The specific characteristics of Transmissible Spongiform Encephalopathy (TSE) strains may be altered during passage across a species barrier. In this study we investigated the biochemical and ...biological characteristics of Bovine Spongiform Encephalopathy (BSE) after transmission in both natural host species (cattle, sheep, pigs and mice) and in transgenic mice overexpressing the corresponding cellular prion protein (PrPC) in comparison with other non-BSE related prions from the same species. After these passages, most features of the BSE agent remained unchanged. BSE-derived agents only showed slight modifications in the biochemical properties of the accumulated PrPSc, which were demonstrated to be reversible upon re-inoculation into transgenic mice expressing bovine-PrPC. Transmission experiments in transgenic mice expressing bovine, porcine or human-PrP revealed that all BSE-derived agents were transmitted with no or a weak transmission barrier. In contrast, a high species barrier was observed for the non-BSE related prions that harboured an identical PrP amino acid sequence, supporting the theory that the prion transmission barrier is modulated by strain properties (presumably conformation-dependent) rather than by PrP amino acid sequence differences between host and donor. As identical results were observed with prions propagated either in natural hosts or in transgenic mouse models, we postulate that the species barrier and its passage consequences are uniquely governed by the host PrPC sequence and not influenced by other host genetic factors. The results presented herein reinforce the idea that the BSE agent is highly promiscuous, infecting other species, maintaining its properties in the new species, and even increasing its capabilities to jump to other species including humans. These data are essential for the development of an accurate risk assessment for BSE.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Photodynamic therapy (PDT) has been used for many years, but it is only now becoming widely accepted and utilized. Originally it was developed as a tumor therapy and some of its most successful ...applications are for non-malignant diseases. This article provides a broad review of different parameters used and mechanisms instituted in PDT such as photosensitizers (PS), photochemistry and photophysics, cellular localization, cellular signaling, cell metabolism and modes of cell death that operate on a cellular level, as well as photosensitizer pharmacokinetics, biodistribution, tumor localization and modes of tumor destruction. These specific cellular mechanisms are most commonly applied in PDT and for the most part are often researched and exploited. If the combination of these specific parameters and mechanisms can be optimized within PDT it could possibly be used as a suitable alternative for the treatment and management of specific cancers.
The minimum dose required to cause infection of Romney and Suffolk sheep of the ARQ/ARQ or ARQ/ARR prion protein gene genotypes following oral inoculation with Romney or Suffolk a sheep Bovine ...spongiform encephalopathy (BSE)-derived or cattle BSE-derived agent was investigated using doses ranging from 0.0005g to 5g. ARQ/ARQ sheep which were methionine (M) / threonine (T) heterozygous or T/T homozygous at codon 112 of the Prnp gene, dosed ARQ/ARR sheep and undosed controls did not show any evidence of infection. Within groups of susceptible sheep, the minimum effective oral dose of BSE was found to be 0.05g, with higher attack rates following inoculation with the 5g dose. Surprisingly, this study found no effect of dose on survival time suggesting a possible lack of homogeneity within the inoculum. All clinical BSE cases showed PrPd accumulation in brain; however, following cattle BSE inoculation, LRS involvement within Romney recipients was found to be significantly lower than within the Suffolk sheep inoculated group which is in agreement with previous reports.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Effects of CO2 on Cu and Cd accumulation were studied in bivalves.•Cd strongly accumulated in organelles and enzymes of clams and oysters.•Cu accumulated in mitochondria of oysters but not in those ...of clams.•Elevated CO2 increased Cd accumulation in organelles and potentially Cd toxicity.•Elevated CO2 enhanced Cd detoxification in clams and suppressed it in in oysters.
Hypercapnia (elevated CO2 levels) and pollution with trace metals such as Cu and Cd are common stressors in estuarine habitats that can negatively affect physiology and health of marine organisms. Hypercapnia can modulate toxicity of trace metals including Cu and Cd; however, the physiological and cellular mechanisms of the metal-CO2 interactions are not well understood. We investigated the effects of elevated PCO2 (∼800 and 2000μatm) and metal exposure (50μgl−1 of Cu or Cd) on subcellular distribution of metals in two common species of marine bivalves, Eastern oysters Crassostrea virginica and hard shell clams Mercenaria mercenaria. Oysters accumulated higher burdens of Cu and Cd in the gill tissues compared to clams. In both studied species, Cu was predominantly associated with the metabolically active cell compartments (mitochondria, lysosomes, microsomes and cytosolic enzymes), with a modest fraction sequestered by metallothioneins (∼30%) and the insoluble metal-containing granules (MCG) (∼15–20%). Unlike Cu, Cd was largely sequestered by metallothioneins (∼60–70%), with a relatively small fraction associated with the organelles and the cytosolic enzymes. Mitochondria were the main intracellular target for trace metals accumulating higher concentrations of Cd (and in the case of oysters – of Cu) than other organelles or cytosolic enzymes. Cu accumulation in the metabolically active cellular compartments was independent of the CO2 levels, while Cd content of the organelles and cytosolic enzymes increased at elevated PCO2 in both studied species indicating that hypercapnia may enhance cellular toxicity of Cd in bivalves. Hypercapnia suppressed the sequestration capacity of metallothioneins for Cu and Cd in oysters but increased Cu and Cd load in clam metallothioneins. Thus, metal-induced metabolic injury in oysters may be exaggerated by hypercapnia which enhances metal accumulation in the potentially sensitive intracellular fractions and suppresses the metal detoxification capacity. In contrast, clams appear to be more resistant to the combined effects of hypercapnia and metal exposure reflecting more efficient and robust detoxification mechanisms of this species.
