Histamine is a developmentally highly conserved autacoid found in most vertebrate tissues. Its physiological functions are mediated by four 7-transmembrane G protein-coupled receptors (H1R, H2R, H3R, ...H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R was identified in the 1970s and led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The crystal structure of ligand-bound H1R has rendered it possible to design new ligands with novel properties. The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. A block of these actions promotes waking. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated.
Alzheimer's disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the ...gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with β-amyloid (Aβ) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process. We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.
Forest loss in hotspots around the world impacts not only local climate where loss occurs, but also influences climate and vegetation in remote parts of the globe through ecoclimate teleconnections. ...The magnitude and mechanism of remote impacts likely depends on the location and distribution of forest loss hotspots, but the nature of these dependencies has not been investigated. We use global climate model simulations to estimate the distribution of ecologically-relevant climate changes resulting from forest loss in two hotspot regions: western North America (wNA), which is experiencing accelerated dieoff, and the Amazon basin, which is subject to high rates of deforestation. The remote climatic and ecological net effects of simultaneous forest loss in both regions differed from the combined effects of loss from the two regions simulated separately, as evident in three impacted areas. Eastern South American Gross Primary Productivity (GPP) increased due to changes in seasonal rainfall associated with Amazon forest loss and changes in temperature related to wNA forest loss. Eurasia's GPP declined with wNA forest loss due to cooling temperatures increasing soil ice volume. Southeastern North American productivity increased with simultaneous forest loss, but declined with only wNA forest loss due to changes in VPD. Our results illustrate the need for a new generation of local-to-global scale analyses to identify potential ecoclimate teleconnections, their underlying mechanisms, and most importantly, their synergistic interactions, to predict the responses to increasing forest loss under future land use change and climate change.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hundreds of gas- and particle-phase organic acids were measured in a rural ponderosa pine forest in Colorado, USA, during BEACHON-RoMBAS (Bio-hydro-atmosphere interactions of Energy, Aerosols, ...Carbon, H2O, Organics & Nitrogen - Rocky Mountain Biogenic Aerosol Study). A recently developed micro-orifice volatilization impactor high-resolution time-of-flight chemical ionization mass spectrometer (MOVI-HRToF-CIMS) using acetate (CH3C(O)O-) as the reagent ion was used to selectively ionize and detect acids semicontinuously from 20 to 30 August 2011, with a measurement time resolution of ~1.5 h. At this site 98% of the organic acid mass is estimated to be in the gas phase, with only ~2% in the particle phase. We investigated gas-particle partitioning, quantified as the fraction in the particle phase (Fp), of C1-C18 alkanoic acids, six known terpenoic acids, and bulk organic acids vs. carbon number. Data were compared to the absorptive partitioning model and suggest that bulk organic acids at this site follow absorptive partitioning to the organic aerosol mass. The rapid response (<1-2 h) of partitioning to temperature changes for bulk acids suggests that kinetic limitations to equilibrium are minor, which is in contrast to conclusions of some recent laboratory and field studies, possibly due to lack of very low ambient relative humidities at this site. Time trends for partitioning of individual and groups of acids were mostly captured by the model, with varying degrees of absolute agreement. Species with predicted substantial fractions in both the gas and particle phases show better absolute agreement, while species with very low predicted fractions in one phase often show poor agreement, potentially due to thermal decomposition, inlet adsorption, or other issues. Partitioning to the aqueous phase is predicted to be smaller than to the organic phase for alkanoic and bulk acids, and has different trends with time and carbon number than observed experimentally. This is due to the limited additional functionalization observed for the bulk acids. Partitioning to water appears to only play a role for the most oxidized acids during periods of high aerosol liquid water. Based on measurement-model comparison we conclude that species carbon number and oxygen content, together with ambient temperature, control the volatility of organic acids and are good predictors for partitioning at this site. Partitioning of bulk acids is more consistent with model predictions for hydroxy acids, hydroperoxyacids, or polyacids, and less so for keto acids.
