Histone deacetylase inhibitors (HDACi) developed as anti-cancer agents have a high degree of selectivity for killing cancer cells. HDACi induce acetylation of histones and nonhistone proteins, which ...affect gene expression, cell cycle progression, cell migration, and cell death. The mechanism of the tumor selective action of HDACi is unclear. Here, we show that the HDACi, vorinostat (Suberoylanilide hydroxamic acid, SAHA), induces DNA double-strand breaks (DSBs) in normal (HFS) and cancer (LNCaP, A549) cells. Normal cells in contrast to cancer cells repair the DSBs despite continued culture with vorinostat. In transformed cells, phosphorylated H2AX (γH2AX), a marker of DNA DSBs, levels increased with continued culture with vorinostat, whereas in normal cells, this marker decreased with time. Vorinostat induced the accumulation of acetylated histones within 30 min, which could alter chromatin structure-exposing DNA to damage. After a 24-h culture of cells with vorinostat, and reculture without the HDACi, γH2AX was undetectable by 2 h in normal cells, while persisting in transformed cells for the duration of culture. Further, we found that vorinostat suppressed DNA DSB repair proteins, e.g., RAD50, MRE11, in cancer but not normal cells. Thus, the HDACi, vorinostat, induces DNA damage which normal but not cancer cells can repair. This DNA damage is associated with cancer cell death. These findings can explain, in part, the selectivity of vorinostat in causing cancer cell death at concentrations that cause little or no normal cell death.
Cutaneous nerves are increased in atopic dermatitis, and itch is a prominent symptom. We studied the functional interactions between eosinophils and nerves in human and mouse skin and in culture. We ...demonstrated that human atopic dermatitis skin has eosinophil granule proteins present in the same region as increased nerves. Transgenic mice in which interleukin-5 (IL-5) expression is driven by a keratin-14 (K14) promoter had many eosinophils in the epidermis, and the number of nerves was also significantly increased in the epidermis. In co-cultures, eosinophils dramatically increased branching of sensory neurons isolated from the dorsal root ganglia (DRG) of mice. This effect did not occur in DRG neurons co-cultured with mast cells or with dead eosinophils. Physical contact of the eosinophils with the neurons was not required, and the effect was not blocked by an antibody to nerve growth factor. DRG neurons express eotaxin-1, ICAM-1 and VCAM-1, which may be important in the recruitment, binding, and activation of eosinophils in the region of cutaneous nerves. These data indicate a pathophysiological role for eosinophils in cutaneous nerve growth in atopic dermatitis, and suggest they may present a therapeutic target in atopic dermatitis and other eosinophilic skin conditions with neuronal symptoms such as itch.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background In the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the composite primary endpoint of stroke, myocardial infarction, or death during the periprocedural ...period or ipsilateral stroke thereafter did not differ between carotid artery stenting and carotid endarterectomy for symptomatic or asymptomatic carotid stenosis. A secondary aim of this randomised trial was to compare the composite endpoint of restenosis or occlusion. Methods Patients with stenosis of the carotid artery who were asymptomatic or had had a transient ischaemic attack, amaurosis fugax, or a minor stroke were eligible for CREST and were enrolled at 117 clinical centres in the USA and Canada between Dec 21, 2000, and July 18, 2008. In this secondary analysis, the main endpoint was a composite of restenosis or occlusion at 2 years. Restenosis and occlusion were assessed by duplex ultrasonography at 1, 6, 12, 24, and 48 months and were defined as a reduction in diameter of the target artery of at least 70%, diagnosed by a peak systolic velocity of at least 3·0 m/s. Studies were done in CREST-certified laboratories and interpreted at the Ultrasound Core Laboratory (University of Washington). The frequency of restenosis was calculated by Kaplan-Meier survival estimates and was compared during a 2-year follow-up period. We used proportional hazards models to assess the association between baseline characteristics and risk of restenosis. Analyses were per protocol. CREST is registered with ClinicalTrials.gov , number NCT00004732. Findings 2191 patients received their assigned treatment within 30 days of randomisation and had eligible ultrasonography (1086 who had carotid artery stenting, 1105 who had carotid endarterectomy). In 2 years, 58 patients who underwent carotid artery stenting (Kaplan-Meier rate 6·0%) and 62 who had carotid endarterectomy (6·3%) had restenosis or occlusion (hazard ratio HR 0·90, 95% CI 0·63–1·29; p=0·58). Female sex (1·79, 1·25–2·56), diabetes (2·31, 1·61–3·31), and dyslipidaemia (2·07, 1·01–4·26) were independent predictors of restenosis or occlusion after the two procedures. Smoking predicted an increased rate of restenosis after carotid endarterectomy (2·26, 1·34–3·77) but not after carotid artery stenting (0·77, 0·41–1·42). Interpretation Restenosis and occlusion were infrequent and rates were similar up to 2 years after carotid endarterectomy and carotid artery stenting. Subsets of patients could benefit from early and frequent monitoring after revascularisation. Funding National Institute of Neurological Disorders and Stroke and Abbott Vascular Solutions.
