Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-β (Aβ), as derived from sequential cleavage of the amyloid precursor protein. ...Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aβ-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D₂ and D₃ analogues decreased Aβ-production and increased Aβ-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aβ-producing enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased β-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention.
Dengue hemorrhagic fever (DHF), a severe manifestation of dengue viral infection that can cause severe bleeding, organ impairment, and even death, affects between 15,000 and 105,000 people each year ...in Thailand. While all Thai provinces experience at least one DHF case most years, the distribution of cases shifts regionally from year to year. Accurately forecasting where DHF outbreaks occur before the dengue season could help public health officials prioritize public health activities. We develop statistical models that use biologically plausible covariates, observed by April each year, to forecast the cumulative DHF incidence for the remainder of the year. We perform cross-validation during the training phase (2000–2009) to select the covariates for these models. A parsimonious model based on preseason incidence outperforms the 10-y median for 65% of province-level annual forecasts, reduces the mean absolute error by 19%, and successfully forecasts outbreaks (area under the receiver operating characteristic curve = 0.84) over the testing period (2010–2014). We find that functions of past incidence contribute most strongly to model performance, whereas the importance of environmental covariates varies regionally. This work illustrates that accurate forecasts of dengue risk are possible in a policy-relevant timeframe.
Mammalian megafauna have been critical to the functioning of Earth's biosphere for millions of years. However, since the Plio-Pleistocene, their biodiversity has declined concurrently with dramatic ...environmental change and hominin evolution. While these biodiversity declines are well-documented, their implications for the ecological function of megafaunal communities remain uncertain. Here, we adapt ecometric methods to evaluate whether the functional link between communities of herbivorous, eastern African megafauna and their environments (i.e., functional trait-environment relationships) was disrupted as biodiversity losses occurred over the past 7.4 Ma. Herbivore taxonomic and functional diversity began to decline during the Pliocene as open grassland habitats emerged, persisted, and expanded. In the mid-Pleistocene, grassland expansion intensified, and climates became more variable and arid. It was then that phylogenetic diversity declined, and the trait-environment relationships of herbivore communities shifted significantly. Our results divulge the varying implications of different losses in megafaunal biodiversity. Only the losses that occurred since the mid-Pleistocene were coincident with a disturbance to community ecological function. Prior diversity losses, conversely, occurred as the megafaunal species and trait pool narrowed towards those adapted to grassland environments.
The glycoproteins of herpesviruses and of HIV/SIV are made late in the replication cycle and are derived from transcripts that use an unusual codon usage that is quite different from that of the host ...cell. Here we show that the actions of natural transinducers from these two different families of persistent viruses (Rev of SIV and ORF57 of the rhesus monkey rhadinovirus) are dependent on the nature of the skewed codon usage. In fact, the transinducibility of expression of these glycoproteins by Rev and by ORF57 can be flipped simply by changing the nature of the codon usage. Even expression of a luciferase reporter could be made Rev dependent or ORF57 dependent by distinctive changes to its codon usage. Our findings point to a new general principle in which different families of persisting viruses use a poor codon usage that is skewed in a distinctive way to temporally regulate late expression of structural gene products.
Concerns about health effects due to emissions from ships have magnified international policy debate regarding low-sulfur fuel mandates for marine fuel. Policy discussions center on setting sulfur ...content levels and the geographic specification of low-sulfur fuel use. We quantify changes in premature mortality due to emissions from ships under several sulfur emissions control scenarios. We compare a 2012 No Control scenario (assuming 2.7% or 27 000 ppm S) with three emissions control scenarios. Two control scenarios represent cases where marine fuel is limited to 0.5% S (5000 ppm) and 0.1% S (1000 ppm) content, respectively, within 200 nautical miles of coastal areas. The third control scenario represents a global limit of 0.5% S. We apply the global climate model ECHAM5/MESSy1-MADE to geospatial emissions inventories to determine worldwide concentrations of particular matter (PM2.5) from oceangoing vessels. Using those PM2.5 concentrations in cardiopulmonary and lung cancer concentration-risk functions and population models, we estimate annual premature mortality. Without control, our central estimate is approximately 87 000 premature deaths annually in 2012. Coastal area control scenarios reduce premature deaths by ∼33 500 for the 0.5% case and ∼43 500 for the 0.1% case. Where fuel sulfur content is reduced globally to 0.5% S, premature deaths are reduced by ∼41 200. These results provide important support that global health benefits are associated with low-sulfur marine fuels, and allow for relative comparison of the benefits of alternative control strategies.