Fractures of the paranasal sinuses often require surgical intervention. Persisting bone defects lead to permanent visible deformities of the facial contours. Bone substitutes for reconstruction of ...defects with simultaneous induction of new bone formation are not commercially available for the paranasal sinus. New materials are urgently needed and have to be tested in their future area of application. For this purpose critical size defect models for the paranasal sinus have to be developed. A ≥2.4 cm large bilateral circular defect was created in the anterior wall of the maxillary sinus in six sheep via an extraoral approach. The defect was filled with two types of an osteoconductive titanium scaffold (empty scaffold vs. scaffold filled with a calcium phosphate bone cement paste) or covered with a titanium mesh either. Sheep were euthanized after four months. All animals performed well, no postoperative complications occured. Meshes and scaffolds were safely covered with soft tissue at the end of the study. The initial defect size of ≥2.4 cm only shrunk minimally during the investigation period confirming a critical size defect. No ingrowth of bone into any of the scaffolds was observed. The anterior wall of the maxillary sinus is a region with low complication rate for performing critical size defect experiments in sheep. We recommend this region for experiments with future scaffold materials whose intended use is not only limited to the paranasal sinus, as the defect is challenging even for bone graft substitutes with proven osteoconductivity.
Graphical abstract
Abstract Background Findings on the association between fish consumption and acute coronary syndrome are inconsistent. We assessed the role of fish consumption in acute coronary syndrome by ...conducting a dose-response meta-analysis. Methods We conducted a literature search of MEDLINE and Embase databases from 1966 to June 2013 for prospective cohort and case-control studies that evaluated the association between fish consumption and acute coronary syndrome among general populations without cardiovascular disease history. Additional studies were identified via hand search of references of relevant articles. Estimates of relative risk (RR) were pooled using random-effects model. Sex and age effects were also evaluated. Results Our search retrieved 11 prospective cohort and 8 case-control studies, totaling 408,305 participants. Among prospective cohort studies, the highest category of fish consumption (ie, ≥4 times per week) was associated with the greatest risk reduction in acute coronary syndrome (RR 0.79; 95% confidence interval CI, 0.70-0.89). In dose-response analysis, each additional 100-g serving of fish per week was associated with a 5% reduced risk (RR per serving 0.95; 95% CI, 0.92-0.97). Subgroup analysis and meta-regression suggested that the risk reduction did not differ across sex or age groups. No heterogeneity was observed among prospective cohort ( P = .73) and case-control ( P = .29) studies. There was no evidence of publication bias. Conclusion Our meta-analysis demonstrated that there is an inverse association between fish consumption and the risk of acute coronary syndrome. Fish consumption appears beneficial in the primary prevention of acute coronary syndrome, and higher consumption is associated with greater protection.
CONTEXT: Vegetation is projected to continue to undergo major structural changes in coming decades due to land conversion and climate change, including widespread forest die-offs. These vegetation ...changes are important not only for their local or regional climatic effects, but also because they can affect climate and subsequently vegetation in other regions or continents through “ecoclimate teleconnections”. OBJECTIVES: We propose that ecoclimate teleconnections are a fundamental link among regions within and across continents, and are central to advancing large-scale macrosystems ecology. METHODS AND RESULTS: We illustrate potential ecoclimate teleconnections in a bounding simulation that assumes complete tree cover loss in western North America due to tree die-off, and which predicts subsequent drying and reduced net primary productivity in other areas of North America, the Amazon and elsewhere. Central to accurately modeling such ecoclimate teleconnections is characterizing how vegetation change alters albedo and other components of the land-surface energy balance and then scales up to impact the climate system. We introduce a framework for rapid field-based characterization of vegetation structure and energy balance to help address this challenge. CONCLUSIONS: Ecoclimate teleconnections are likely a fundamental aspect of macrosystems ecology needed to account for alterations to large-scale atmospheric-ecological couplings in response to vegetation change, including deforestation, afforestation and die-off.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
ABSTRACT The well-studied M9 dwarf TVLM 513-46546 is a rapid rotator ( hr) hosting a stable, dipolar magnetic field of ∼3 kG surface strength. Here we report its detection with ALMA at 95 GHz at a ...mean flux density of 56 12 Jy, making it the first ultracool dwarf detected in the millimeter band, excluding young, disk-bearing objects. We also report flux density measurements from unpublished archival VLA data and new optical monitoring data from the Liverpool Telescope. The ALMA data are consistent with a power-law radio spectrum that extends continuously between centimeter and millimeter wavelengths. We argue that the emission is due to the synchrotron process, excluding thermal, free-free, and electron cyclotron maser emission as possible sources. During the interval of the ALMA observation that phases with the maximum of the object's optical variability, the flux density is higher at a ∼1.8 significance level. These early results show how ALMA opens a new window for studying the magnetic activity of ultracool dwarfs, particularly shedding light on the particle acceleration mechanism operating in their immediate surroundings.
