Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end joining (NHEJ) pathway required for the repair of DNA double strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. Methods: We evaluated clinicopathological significance of DNA-PKcs protein expression in 1161 tumours and DNA-PKcs mRNA expression in 1950 tumours. We correlated DNA-PKcs to other markers of aggressive phenotypes, DNA repair, apoptosis and cell cycle regulation. Results: Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps<0.05). Absence of BRCA1, low XRCC1/SMUG1/APE1/Polβ were also more likely in low DNA-PKcs expressing tumours (ps<0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer specific survival (BCCS) in univariate and multivariate analysis (ps<0.01). At the mRNA level, low DNA-PKcs was associated with PAM50.Her2 and PAM50.LumA molecular phenotypes (ps<0.01) and poor BCSS. In patients with ER positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Conclusions: Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers

A global analysis of the spatial and temporal variability of usable Landsat observations at the pixel scale

The Landsat program has the longest collection of moderate-resolution satellite imagery, and the data are free to everyone. With the improvements of standardized image products, the flexibility of cloud computing platforms, and the development of time series approaches, it is now possible to conduct global-scale analyses of time series using Landsat data over multiple decades. Efforts in this regard are limited by the density of usable observations. The availability of usable Landsat Tier 1 observations at the scale of individual pixels from the perspective of time series analysis for land change monitoring is remarkably variable both in space (globally) and time (1985–2020), depending most immediately on which sensors were in operation, the technical capabilities of the mission, and the acquisition strategies and objectives of the satellite operators (e.g., USGS, commercial company) and the international ground receiving stations. Additionally, analysis of data density at the pixel scale allows for the integration of quality control data on clouds, cloud shadows, and snow as well as other properties returned from the atmospheric correction process. Maps for different time periods show the effect of excluding observations based on the presence of clouds, cloud shadows, snow, sensor saturation, hazy observations (based on atmospheric opacity), and lack of aerosol optical depth information. Two major discoveries are: 1) that filtering saturated and hazy pixels is helpful to reduce noise in the time series, although the impact may vary across different continents; 2) the atmospheric opacity band needs to be used with caution because many images are removed when no value is given in this band, when many of those observations are usable. The results provide guidance on when and where time series analysis is feasible, which will benefit many users of Landsat data.University of Connecticut; National Aeronautics and Space Administration; 80NSSC20K0022 - NASA; 20-DG-11132762-017 - Department of Agriculture/Forest Service; G12PC00070 - Department of the Interior/U.S. Geological SurveyPublished versio

Algal genomes reveal evolutionary mosaicism and the fate of nucleomorphs

Cryptophyte and chlorarachniophyte algae are transitional forms in the widespread secondary endosymbiotic acquisition of photosynthesis by engulfment of eukaryotic algae. Unlike most secondary plastid-bearing algae, miniaturized versions of the endosymbiont nuclei (nucleomorphs) persist in cryptophytes and chlorarachniophytes. To determine why, and to address other fundamental questions about eukaryote–eukaryote endosymbiosis, we sequenced the nuclear genomes of the cryptophyte Guillardia theta and the chlorarachniophyte Bigelowiella natans. Both genomes have \u3e21,000 protein genes and are intron rich, and B. natans exhibits unprecedented alternative splicing for a single-celled organism. Phylogenomic analyses and subcellular targeting predictions reveal extensive genetic and biochemical mosaicism, with both host- and endosymbiont-derived genes servicing the mitochondrion, the host cell cytosol, the plastid and the remnant endosymbiont cytosol of both algae. Mitochondrion-to-nucleus gene transfer still occurs in both organisms but plastid-to-nucleus and nucleomorph-to-nucleus transfers do not, which explains why a small residue of essential genes remains locked in each nucleomorph

CLOVER (CLOstridium difficile Vaccine Efficacy Trial) study: A phase 3, randomized trial investigating the efficacy and safety of a detoxified toxin A/B vaccine in adults 50 years and older at increased risk of Clostridioides difficile infection

BACKGROUND: Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention. METHODS: This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N = 17 535) to receive 3 PF-06425090 or placebo doses (0, 1, and 6 months). Primary end points were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary end points), and antibiotic use (post hoc analysis) PD3 were evaluated. Tolerability and safety were assessed. RESULTS: The primary end point was not met (17 PF-06425090 and 25 placebo recipients had first CDI episode ≥14 days PD3 [vaccine efficacy (VE) = 31.0% (96.4% confidence interval [CI], -38.7% to 66.6%)]; 24 PF-06425090 and 34 placebo recipients had first CDI episode ≥14 days PD2 [VE = 28.6% (96.4% CI, -28.4% to 61.0%)]. Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days; 2-sided nominal P = .02). Of participants with first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post hoc analysis estimated VE = 100%; 95% CI, 59.6% to 100.0%) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE = 100%; 95% CI, 54.8% to 100.0%). Local reactions were more frequent in PF-06425090 recipients, and systemic events were generally similar between groups; most were mild to moderate. Adverse event rates were similar between groups. CONCLUSIONS: Three PF-06425090 doses were safe and well tolerated. Although the primary end point was not met, PF-06425090 reduced symptom duration, CDI that required medical attention, and CDI-directed antibiotic treatment, highlighting its potential to reduce CDI-associated healthcare burden. CLINICAL TRIALS REGISTRATION: NCT03090191

Importance of heterogeneity in Porhyromonas gingivalis lipopolysaccharide lipid A in tissue specific inflammatory signaling