This multiagency report developed by the Interagency Collaboration for Genomics for Food and Feed Safety provides an overview of the use of and transition to whole genome sequencing (WGS) technology ...for detection and characterization of pathogens transmitted commonly by food and for identification of their sources. We describe foodborne pathogen analysis, investigation, and harmonization efforts among the following federal agencies: National Institutes of Health; Department of Health and Human Services, Centers for Disease Control and Prevention (CDC) and U.S. Food and Drug Administration (FDA); and the U.S. Department of Agriculture, Food Safety and Inspection Service, Agricultural Research Service, and Animal and Plant Health Inspection Service. We describe single nucleotide polymorphism, core-genome, and whole genome multilocus sequence typing data analysis methods as used in the PulseNet (CDC) and GenomeTrakr (FDA) networks, underscoring the complementary nature of the results for linking genetically related foodborne pathogens during outbreak investigations while allowing flexibility to meet the specific needs of Interagency Collaboration partners. We highlight how we apply WGS to pathogen characterization (virulence and antimicrobial resistance profiles) and source attribution efforts and increase transparency by making the sequences and other data publicly available through the National Center for Biotechnology Information. We also highlight the impact of current trends in the use of culture-independent diagnostic tests for human diagnostic testing on analytical approaches related to food safety and what is next for the use of WGS in the area of food safety.
Coronavirus disease 2019 (COVID-19) has caused strain on health systems worldwide due to its high mortality rate and the large portion of cases requiring critical care and mechanical ventilation. ...During these uncertain times, public health decision makers, from city health departments to federal agencies, sought the use of epidemiological models for decision support in allocating resources, developing non-pharmaceutical interventions, and characterizing the dynamics of COVID-19 in their jurisdictions. In response, we developed a flexible scenario modeling pipeline that could quickly tailor models for decision makers seeking to compare projections of epidemic trajectories and healthcare impacts from multiple intervention scenarios in different locations. Here, we present the components and configurable features of the COVID Scenario Pipeline, with a vignette detailing its current use. We also present model limitations and active areas of development to meet ever-changing decision maker needs.
The properties of the human immunodeficiency virus (HIV) pose serious difficulties for the development of an effective prophylactic vaccine. Here we describe the construction and characterization of ...recombinant (r), replication-competent forms of rhesus monkey rhadinovirus (RRV), a gamma-2 herpesvirus, containing a near-full-length (nfl) genome of the simian immunodeficiency virus (SIV). A 306-nucleotide deletion in the pol gene rendered this nfl genome replication-incompetent as a consequence of deletion of the active site of the essential reverse transcriptase enzyme. Three variations were constructed to drive expression of the SIV proteins: one with SIV's own promoter region, one with a cytomegalovirus (cmv) immediate-early promoter/enhancer region, and one with an RRV dual promoter (p26 plus PAN). Following infection of rhesus fibroblasts in culture with these rRRV vectors, synthesis of the early protein Nef and the late structural proteins Gag and Env could be demonstrated. Expression levels of the SIV proteins were highest with the rRRV-SIVcmv-nfl construct. Electron microscopic examination of rhesus fibroblasts infected with rRRV-SIVcmv-nfl revealed numerous budding and mature SIV particles and these infected cells released impressive levels of p27 Gag protein (>150 ng/ml) into the cell-free supernatant. The released SIV particles were shown to be incompetent for replication. Monkeys inoculated with rRRV-SIVcmv-nfl became persistently infected, made readily-detectable antibodies against SIV, and developed T-cell responses against all nine SIV gene products. Thus, rRRV expressing a near-full-length SIV genome mimics live-attenuated strains of SIV in several important respects: the infection is persistent; >95% of the SIV proteome is naturally expressed; SIV particles are formed; and CD8+ T-cell responses are maintained indefinitely in an effector-differentiated state. Although the magnitude of anti-SIV immune responses in monkeys infected with rRRV-SIVcmv-nfl falls short of what is seen with live-attenuated SIV infection, further experimentation seems warranted.
Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food, several synthetic ...but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling, histone deacetylase activation and gene regulation. By affecting several pathways associated with neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative diseases has been extensively studied and several new aspects have been elucidated. In this review we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson's disease and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing the underlying molecular mechanisms in cell culture experiments and animal studies in order to assess the neuroprotective potential of methylxanthines in these diseases.
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