Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study ...thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.
BackgroundNoroviruses (NoVs) are the most common cause of viral gastroenteritis. Their high incidence and importance in health care facilities result in a great impact on public health. Studies from ...around the world describing increasing prevalence have been difficult to compare because of differing nomenclatures for variants of the dominant genotype, GII.4. We studied the global patterns of GII.4 epidemiology in relation to its genetic diversity MethodsData from NoV outbreaks with dates of onset from January 2001 through March 2007 were collected from 15 institutions on 5 continents. Partial genome sequences (n=775) were collected, allowing phylogenetic comparison of data from different countries ResultsThe 15 institutions reported 3098 GII.4 outbreaks, 62% of all reported NoV outbreaks. Eight GII.4 variants were identified. Four had a global distribution—the 1996, 2002, 2004, and 2006b variants. The 2003Asia and 2006a variants caused epidemics, but they were geographically limited. Finally, the 2001Japan and 2001Henry variants were found across the world but at low frequencies ConclusionsNoV epidemics resulted from the global spread of GII.4 strains that evolved under the influence of population immunity. Lineages show notable (and currently unexplained) differences in geographic prevalence. Establishing a global NoV network by which data on strains with the potential to cause pandemics can be rapidly exchanged may lead to improved prevention and intervention strategies
Abstract
Outdoor and nature-based recreation provides countless social benefits, yet public land managers often lack information on the spatial and temporal extent of recreation activities. Social ...media is a promising source of data to fill information gaps because the amount of recreational use is positively correlated with social media activity. However, despite the implication that these correlations could be employed to accurately estimate visitation, there are no known transferable models parameterized for use with multiple social media data sources. This study tackles these issues by examining the relative value of multiple sources of social media in models that estimate visitation at unmonitored sites and times across multiple destinations. Using a novel dataset of over 30,000 social media posts and 286,000 observed visits from two regions in the United States, we compare multiple competing statistical models for estimating visitation. We find social media data substantially improve visitor estimates at unmonitored sites, even when a model is parameterized with data from another region. Visitation estimates are further improved when models are parameterized with on-site counts. These findings indicate that while social media do not fully substitute for on-site data, they are a powerful component of recreation research and visitor management.
Wildfire risk as a socioecological pathology Fischer, A Paige; Thomas A Spies; Toddi A Steelman ...
Frontiers in ecology and the environment,
June 2016, Letnik:
14, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Wildfire risk in temperate forests has become a nearly intractable problem that can be characterized as a socioecological âpathologyâ: that is, a set of complex and problematic interactions among ...social and ecological systems across multiple spatial and temporal scales. Assessments of wildfire risk could benefit from recognizing and accounting for these interactions in terms of socioecological systems, also known as coupled natural and human systems (CNHS). We characterize the primary social and ecological dimensions of the wildfire risk pathology, paying particular attention to the governance system around wildfire risk, and suggest strategies to mitigate the pathology through innovative planning approaches, analytical tools, and policies. We caution that even with a clear understanding of the problem and possible solutions, the system by which human actors govern fireâprone forests may evolve incrementally in imperfect ways and can be expected to resist change even as we learn better ways to manage CNHS.
The emergence of SARS-CoV-2 has created an international health crisis, and small animal models mirroring SARS-CoV-2 human disease are essential for medical countermeasure (MCM) development. Mice are ...refractory to SARS-CoV-2 infection owing to low-affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here, we evaluated the pathogenesis of SARS-CoV-2 in male and female mice expressing the human ACE2 gene under the control of the keratin 18 promoter (K18). In contrast to nontransgenic mice, intranasal exposure of K18-hACE2 animals to 2 different doses of SARS-CoV-2 resulted in acute disease, including weight loss, lung injury, brain infection, and lethality. Vasculitis was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals showed increases in transcripts involved in lung injury and inflammatory cytokines. In the low-dose challenge groups, there was a survival advantage in the female mice, with 60% surviving infection, whereas all male mice succumbed to disease. Male mice that succumbed to disease had higher levels of inflammatory transcripts compared with female mice. To our knowledge, this is the first highly lethal murine infection model for SARS-CoV-2 and should be valuable for the study of SARS-CoV-2 pathogenesis and for the assessment of MCMs.