Lipopolysaccharide (LPS) of Porphyromonas gingivalis exists in at least two known forms, O-LPS and A-LPS. A-LPS shows heterogeneity in which two isoforms designated LPS1435/1449 and LPS1690 appear responsible for tissue specific immune signalingpathways activation and increased virulence. The modification of lipid A to tetra-acylated1435/1449 and/or penta-acylated1690 fatty acids indicates poor growth conditions and bioavailability of hemin. Hemin protects P. gingivalis from serum resistance and the lipid A serves as a site for its binding. The LPS1435/1449 and LPS1690 isoforms can produce opposite effects on the human Toll-like receptors (TLR) TLR 2 and TLR 4 activation. This enabless P. gingivalis to select the conditions for its entry, survival and that of its co-habiting species in the host, orchestrating its virulence to control innate immune pathway activation and biofilm dysbiosis. Thismini review describes a number of effects that LPS1435/1449 and LPS1690 can exert on the host tissues such as deregulation of the innate immune system, subversion of host cell autophagy, regulation of outer membrane vesicle production and adverse effects on pregnancy outcome. The ability to change its LPS1435/1449 and/or LPS1690 composition may enables P. gingivalis to paralyze local pro-inflammatory cytokine production, thereby gaining access to its primary location in periodontal tissue

Out of the ashes: Ecological resilience to extreme wildfire, prescribed burns, and indigenous burning in ecosystems

Until Euro-American colonization, Indigenous people used fire to modify eco-cultural systems, developing robust Traditional Ecological Knowledge (TEK). Since 1980, wildfire activity has increased due to fire suppression and climate change. In 2017, in Waterton Lakes National Park, AB, the Kenow wildfire burned 19,303 ha, exhibiting extreme fire behavior. It affected forests and the Eskerine Complex, a native-grass prairie treated with prescribed burns since 2006 to reduce aspen (Populus tremuloides) encroachment linked to fire suppression and bison (Bison bison bison) extirpation. One year post-fire, the Kenow wildfire caused vigorous aspen sprouting, altered stand structure to an early-seral state and changed dominant land cover from grass to mineral soil. It did not change aspen-cover extent or cause non-native grass eruption, but it reduced native-grass diversity and produced more pronounced shifts in ecosystem structure and biodiversity than the prescribed burn. The 2017 Kenow wildfire and prescribed burns differed in phenological timing, scale, and severity. Prescribed burns occurred in late spring, with little fuel available, while the Kenow wildfire occurred in late summer, with abundant fuel—amplifying the difference in severity. As in other climate-limited fire regimes, prescribed burns treatments did not mitigate the severity of the Kenow wildfire. To more effectively reduce the extent of aspen cover, future prescribed burns in this system could be applied in the late season. Incorporating TEK in adaptive co-management can help create ecosystems more resilient to fire and pervasive stressors such as invasive plants, provided one contextualizes current conditions and how they differ from historical conditions

Meta-analysis of genome-wide association studies for cattle stature identifies common genes that regulate body size in mammals

Stature is affected by many polymorphisms of small effect in humans1. In contrast, variation in dogs, even within breeds, has been suggested to be largely due to variants in a small number of genes2,3. Here we use data from cattle to compare the genetic architecture of stature to those in humans and dogs. We conducted a meta-analysis for stature using 58,265 cattle from 17 populations with 25.4 million imputed whole-genome sequence variants. Results showed that the genetic architecture of stature in cattle is similar to that in humans, as the lead variants in 163 significantly associated genomic regions (P \u3c 5 × 10−8) explained at most 13.8% of the phenotypic variance. Most of these variants were noncoding, including variants that were also expression quantitative trait loci (eQTLs) and in ChIP–seq peaks. There was significant overlap in loci for stature with humans and dogs, suggesting that a set of common genes regulates body size in mammals

Trends in protected area representation of biodiversity and ecosystem services in five tropical countries

In late 2020, governments will set the next decade of conservation targets under the UN Convention on Biological Diversity. Setting new targets requires understanding how well national protected area (PA) networks are spatially representing important areas for biodiversity and ecosystem services. We analyzed the representation of biodiversity priority areas (BPAs), forests, forest carbon stocks, non-timber forest products (NTFPs), and freshwater ecosystem services (FES) within terrestrial PA systems in Cambodia, Guyana, Liberia, Madagascar, and Suriname in 2003 and 2017. Four of the countries (all except Suriname) expanded their terrestrial PA networks during the study period. In all five countries, we found that PAs represented BPAs, forests, and forest carbon stocks relatively well, based on their size. PAs did not represent NTFPs and FES particularly well, except in Cambodia where FES were well represented. Countries that expanded PA networks during the study period also increased representation of forests, BPAs, and ES; in Cambodia and Madagascar these increases were substantial. Representation could be improved across all five countries, however, indicating that additional efforts are needed to safeguard biodiversity and ecosystem benefits to people in these countries

Disgust trumps lust:women’s disgust and attraction towards men is unaffected by sexual arousal

Mating is a double-edged sword. It can have great adaptive benefits, but also high costs, depending on the mate. Disgust is an avoidance reaction that serves the function of discouraging costly mating decisions, for example if the risk of pathogen transmission is high. It should, however, be temporarily inhibited in order to enable potentially adaptive mating. We therefore tested the hypothesis that sexual arousal inhibits disgust if a partner is attractive, but not if he is unattractive or shows signs of disease. In an online experiment, women rated their disgust towards anticipated behaviors with men depicted on photographs. Participants did so in a sexually aroused state and in a control state. The faces varied in attractiveness and the presence of disease cues (blemishes). We found that disease cues and attractiveness, but not sexual arousal, influenced disgust. The results suggest that women feel disgust at sexual contact with unattractive or diseased men independently of their sexual arousal