Real-time PCR assays using TaqMan or Molecular Beacon probes were developed and optimized for the quantification of total bacteria, the nitrite-oxidizing bacteria Nitrospira, and Nitrosomonas ...oligotropha-like ammonia oxidizing bacteria (AOB) in mixed liquor suspended solids (MLSS) from a municipal wastewater treatment plant (WWTP) using a single-sludge nitrification process. The targets for the real-time PCR assays were the 16S rRNA genes (16S rDNA) for bacteria and Nitrospira spp. and the amoA gene for N. oligotropha. A previously reported assay for AOB 16S rDNA was also tested for its application to activated sludge. The Nitrospira 16S rDNA, AOB 16S rDNA, and N. oligotropha-like amoA assays were log- linear over 6 orders of magnitude and the bacterial 16S rDNA real-time PCR assay was log-linear over 4 orders of magnitude with DNA standards. When these real-time PCR assays were applied to DNA extracted from MLSS, dilution of the DNA extracts was necessary to prevent PCR inhibition. The optimal DNA dilution range was broad for the bacterial 16S rDNA (1000-fold) and Nitrospira 16S rDNA assays (2500-fold) but narrow for the AOB 16S rDNA assay (10-fold) and N. oligotropha- like amoA real-time PCR assay (5-fold). In twelve MLSS samples collected over one year, mean cell per L values were 4.3 ± 2.0 × 1011 for bacteria, 3.7 ± 3.2 × 1010 for Nitrospira, 1.2 ± 0.9 × 1010 for all AOB, and 7.5 ± 6.0 × 109 for N. oligotropha-like AOB. The percent of the nitrifying population was 1.7% N. oligotropha-like AOB based on the N. oligotropha amoA assay, 2.9% total AOB based on the AOB 16S rDNA assay, and 8.6% nitrite-oxidizing bacteria based on the Nitrospira 16S rDNA assay. Ammonia-oxidizing bacteria in the wastewater treatment plant were estimated to oxidize 7.7 ± 6.8 fmol/hr/cell based on the AOB 16S rDNA assay and 12.4 ± 7.3 fmol/hr/cell based on the N. oligotropha amoA assay.
Decadal predictions have a high profile in the climate science community and beyond, yet very little is known about their skill. Nor is there any agreed protocol for estimating their skill. This ...paper proposes a sound and coordinated framework for verification of decadal hindcast experiments. The framework is illustrated for decadal hindcasts tailored to meet the requirements and specifications of CMIP5 (Coupled Model Intercomparison Project phase 5). The chosen metrics address key questions about the information content in initialized decadal hindcasts. These questions are: (1) Do the initial conditions in the hindcasts lead to more accurate predictions of the climate, compared to un-initialized climate change projections? and (2) Is the prediction model’s ensemble spread an appropriate representation of forecast uncertainty on average? The first question is addressed through deterministic metrics that compare the initialized and uninitialized hindcasts. The second question is addressed through a probabilistic metric applied to the initialized hindcasts and comparing different ways to ascribe forecast uncertainty. Verification is advocated at smoothed regional scales that can illuminate broad areas of predictability, as well as at the grid scale, since many users of the decadal prediction experiments who feed the climate data into applications or decision models will use the data at grid scale, or downscale it to even higher resolution. An overall statement on skill of CMIP5 decadal hindcasts is not the aim of this paper. The results presented are only illustrative of the framework, which would enable such studies. However, broad conclusions that are beginning to emerge from the CMIP5 results include (1) Most predictability at the interannual-to-decadal scale, relative to climatological averages, comes from external forcing, particularly for temperature; (2) though moderate, additional skill is added by the initial conditions over what is imparted by external forcing alone; however, the impact of initialization may result in overall worse predictions in some regions than provided by uninitialized climate change projections; (3) limited hindcast records and the dearth of climate-quality observational data impede our ability to quantify expected skill as well as model biases; and (4) as is common to seasonal-to-interannual model predictions, the spread of the ensemble members is not necessarily a good representation of forecast uncertainty. The authors recommend that this framework be adopted to serve as a starting point to compare prediction quality across prediction systems. The framework can provide a baseline against which future improvements can be quantified. The framework also provides guidance on the use of these model predictions, which differ in fundamental ways from the climate change projections that much of the community has become familiar with, including adjustment of mean and conditional biases, and consideration of how to best approach forecast uncertainty.