Aberrant regulation of growth signaling is a hallmark of cancer development that often occurs through the constitutive activation of growth factor receptors or their downstream effectors. Using ...validation-based insertional mutagenesis (VBIM), we identified family with sequence similarity 83, member B (FAM83B), based on its ability to substitute for RAS in the transformation of immortalized human mammary epithelial cells (HMECs). We found that FAM83B coprecipitated with a downstream effector of RAS, CRAF. Binding of FAM83B with CRAF disrupted CRAF/14-3-3 interactions and increased CRAF membrane localization, resulting in elevated MAPK and mammalian target of rapamycin (mTOR) signaling. Ablation of FAM83B inhibited the proliferation and malignant phenotype of tumor-derived cells or RAS-transformed HMECs, implicating FAM83B as a key intermediary in EGFR/RAS/MAPK signaling. Analysis of human tumor specimens revealed that FAM83B expression was significantly elevated in cancer and was associated with specific cancer subtypes, increased tumor grade, and decreased overall survival. Cumulatively, these results suggest that FAM83B is an oncogene and potentially represents a new target for therapeutic intervention.
Summary
Despite its effectiveness, bisphosphonate use for osteoporosis is low. We assessed bisphosphonate information on the internet and found the most commonly listed benefits/risks were bone ...density loss, gastrointestinal issues, and jaw necrosis, that risk quantification was rare, and information quality varied. Findings underscore the importance of clinical communication about bisphosphonates.
Introduction
The US Preventative Services Task Force recommends osteoporosis screening and treatment with bisphosphonates in high-risk populations. However, bisphosphonate use among individuals with osteoporosis remains low. The content and quality of information from outside sources may influence individuals’ bisphosphonate decisions. Therefore, we sought to assess the content and quality of osteoporosis treatment information available to the public by conducting an internet search and coding available bisphosphonate information.
Methods
Eleven search terms about osteoporosis and bisphosphonates were entered into four search engines. Two raters assessed websites for information about bisphosphonates, whether and how benefits and side effects were described and quantified, contraindications, and dosing instructions. Coders also assessed website interface and slant/balance of information.
Results
One thousand four hundred seventy-three websites were identified. Two hundred twenty-seven websites met inclusion criteria and were coded. The most common bisphosphonate benefit described was prevention of bone density loss (77.1% of websites). The most common side effects described were gastrointestinal problems (66.1%) and jaw osteonecrosis (58.6%). Most websites did not quantify bisphosphonate benefits (78.0%) or side effects (82.4%). Complementary/integrative health websites (
p
< .001) and pharmaceutical litigation websites (
p
< .001) were more often slanted against taking bisphosphonates, compared to all websites coded. General medical knowledge websites were more balanced than other websites (
p
= .023).
Conclusions
The quality of bisphosphonate information on the internet varies substantially. Providers counseling patients about osteoporosis treatment should inquire about patients’ baseline bisphosphonate knowledge. Providers can complement accurate information and address potential bisphosphonate misconceptions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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