As more clinically relevant cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies, raising the challenge of optimization and analytical validation ...of assays that interrogate millions of bases of cancer genomes altered by multiple mechanisms. Here we describe a test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes from routine formalin-fixed and paraffin-embedded (FFPE) clinical specimens. We implemented a practical validation strategy with reference samples of pooled cell lines that model key determinants of accuracy, including mutant allele frequency, indel length and amplitude of copy change. Test sensitivity achieved was 95-99% across alteration types, with high specificity (positive predictive value >99%). We confirmed accuracy using 249 FFPE cancer specimens characterized by established assays. Application of the test to 2,221 clinical cases revealed clinically actionable alterations in 76% of tumors, three times the number of actionable alterations detected by current diagnostic tests.
Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site ...alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting.
Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors.
Outdoor recreation is one of many important benefits provided by public lands. Data on recreational use are critical for informing management of recreation resources, however, managers often lack ...actionable information on visitor use for large protected areas that lack controlled access points. The purpose of this study is to explore the potential for social media data (e.g., geotagged images shared on Flickr and trip reports shared on a hiking forum) to provide land managers with useful measures of recreational use to dispersed areas, and to provide lessons learned from comparing several more traditional counting methods. First, we measure daily and monthly visitation rates to individual trails within the Mount Baker-Snoqualmie National Forest (MBSNF) in western Washington. At 15 trailheads, we compare counts of hikers from infrared sensors, timelapse cameras, and manual on-site counts, to counts based on the number of shared geotagged images and trip reports from those locations. Second, we measure visitation rates to each National Forest System (NFS) unit across the US and compare annual measurements derived from the number of geotagged images to estimates from the US Forest Service National Visitor Use Monitoring Program. At both the NFS unit and the individual-trail scales, we found strong correlations between traditional measures of recreational use and measures based on user-generated content shared on the internet. For national forests in every region of the country, correlations between official Forest Service statistics and geotagged images ranged between 55% and 95%. For individual trails within the MBSNF, monthly visitor counts from on-site measurements were strongly correlated with counts from geotagged images (79%) and trip reports (91%). The convenient, cost-efficient and timely nature of collecting and analyzing user-generated data could allow land managers to monitor use over different seasons of the year and at sites and scales never previously monitored, contributing to a more comprehensive understanding of recreational use patterns and values.
•Social media data create new opportunities to measure and model recreational use on public lands.•Across scales, there are strong correlations between traditional measures of use and measures based on social media content.•Nationally, forest visitation is correlated with counts from geotagged images, with some geographic variation.•Monthly visitor counts at trails are correlated with counts from geotagged images (79%) and online trip reports (91%).•New data sources can inform models that predict visitor numbers across an unprecedented number of sites.
There is significant policy and research interest in (a) ecosystem services as a framework for understanding the benefits humans receive from natural systems and (b) subjective well-being as a lens ...for understanding the effects of public policy decisions. The present study occurred at the intersection of these two fields. Choice experiment and contingent subjective well-being (SWB) models were estimated to understand the potential effects of coastal marine and forest reserves in Oregon, USA. Both models indicated heterogeneity in effects across groups defined by environmental worldview and, for marine reserves, recreation use of reserve areas and employment in the commercial fisheries sector. Methodologically, results suggested that a similar process underlays responses to both types of survey task, with similar model coefficient patterns and frequent consistency in responses. However, differences also were indicated, and differences may be more pronounced in other studies, such as those involving between-subject designs. Contingent SWB is a potentially important measurement approach, but further evaluation is needed, including with respect to the effects of task complexity and evaluation object salience.
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