Summary
In Escherichia coli and some other γ‐Proteobacteria, the alternative σ factor RpoS functions as a regulator of the general stress response. The role of RpoS in Pseudomonas aeruginosa is not ...clear. Although P. aeruginosa RpoS contributes to the resistance to several environmental stresses, its role appears to be less pivotal than in E. coli. In P. aeruginosa, RpoS also regulates the production of several virulence factors and influences the expression of individual genes that are controlled by quorum sensing. Some quorum‐controlled genes are induced by RpoS, whereas others are repressed. To gain insights about RpoS function in P. aeruginosa and to understand better the regulation of quorum‐controlled genes, we used transcript profiling to define an RpoS regulon. We identified 772 genes regulated by RpoS in stationary but not in logarithmic growth phase (504 were induced and 268 were repressed), and we identified putative RpoS promoter sequence elements with similarity to the E. coli RpoS consensus in several of these genes. Many genes in the regulon, for example a set of chemotaxis genes, have assigned functions that are distinct from those in E. coli and are not obviously related to a stress response. Furthermore, RpoS affects the expression of more than 40% of all quorum‐controlled genes identified in our previous transcriptome analysis. This highlights the significance of RpoS as a global factor that controls quorum‐sensing gene expression at the onset of stationary phase. The transcription profiling results have allowed us to build a model that accommodates previous seemingly conflicting reports.
The performance of a new historical reanalysis, the NOAA–CIRES–DOE Twentieth Century Reanalysis version 3 (20CRv3), is evaluated via comparisons with other reanalyses and independent observations. ...This dataset provides global, 3-hourly estimates of the atmosphere from 1806 to 2015 by assimilating only surface pressure observations and prescribing sea surface temperature, sea ice concentration, and radiative forcings. Comparisons with independent observations, other reanalyses, and satellite products suggest that 20CRv3 can reliably produce atmospheric estimates on scales ranging from weather events to long-term climatic trends. Not only does 20CRv3 recreate a ‘‘best estimate’’ of the weather, including extreme events, it also provides an estimate of its confidence through the use of an ensemble. Surface pressure statistics suggest that these confidence estimates are reliable. Comparisons with independent upper-air observations in the Northern Hemisphere demonstrate that 20CRv3 has skill throughout the twentieth century. Upper-air fields from 20CRv3 in the late twentieth century and early twenty-first century correlate well with full-input reanalyses, and the correlation is predicted by the confidence fields from 20CRv3. The skill of analyzed 500-hPa geopotential heights from 20CRv3 for 1979–2015 is comparable to that of modern operational 3–4-day forecasts. Finally, 20CRv3 performs well on climate time scales. Long time series and multidecadal averages of mass, circulation, and precipitation fields agree well with modern reanalyses and station- and satellite-based products. 20CRv3 is also able to capture trends in tropospheric-layer temperatures that correlate well with independent products in the twentieth century, placing recent trends in a longer historical context.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lung transplant recipients are encouraged to perform self‐management behaviors, including (i) monitoring health indicators, (ii) adhering to their regimen, and (iii) reporting abnormal health ...indicators to the transplant coordinator, yet performance is suboptimal. When hospital discharge was imminent, this two‐group trial randomized 201 recipients to use either the mobile health (mHealth) intervention (n = 99) or usual care (n = 102), to compare efficacy for promoting self‐management behaviors (primary outcomes) and self‐care agency, rehospitalization, and mortality (secondary outcomes) at home during the first year after transplantation. The mHealth intervention group performed self‐monitoring (odds ratio OR 5.11, 95% confidence interval CI 2.95–8.87, p < 0.001), adhered to medical regimen (OR 1.64, 95% CI 1.01–2.66, p = 0.046), and reported abnormal health indicators (OR 8.9, 95% CI 3.60–21.99, p < 0.001) more frequently than the usual care group. However, the two groups did not differ in rehospitalization (OR 0.78, 95% CI 0.36–1.66, p = 0.51) or mortality (hazard ratio 1.71, 0.68–4.28, p = 0.25). The positive impact of the mHealth intervention on self‐management behaviors suggests that the intervention holds promise and warrants further testing.
This randomized controlled trial of lung recipients followed for one year after transplant demonstrates that a mobile health intervention is superior to usual care in promoting self‐management behaviors, though the two groups did not differ in health outcomes, suggesting that mHealth interventions hold promise but warrant further testing.
The generation of conformations for small molecules is a problem of continuing interest in cheminformatics and computational drug discovery. This review will present an overview of methods used to ...sample conformational space, focusing on those methods designed for organic molecules commonly of interest in drug discovery. Different approaches to both the sampling of conformational space and the scoring of conformational stability will be compared and contrasted, with an emphasis on those methods suitable for conformer sampling of large numbers of drug-like molecules. Particular attention will be devoted to the appropriate utilization of information from experimental solid-state structures in validating and evaluating the performance of these tools. The review will conclude with some areas worthy of further investigation.
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