0.57; P<0.001), mortality (odds ratio, 1.57 95% confidence interval, 1.50-1.64; P<0.001), and risk of intracerebral hemorrhage after tPA (odds ratio, 1.34 95% confidence interval, 1.22-1.46; P<0.001). The relationship between THRIVE score and outcome is not influenced by the independent relationship of tPA administration and outcome. In receiver operator characteristic curve analysis, the THRIVE score was superior to several other available outcome prediction scores in the prediction of clinical outcome and mortality.
The THRIVE score is a simple-to-use tool to predict clinical outcome, mortality, and risk of hemorrhage after thrombolysis in patients with ischemic stroke. Despite its simplicity, the THRIVE score performs better than several other outcome prediction tools. A free Web calculator for the THRIVE score is available at http://www.thrivescore.org.
The lack of rigorous quality standards in pre-clinical radiation dosimetry has renewed interest in the development of anthropomorphic phantoms. Using 3D printing customisable phantoms can be created ...to assess all parts of pre-clinical radiation research: planning, image guidance and treatment delivery. We present the full methodology, including material development and printing designs, for the production of a high spatial resolution, anatomically realistic heterogeneous small animal phantom. A methodology for creating and validating tissue equivalent materials is presented. The technique is demonstrated through the development of a bone-equivalent material. This material is used together with a soft-tissue mimicking ABS plastic filament to reproduce the corresponding structure geometries captured from a CT scan of a nude mouse. Air gaps are used to represent the lungs. Phantom validation was performed through comparison of the geometry and x-ray attenuation of CT images of the phantom and animal images. A 6.6% difference in the attenuation of the bone-equivalent material compared to the reference standard in softer beams (0.5 mm Cu HVL) rapidly decreases as the beam is hardened. CT imaging shows accurate (sub-millimetre) reproduction of the skeleton (Distance-To-Agreement 0.5 mm ± 0.4 mm) and body surface (0.7 mm ± 0.5 mm). Histograms of the voxel intensity profile of the phantom demonstrate suitable similarity to those of both the original mouse image and that of a different animal. We present an approach for the efficient production of an anthropomorphic phantom suitable for the quality assurance of pre-clinical radiotherapy. Our design and full methodology are provided as open source to encourage the pre-clinical radiobiology community to adopt a common QA standard.
Inflammation triggered by infection or cellular necrosis is initiated by a battery of pattern-recognition receptors, such as Toll-like receptors or IL-1 family receptors. Diverse forms of cell ...stress, such as ER stress or mitochondrial stress, can also promote inflammatory responses that contribute to the chronic inflammation observed in cancer, obesity, and other conditions. However, the molecular mechanisms of cell-stress-induced inflammation are poorly understood. Here, we show that ER stress initiated NF-κB activation and inflammation through transcriptional upregulation and ligand-independent activation of TRAIL receptors. ER-stress-induced TRAIL receptor activation resulted in caspase-8/FADD/RIPK1-dependent NF-κB activation and inflammatory cytokine production. Silencing or deletion of TRAIL receptors, or their downstream effectors caspase-8, FADD, or RIPK1, suppressed ER-stress-induced inflammation. Furthermore, chemotherapeutic stress-induced inflammatory responses were blunted in DR5/TRAIL-R null animals. We propose that, upon ER stress, TRAIL receptors serve as “stress-associated molecular patterns (SAMPs)” coupling ER stress to NF-κB-dependent inflammation.
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•Chemotherapeutic drugs, taxol and taxotere, can promote inflammation•Taxanes promote an ER stress response leading to upregulation of TRAIL receptors•ER-stress-induced DR5/TRAIL-R2 activation promotes inflammatory cytokine production•TRAIL receptors act as sensors of ER perturbation, leading to death or inflammation
Diverse forms of cell stress, such as ER stress or mitochondrial stress, promote inflammatory responses that are poorly understood. Sullivan et al. now show that diverse ER stressors initiate inflammation through upregulation and activation of TRAIL receptors. Thus, TRAIL receptors serve as stress-associated molecular patterns coupling ER stress to inflammation.
The rarity of renal trauma limits its study and the strength of evidence-based guidelines. Although management of renal injuries has shifted toward a nonoperative approach, nephrectomy remains the ...most common intervention for high-grade renal trauma (HGRT). We aimed to describe the contemporary management of HGRT in the United States and also evaluate clinical factors associated with nephrectomy after HGRT.
From 2014 to 2017, data on HGRT (American Association for the Surgery of Trauma grades III-V) were collected from 14 participating Level-1 trauma centers. Data were gathered on demographics, injury characteristics, management, and short-term outcomes. Management was classified into three groups-expectant, conservative/minimally invasive, and open operative. Descriptive statistics were used to report management of renal trauma. Univariate and multivariate logistic mixed effect models with clustering by facility were used to look at associations between proposed risk factors and nephrectomy.
A total of 431 adult HGRT were recorded; 79% were male, and mechanism of injury was blunt in 71%. Injuries were graded as III, IV, and V in 236 (55%), 142 (33%), and 53 (12%), respectively. Laparotomy was performed in 169 (39%) patients. Overall, 300 (70%) patients were managed expectantly and 47 (11%) underwent conservative/minimally invasive management. Eighty-four (19%) underwent renal-related open operative management with 55 (67%) of them undergoing nephrectomy. Nephrectomy rates were 15% and 62% for grades IV and V, respectively. Penetrating injuries had significantly higher American Association for the Surgery of Trauma grades and higher rates of nephrectomy. In multivariable analysis, only renal injury grade and penetrating mechanism of injury were significantly associated with undergoing nephrectomy.
Expectant and conservative management is currently utilized in 80% of HGRT; however, the rate of nephrectomy remains high. Clinical factors, such as surrogates of hemodynamic instability and metabolic acidosis, are associated with nephrectomy for HGRT; however, higher renal injury grade and penetrating trauma remain the strongest associations.
Prognostic/epidemiologic study, level III; Therapeutic study, level IV.
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