Greater Sage-Grouse Vital Rates After Wildfire FOSTER, LEE J.; DUGGER, KATIE M.; HAGEN, CHRISTIAN A. ...
The Journal of wildlife management,
01/2019, Letnik:
83, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Greater sage-grouse (Centrocercus urophasianus) have been subject to long-term and continuing declines in population and habitat since European settlement of western North America. Increased wildfire ...activity constitutes a primary threat to the species in western portions of their range, with documented declines in wildfire-affected populations. Following a 187,000-ha wildfire in southeastern Oregon and northern Nevada, USA, we used global positioning system (GPS) telemetry to monitor nest initiation, nest survival, nesting habitat, and adult survival of female sage-grouse during 2013 and 2014. We used known-fate models in Program MARK to estimate daily nest survival and monthly adult survival in relation to temporal patterns, physiological characteristics of females, and habitat and land-cover characteristics. We assessed habitat characteristics using geographic information system (GIS)-derived measures of post-fire habitat condition and land cover. Nest initiation rate following the fire was comparable to that observed in unaltered habitat. We observed nesting rates of 90% and 100% during 2013 and 2014, respectively, and renesting rates of 23% and 57% during the same years. Daily nest survival was consistently low in comparison to rates observed in concurrent studies in the region, for first nests during both years, and for second nests during 2013, but survival markedly increased for second nests during 2014. Sage-grouse generally did not leave the fire perimeter to nest, with 64% and 73% of nests located in the fire boundary during 2013 and 2014, respectively. Approximately 27% of nests were located in burned habitat during 2013, and 20% of nests in 2014 were located in burned habitat. Adult survival varied by month, and although patterns of monthly survival were similar between years, monthly survival rates were significantly reduced from the beginning of the study through the end of the first post-fire growing season. Our results indicate that sage-grouse continue to use fire-affected habitat in the years immediately following wildfire and sage-grouse experienced lower nest survival and adult female survival than other populations during the same period.
Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These ...disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease.
Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis marked by ocular autoantigen-specific regulatory immunity in the spleen. The melanocortin 5 receptor (MC5r) ...and adenosine 2 A receptor (A2Ar) are required for induction of post-EAU regulatory T cells (Tregs) which provide resistance to EAU. We show that blocking the PD-1/PD-L1 pathway prevented suppression of EAU by post-EAU Tregs. A2Ar induction of PD-1
FoxP3
Tregs in uveitis patients was similar compared to healthy controls, but was significantly reduced with melanocortin stimulation. Further, lower body mass index correlated with responsiveness to stimulation of this pathway. These observations indicate an importance of the PD-1/PD-L1 pathway to provide resistance to relapsing uveitis and shows a reduced capacity of uveitis patients to induce Tregs when stimulated through melanocortin receptors, but that it is possible to bypass this part of the pathway through direct stimulation of A2Ar.
Species responses to disturbance influence their extinction risks. Greater sage‐grouse (Centrocercus urophasianus) are bioindicators of sagebrush ecosystem health and the loss of sagebrush (Artemisia ...spp.) due to wildfire, can cause long‐term declines in sage‐grouse populations and other sagebrush obligate species. We examined the demographic response of a greater sage‐grouse population following a mega‐wildfire using stochastic age‐structured female‐based matrix models over 6 years (2013–2018). Notably, chick survival (range = 0.18–0.38) and female survival (yearling range: 0.20–0.68; adult range: 0.27–0.75) were low compared to values reported for greater sage‐grouse in other parts of their distribution. Greater sage‐grouse displayed variation in demographic tactics after the fire; however, adult female survival explained most of the variation in λ during each year, which reflected a declining population in 3 of 6 years with more uncertainty observed in 2015 when populations may have been increasing, and 2017 and 2018, when populations may have been declining. The continued annual population decline observed since 2016 suggested there were additional strong environmental impacts that may have been compounded by the fire effects, prolonging recovery of greater sage‐grouse. Our results support others that reported negative effects to greater sage‐grouse demographics from broad‐scale fire and provide a baseline for understanding how this species responds to loss of sagebrush cover based on their life history strategy.
Chick survival and female survival were low for Greater sage‐grouse a megafire, compared to values reported throughout their range. Greater sage‐grouse exhibited variation in demographic tactics; however, adult female survival explained most of the variation in the finite rate of population change, which reflected a declining population in 3 of 6 years following the fire.
The persistence of wildlife species in fire‐prone ecosystems is under increasing pressure from global change, including alterations in fire regimes caused by climate change. However, unburned islands ...might act to mitigate negative effects of fire on wildlife populations by providing habitat in which species can survive and recolonize burned areas. Nevertheless, the characteristics of unburned islands and their role as potential refugia for the postfire population dynamics of wildlife species remain poorly understood.
