The majority of known Toxoplasma gondii isolates from Europe and North America belong to three clonal lines that differ dramatically in their virulence, depending on the host. To identify the ...responsible genes, we mapped virulence in F₁ progeny derived from crosses between type II and type III strains, which we introduced into mice. Five virulence (VIR) loci were thus identified, and for two of these, genetic complementation showed that a predicted protein kinase (ROP18 and ROP16, respectively) is the key molecule. Both are hypervariable rhoptry proteins that are secreted into the host cell upon invasion. These results suggest that secreted kinases unique to the Apicomplexa are crucial in the host-pathogen interaction.
The median age of prostate cancer diagnosis is 66 years, and the median age of men who die of the disease is eighty years. The public health impact of prostate cancer is already substantial and, ...given the rapidly ageing world population, can only increase. In this context, the International Society of Geriatric Oncology (SIOG) Task Forces have, since 2010, been developing guidelines for the management of senior adults with prostate cancer.
Since prostate cancer and geriatric oncology are both rapidly evolving fields, a new multidisciplinary Task Force was formed in 2018 to update SIOG recommendations, principally on health status screening tools and treatment. The task force reviewed pertinent articles published between June 2016 and June 2018 and abstracts from European Association of Urology (EAU), European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and American Society of Clinical Oncology Genito-urinary (ASCO GU) meetings over the same period, using search terms relevant to prostate cancer, the elderly, geriatric evaluation, local treatments and advanced disease. Each member of the group proposed modifications to the previous guidelines. These were collated and circulated. The final manuscript reflects the expert consensus.
The 2019 consensus is that men aged 75 years and older with prostate cancer should be managed according to their individual health status, and not according to age. Based on available rapid health screening tools, geriatric evaluation and geriatric interventions, the Task Force recommends that patients are classified according to health status into three groups: (1) 'healthy' or 'fit' patients should have the same treatment options as younger patients; (2) 'vulnerable' patients are candidates for geriatric interventions which-if successful-may make it appropriate for them to receive standard treatment and (3) 'frail' patients with major impairments who should receive adapted or palliative treatment. The 2019 SIOG Task Force recommendations also discuss prospects and unmet needs for health status evaluation in everyday practice in older patients with prostate cancer.
Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, can cause severe disease in humans with an immature or suppressed immune system. The outcome of Toxoplasma infection ...is highly dependent on the strain type, as are many of its in vitro growth properties. Here we use genetic crosses between type II and III lines to show that strain-specific differences in the modulation of host cell transcription are mediated by a putative protein kinase, ROP16. Upon invasion by the parasite, this polymorphic protein is released from the apical organelles known as rhoptries and injected into the host cell, where it ultimately affects the activation of signal transducer and activator of transcription (STAT) signalling pathways and consequent downstream effects on a key host cytokine, interleukin (IL)-12. Our findings provide a new mechanism for how an intracellular eukaryotic pathogen can interact with its host and reveal important differences in how different Toxoplasma lineages have evolved to exploit this interaction.
Abstract
We report on the discovery of FRB 20200120E, a repeating fast radio burst (FRB) with a low dispersion measure (DM) detected by the Canadian Hydrogen Intensity Mapping Experiment FRB project. ...The source DM of 87.82 pc cm
−3
is the lowest recorded from an FRB to date, yet it is significantly higher than the maximum expected from the Milky Way interstellar medium in this direction (∼50 pc cm
−3
). We have detected three bursts and one candidate burst from the source over the period 2020 January–November. The baseband voltage data for the event on 2020 January 20 enabled a sky localization of the source to within ≃14 arcmin
2
(90% confidence). The FRB localization is close to M81, a spiral galaxy at a distance of 3.6 Mpc. The FRB appears on the outskirts of M81 (projected offset ∼20 kpc) but well inside its extended H
i
and thick disks. We empirically estimate the probability of a chance coincidence with M81 to be <10
−2
. However, we cannot reject a Milky Way halo origin for the FRB. Within the FRB localization region, we find several interesting cataloged M81 sources and a radio point source detected in the Very Large Array Sky Survey. We search for prompt X-ray counterparts in Swift Burst Alert Telescope and Fermi/GBM data, and, for two of the FRB 20200120E bursts, we rule out coincident SGR 1806−20-like X-ray bursts. Due to the proximity of FRB 20200120E, future follow-up for prompt multiwavelength counterparts and subarcsecond localization could be constraining of proposed FRB models.
Since the mid-1980s, our understanding of nutrient limitation of oceanic primary production has radically changed. Mesoscale iron addition experiments (FeAXs) have unequivocally shown that iron ...supply limits production in one-third of the world ocean, where surface macronutrient concentrations are perennially high. The findings of these 12 FeAXs also reveal that iron supply exerts controls on the dynamics of plankton blooms, which in turn affect the biogeochemical cycles of carbon, nitrogen, silicon, and sulfur and ultimately influence the Earth climate system. However, extrapolation of the key results of FeAXs to regional and seasonal scales in some cases is limited because of differing modes of iron supply in FeAXs and in the modern and paleo-oceans. New research directions include quantification of the coupling of oceanic iron and carbon biogeochemistry.
Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes
. Their physical origin remains unknown, but dozens of possible models have been postulated
. Some FRB sources exhibit repeat ...bursts
. Although over a hundred FRB sources have been discovered
, only four have been localized and associated with a host galaxy
, and just one of these four is known to emit repeating FRBs
. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source
, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure
further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.
Cosmic-ray proton and helium spectra have been measured with the balloon-borne Cosmic Ray Energetics And Mass experiment flown for 42 days in Antarctica in the 2004-2005 austral summer season. ...High-energy cosmic-ray data were collected at an average altitude of ~38.5 km with an average atmospheric overburden of ~3.9 g cm--2. Individual elements are clearly separated with a charge resolution of ~0.15 e (in charge units) and ~0.2 e for protons and helium nuclei, respectively. The measured spectra at the top of the atmosphere are represented by power laws with a spectral index of --2.66 ? 0.02 for protons from 2.5 TeV to 250 TeV and --2.58 ? 0.02 for helium nuclei from 630 GeV nucleon--1 to 63 TeV nucleon--1. They are harder than previous measurements at a few tens of GeV nucleon--1. The helium flux is higher than that expected from the extrapolation of the power law fitted to the lower-energy data. The relative abundance of protons to helium nuclei is 9.1 ? 0.5 for the range from 2.5 TeV nucleon--1 to 63 TeV nucleon--1. This ratio is considerably smaller than the previous measurements at a few tens of GeV nucleon--1.
Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an extraordinarily successful parasite, ...infecting an estimated 30% of humans worldwide. The outcome of Toxoplasma infection is highly dependent on allelic differences in the large number of effectors that the parasite secretes into the host cell. Here, we show that the largest determinant of the virulence difference between two of the most common strains of Toxoplasma is the ROP5 locus. This is an unusual segment of the Toxoplasma genome consisting of a family of 4-10 tandem, highly divergent genes encoding pseudokinases that are injected directly into host cells. Given their hypothesized catalytic inactivity, it is striking that deletion of the ROP5 cluster in a highly virulent strain caused a complete loss of virulence, showing that ROP5 proteins are, in fact, indispensable for Toxoplasma to cause disease in mice. We find that copy number at this locus varies among the three major Toxoplasma lineages and that extensive polymorphism is clustered into hotspots within the ROP5 pseudokinase domain. We propose that the ROP5 locus represents an unusual evolutionary strategy for sampling of sequence space in which the gene encoding an important enzyme has been (i) catalytically inactivated, (ii) expanded in number, and (iii) subject to strong positive selection. Such a strategy likely contributes to Toxoplasma's successful adaptation to a wide host range and has resulted in dramatic differences in virulence.
Organophosphate esters (OPEs) are synthetic chemicals found in many consumer products, including furniture, electronics, processed foods, and building materials. Emerging in vitro and in vivo studies ...suggest that OPEs are metabolism disrupting compounds; however, epidemiologic studies investigating their associations with adiposity markers are sparse.
We examined cross-sectional associations between OPE biomarkers and adiposity measures among U.S. children and adults participating in the National Health and Nutrition Examination Survey (NHANES: 2013–2014).
Concentrations of five OPE metabolites were quantified in urine: diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), bis(2-chloroethyl) phosphate (BCEP), dibutyl phosphate (DBUP), and bis(1-chloro-2-propyl) phosphate (BCPP). We conducted covariate-adjusted logistic and linear regressions to examine associations between log2-transformed and dichotomized OPE metabolite concentrations and obesity, body mass index (BMI), and waist circumference (WC), separately among 784 children (6–19 years) and 1672 adults (≥20 years). We also assessed heterogeneity of associations by sex.
DBUP concentrations were inversely associated with the prevalence odds of being obese vs. normal weight in children (adjusted Prevalence Odds Ratio, aPOR: 0.82, 95% Confidence Interval, 95% CI: 0.70, 0.95) and adults (aPOR: 0.83, 95% CI: 0.72, 0.96). DBUP was also significantly associated with lower BMI z-scores (β:-0.08, 95% CI:-0.17, 0.01) and WC (β:-0.71, 95% CI: -1.49, 0.07) in children. BCEP concentrations were associated with increased prevalence odds of being overweight vs. normal weight (aPOR: 1.15, 95% CI: 1.01, 1.32) among children; similar, albeit not statistically significant, relationships were observed with other child adiposity outcomes. Among adults, detectable BCPP concentrations were associated with increased prevalence odds of being obese vs. normal weight (aPOR: 1.70, 95% CI: 1.21, 2.38) and having a high vs. normal WC (aPOR: 1.51, 95% CI: 1.11, 2.07) as well as higher BMI (β: 1.31, 95% CI: 0.30, 2.33). Other OPE metabolites were not consistently associated with adiposity measures among adults. Although associations of BCPP exposure with adiposity outcomes were generally inverse among boys, but not girls, we did not observe consistent evidence of sexually-dimorphic associations for other OPE metabolites.
Exposure to select OPEs may be differentially associated with body size among children and adults. Given the cross-sectional design of the present study, future prospective studies are needed to confirm these findings.
•DBUP was inversely associated with adiposity markers among children.•BCPP detection was positively associated with adiposity markers among adults.•Associations of BCPP with adiposity outcomes were generally inverse among boys.•Select OPEs may be differentially associated with body size in children and adults.
PDF
