Prion-like propagation of tau aggregation might underlie the stereotyped progression of neurodegenerative tauopathies. True prions stably maintain unique conformations (“strains”) in vivo that link ...structure to patterns of pathology. We now find that tau meets this criterion. Stably expressed tau repeat domain indefinitely propagates distinct amyloid conformations in a clonal fashion in culture. Reintroduction of tau from these lines into naive cells reestablishes identical clones. We produced two strains in vitro that induce distinct pathologies in vivo as determined by successive inoculations into three generations of transgenic mice. Immunopurified tau from these mice recreates the original strains in culture. We used the cell system to isolate tau strains from 29 patients with 5 different tauopathies, finding that different diseases are associated with different sets of strains. Tau thus demonstrates essential characteristics of a prion. This might explain the phenotypic diversity of tauopathies and could enable more effective diagnosis and therapy.
•Tau stably propagates multiple amyloid conformations (strains) in dividing cells•Strains induce unique pathologies in transgenic mice•Strains can be passaged through multiple generations of mice and back to cells•Different tauopathies are associated with different sets of strains
Prions stably propagate unique conformations (strains) that produce different pathologies. Sanders et al. now report that tau acts as a prion in cells and in vivo by this criterion and find that different tauopathies are associated with unique tau strains.
The occurrence of false positive detections in presence-absence data, even when they occur infrequently, can lead to severe bias when estimating species occupancy patterns. Building upon previous ...efforts to account for this source of observational error, we established a general framework to model false positives in occupancy studies and extend existing modeling approaches to encompass a broader range of sampling designs. Specifically, we identified three common sampling designs that are likely to cover most scenarios encountered by researchers. The different designs all included ambiguous detections, as well as some known-truth data, but their modeling differed in the level of the model hierarchy at which the known-truth information was incorporated (site level or observation level). For each model, we provide the likelihood, as well as R and BUGS code needed for implementation. We also establish a clear terminology and provide guidance to help choosing the most appropriate design and modeling approach.
Power density is the rate of energy generation per unit of land surface area occupied by an energy system. The power density of low-carbon energy sources will play an important role in mediating the ...environmental consequences of energy system decarbonization as the world transitions away from high power-density fossil fuels. All else equal, lower power densities mean larger land and environmental footprints. The power density of solar and wind power remain surprisingly uncertain: estimates of realizable generation rates per unit area for wind and solar power span 0.3-47 We m−2 and 10-120 We m−2 respectively. We refine this range using US data from 1990-2016. We estimate wind power density from primary data, and solar power density from primary plant-level data and prior datasets on capacity density. The mean power density of 411 onshore wind power plants in 2016 was 0.50 We m−2. Wind plants with the largest areas have the lowest power densities. Wind power capacity factors are increasing, but that increase is associated with a decrease in capacity densities, so power densities are stable or declining. If wind power expands away from the best locations and the areas of wind power plants keep increasing, it seems likely that wind's power density will decrease as total wind generation increases. The mean 2016 power density of 1150 solar power plants was 5.4 We m−2. Solar capacity factors and (likely) power densities are increasing with time driven, in part, by improved panel efficiencies. Wind power has a 10-fold lower power density than solar, but wind power installations directly occupy much less of the land within their boundaries. The environmental and social consequences of these divergent land occupancy patterns need further study.
Tauopathies are neurodegenerative disorders that affect distinct brain regions, progress at different rates, and exhibit specific patterns of tau accumulation. The source of this diversity is ...unknown. We previously characterized two tau strains that stably maintain unique conformations in vitro and in vivo, but did not determine the relationship of each strain to parameters that discriminate between tauopathies such as regional vulnerability or rate of spread. We have now isolated and characterized 18 tau strains in cells based on detailed biochemical and biological criteria. Inoculation of PS19 transgenic tau (P301S) mice with these strains causes strain-specific intracellular pathology in distinct cell types and brain regions, and induces different rates of network propagation. In this system, strains alone are sufficient to account for diverse neuropathological presentations, similar to those that define human tauopathies. Further study of these strains can thus establish a structural logic that governs these biological effects.
•Tau forms multiple, unique prion strains with distinct biochemical properties•Tau strains induce diverse pathological phenotypes in vitro and in vivo•Tau strains target different brain regions and propagate pathology at unique rates•We present a framework to understand the diversity of human tauopathies
Kaufman et al. observe that tau forms multiple self-propagating amyloid strains. The introduction of each into transgenic mouse brain creates a distinct pathology that targets different brain regions and induces unique rates of spread. Thus, strain variation can account for the diversity of human tauopathies.
Germline mutations in LKB1 (STK11) are associated with the Peutz-Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous ...melanoma. By somatically inactivating Lkb1 with K-Ras activation (±p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC family kinase (SFK) YES, increased expression of WNT target genes, and expansion of a CD24+ cell population, which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24− cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing an SFK-dependent expansion of a prometastatic, CD24+ tumor subpopulation.