We used a newly developed unburned island database of the northwestern United States from 1984 to 2014 to assess the postfire response of the greater sage‐grouse (Centrocercus urophasianus), a large gallinaceous bird inhabiting the sagebrush ecosystems of North America, in which wildfires are common. Specifically, we tested whether prefire and postfire male attendance trends at mating locations (leks) differed between burned and unburned areas, and to what extent postfire habitat composition at multiple scales could explain such trends.
Using time‐series of male counts at leks together with spatially explicit fire history information, we modeled whether male attendance was negatively affected by fire events. Results revealed that burned leks often exhibit sustained decline in male attendance, whereas leks within unburned islands or >1.5 km away from fire perimeters tend to show stable or increasing trends.
Analyses of postfire habitat composition further revealed that sagebrush vegetation height within 0.8 km around leks, as well elevation within 0.8 km, 6.4 km, and 18 km around leks, had a positive effect on male attendance trends. Moreover, the proportion of the landscape with cheatgrass (Bromus tectorum) cover >8% had negative effects on male attendance trends within 0.8 km, 6.4 km, and 18 km of leks, respectively.
Synthesis and applications. Our results indicate that maintaining areas of unburned vegetation within and outside fire perimeters may be crucial for sustaining sage‐grouse populations following wildfire. The role of unburned islands as fire refugia requires more attention in wildlife management and conservation planning because their creation, protection, and maintenance may positively affect wildlife population dynamics in fire‐prone ecosystems.
Unburned islands of vegetation within fire perimeters might mitigate the negative effects of wildfire on wildlife populations in fire‐prone ecosystems, but they remain poorly understood. In this article, we researched and found out that unburned islands allow for the persistence of greater sage‐grouse after fire, thus acting as potential fire refugia. This is important for management because it suggests that creating, protecting, and enhancing unburned islands within fire perimeters may positively impact wildlife populations in these ecosystems.
1. Expanding human enterprise across remote environments impacts numerous wildlife species. Anthropogenic resources provide subsidies for generalist predators that can lead to cascading effects on ...prey species at lower trophic levels. A fundamental challenge for applied ecologists is to disentangle natural and anthropogenic influences on species occurrence, and subsequently develop spatially explicit models to help inform management and conservation decisions. 2. Using Bayesian hierarchical occupancy models, we mapped the broad-scale occurrence of common ravens Corvus corax as a function of natural and anthropogenic landscape covariates using >15,000 point count surveys performed during 2007-2016 within the Great Basin region, USA. Raven abundance and distribution is substantially increasing across the American west due to unintended anthropogenic resource subsidies. Importantly, ravens prey on eggs and chicks of numerous species including greater sage-grouse Centrocercus urophasianus, an indicator species whos decline is at the centre of national conservation strategies and land-use policies. 3. Anthropogenic factors that contributed to greater raven occurrence were: increased road density, presence of transmission lines, agricultural activity, and presence of roadside rest areas. Natural landscape characteristics included lower elevations with greener vegetation (Normalized Difference Vegetation Index), greater stream and habitat edge densities, and lower percentages of big sagebrush Artemisia tridentata spp. 4. Interactions between anthropogenic sources of nesting substrate and food subsidies suggested that raven occurrence increased multiplicatively when these resource subsidies co-occurred. Overall, the average probability of raven occurrence estimated within sagebrush ecosystems of the study area was c. 0.83. 5. Synthesis and applications. W e demonstrate how anthropogenic factors can be disentangled from natural effects when making spatially explicit predictions of subsidized predators occurring across expansive landscapes. This approach can guide management decisions where subsidized predators overlap sensitive prey habitats. For example, we identify areas where elevated raven occurrence coincides with breeding sage-grouse concentration areas and appears to be largely driven by anthropogenic factors. Management applications could focus on reducing raven access to anthropogenic subsidies in these areas, while prioritizing habitat improvements for sage-grouse elsewhere. Our approach is applicable to other species where widespread survey data are available.
Systemic lupus erythematosus (SLE) can involve many parts of the eye, including the eyelid, ocular adnexa, sclera, cornea, uvea, retina and optic nerve. Ocular manifestations of SLE are common and ...may lead to permanent blindness from the underlying disease or therapeutic side effects. Keratoconjunctivitis sicca is the most common manifestation. However, vision loss may result from involvement of the retina, choroid and optic nerve. Ocular symptoms are correlated to systemic disease activity and can present as an initial manifestation of SLE. The established treatment includes prompt systemic corticosteroids, steroid-sparing immunosuppressive drugs and biological agents. Local ocular therapies are options with promising efficacy. The early recognition of disease and treatment provides reduction of visual morbidity and mortality.
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