► Loss of LKB1 in melanoma promotes widespread and high-grade metastasis ► This enhancement of metastasis requires activation of YES kinase, a SRC family member ► LKB1 inactivation leads to the expansion of a prometastatic CD24+ tumor subfraction ► YES and CD24 are therapeutic targets in LKB1-defcient melanoma
With the advance of methods for estimating species distribution models has come an interest in how to best combine datasets to improve estimates of species distributions. This has spurred the ...development of data integration methods that simultaneously harness information from multiple datasets while dealing with the specific strengths and weaknesses of each dataset.
We outline the general principles that have guided data integration methods and review recent developments in the field. We then outline key areas that allow for a more general framework for integrating data and provide suggestions for improving sampling design and validation for integrated models.
Key to recent advances has been using point‐process thinking to combine estimators developed for different data types. Extending this framework to new data types will further improve our inferences, as well as relaxing assumptions about how parameters are jointly estimated. These along with the better use of information regarding sampling effort and spatial autocorrelation will further improve our inferences.
Recent developments form a strong foundation for implementation of data integration models. Wider adoption can improve our inferences about species distributions and the dynamic processes that lead to distributional shifts.
The effects of phenological mismatches on demography Miller-Rushing, Abraham J.; Høye, Toke Thomas; Inouye, David W. ...
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
10/2010, Letnik:
365, Številka:
1555
Journal Article
Recenzirano
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Climate change is altering the phenology of species across the world, but what are the consequences of these phenological changes for the demography and population dynamics of species? Time-sensitive ...relationships, such as migration, breeding and predation, may be disrupted or altered, which may in turn alter the rates of reproduction and survival, leading some populations to decline and others to increase in abundance. However, finding evidence for disrupted relationships, or lack thereof, and their demographic effects, is difficult because the necessary detailed observational data are rare. Moreover, we do not know how sensitive species will generally be to phenological mismatches when they occur. Existing long-term studies provide preliminary data for analysing the phenology and demography of species in several locations. In many instances, though, observational protocols may need to be optimized to characterize timing-based multi-trophic interactions. As a basis for future research, we outline some of the key questions and approaches to improving our understanding of the relationships among phenology, demography and climate in a multi-trophic context. There are many challenges associated with this line of research, not the least of which is the need for detailed, long-term data on many organisms in a single system. However, we identify key questions that can be addressed with data that already exist and propose approaches that could guide future research.
Carnivore predation on livestock often leads people to retaliate. Persecution by humans has contributed strongly to global endangerment of carnivores. Preventing livestock losses would help to ...achieve three goals common to many human societies: preserve nature, protect animal welfare, and safeguard human livelihoods. Between 2016 and 2018, four independent reviews evaluated >40 years of research on lethal and nonlethal interventions for reducing predation on livestock. From 114 studies, we find a striking conclusion: scarce quantitative comparisons of interventions and scarce comparisons against experimental controls preclude strong inference about the effectiveness of methods. For wise investment of public resources in protecting livestock and carnivores, evidence of effectiveness should be a prerequisite to policy making or large-scale funding of any method or, at a minimum, should be measured during implementation. An appropriate evidence base is needed, and we recommend a coalition of scientists and managers be formed to establish and encourage use of consistent standards in future experimental evaluations.
Brain-derived neurotrophic factor (BDNF), a cognate ligand for the tyrosine kinase receptor B (TrkB) receptor, mediates neuronal survival, differentiation, synaptic plasticity, and neurogenesis. ...However, BDNF has a poor pharmacokinetic profile that limits its therapeutic potential. Here we report the identification of 7,8-dihydroxyflavone as a bioactive high-affinity TrkB agonist that provokes receptor dimerization and autophosphorylation and activation of downstream signaling. 7,8-Dihydroxyflavone protected wild-type, but not TrkB-deficient, neurons from apoptosis. Administration of 7,8-dihydroxyflavone to mice activated TrkB in the brain, inhibited kainic acid-induced toxicity, decreased infarct volumes in stroke in a TrkB-dependent manner, and was neuroprotective in an animal model of Parkinson disease. Thus, 7,8-dihydroxyflavone imitates BDNF and acts as a robust TrkB agonist, providing a powerful therapeutic tool for the treatment of various neurological diseases.
The current paradigm, widely incorporated in soil biogeochemical models, is that microbial methanogenesis can only occur in anoxic habitats. In contrast, here we show clear geochemical and biological ...evidence for methane production in well-oxygenated soils of a freshwater wetland. A comparison of oxic to anoxic soils reveal up to ten times greater methane production and nine times more methanogenesis activity in oxygenated soils. Metagenomic and metatranscriptomic sequencing recover the first near-complete genomes for a novel methanogen species, and show acetoclastic production from this organism was the dominant methanogenesis pathway in oxygenated soils. This organism, Candidatus Methanothrix paradoxum, is prevalent across methane emitting ecosystems, suggesting a global significance. Moreover, in this wetland, we estimate that up to 80% of methane fluxes could be attributed to methanogenesis in oxygenated soils. Together, our findings challenge a widely held assumption about methanogenesis, with significant ramifications for global methane estimates and Earth system modeling.
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