Background
The increasing production of nanoplastics and the fragmentation of microplastics into smaller particles suggest a plausible yet unclear hazard in the natural environment, such as soil. We ...investigated the short-term effects (28 days) of polystyrene nanoparticles (PS-NPs) on the activity and biomass of soil microbiota, and the functional diversity of soil enzymes at environmental relevant low levels in an incubation experiment.
Results
Our results showed a significant decrease in microbial biomass in treatments of 100 and 1000 ng PS-NP g
−1
DM throughout the incubation period. Dehydrogenase activity and activities of enzymes involved in
N
-(leucine-aminopeptidase),
P
-(alkaline-phosphatase), and C-(β-glucosidase and cellobiohydrolase) cycles in the soil were significantly reduced at day 28 suggesting a broad and detrimental impact of PS-NPs on soil microbiota and enzymes. Leucine-aminopeptidase and alkaline-phosphatase activities tended to decrease consistently, while β-glucosidase and cellobiohydrolase activities increased at high concentrations (e.g., PS-NP-1000) in the beginning of the incubation period, e.g., at day 1. On the other hand, basal respiration and metabolic quotient increased with increasing PS-NP application rate throughout the incubation period possibly due to increased cell death that caused substrate-induced respiration (cryptic growth).
Conclusions
We herewith demonstrated for the first time the potential antimicrobial activity of PS-NPs in soil, and this may serve as an important resource in environmental risk assessment of PS-NPs in the soil environment.
•Investigator-assessed PFS data in the ALEX study are now mature (53% of events in the alectinib arm).•Alectinib significantly prolonged PFS vs crizotinib (stratified HR 0.43, 95% CI 0.32–0.58; ...median 34.8 vs 10.9 months).•OS data are immature (37% of events); median NR alectinib vs 57.4 months crizotinib (stratified HR 0.67, 95% CI 0.46–0.98).•5-year OS rate of 62.5% with alectinib and 45.5% with crizotinib.•Median treatment duration was longer with alectinib (28.1 vs 10.8 months crizotinib), with no new safety signals seen.
The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019).
Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety.
Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32–0.58; median PFS 34.8 versus 10.9 months crizotinib. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46–0.98). The 5-year OS rate was 62.5% (95% CI 54.3–70.8) with alectinib and 45.5% (95% CI 33.6–57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline HR 0.58 (95% CI 0.34–1.00) and those without HR 0.76 (95% CI 0.45–1.26). Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed.
Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC.
NCT02075840.
Homology-directed gene editing of hematopoietic stem and progenitor cells (HSPCs) is a promising strategy for the treatment of inherited blood disorders, obviating many of the limitations associated ...with viral vector-mediated gene therapies. The use of CRISPR/Cas9 or other programmable nucleases and improved methods of homology template delivery have enabled precise ex vivo gene editing. These transformative advances have also highlighted technical challenges to achieve high-efficiency gene editing in HSPCs for therapeutic applications. In this review, we discuss recent pre-clinical investigations utilizing homology-mediated gene editing in HSPCs and highlight various strategies to improve editing efficiency in these cells.
NaNbO3 powders from different processing routes and various near equimolar concentrations of metal ions were sintered to ceramics and investigated concerning their structural and electric properties. ...The particle sizes obtained from two different conventional solid state reactions and one solvent – based route were in the range of 40 nm - 10 μm and the variation of precursor composition covered 48–52 mol% Na. Sintering temperatures were defined by the deviation from the equimolar composition between 950 and 1375 °C, which is due to the coexistence of second phases Na3NbO4, Na2Nb4O11 and NaNb3O8. Small particle sizes (40 nm–3 μm) on deviation from equimolar composition resulted in higher relative densities at lower sintering temperatures. The coexistence of second phases influences structural and electric characteristics. The former were investigated by X-ray Diffraction (XRD) for phase analysis, Scanning Electron Microscopy (SEM) for defining grain sizes and Energy-Dispersive X-ray (EDX) spectroscopy for deciding the elemental composition. The impact on electrical conductivity and dielectric properties are examined by impedance spectroscopy and the resulting d33 coefficients of 15–29 pC/N are measured by Berlincourt method.
•Decisive role of second phases of pseudobinary phase diagram Na2O/Nb2O5 in NaNbO3 ceramics is elucidated.•Representative precursor compositions chosen.•Small deviations from equimolar composition result in reduction of over 400 K for sintering temperature.•Even for “stoichiometric” samples, formation of second phases is a vital aspect due to Na2O volatilization.•Partly superior dielectric and piezoelectric properties for non-equimolar samples at lower processing temperatures.
The assessment of valvular pathologies in multiple valvular heart disease by echocardiography remains challenging. Data on echocardiographic assessment—especially in patients with combined aortic and ...mitral regurgitation—are rare in the literature. The proposed integrative approach using semi-quantitative parameters to grade the severity of regurgitation often yields inconsistent findings and results in misinterpretation. Therefore, this proposal aims to focus on a practical systematic echocardiographic analysis to understand the pathophysiology and hemodynamics in patients with combined aortic and mitral regurgitation. The quantitative approach of grading the regurgitant severity of each compound might be helpful in elucidating the scenario in combined aortic and mitral regurgitation. To this end, both the individual regurgitant fraction of each valve and the total regurgitant fraction of both valves must be determined. This work also outlines the methodological issues and limitations of the quantitative approach by echocardiography. Finally, we present a proposal that enables verifiable assessment of regurgitant fractions. The overall interpretation of echocardiographic results includes the symptomatology of patients with combined aortic and mitral regurgitation and the individual treatment options with respect to their individual risk. In summary, a reproducible, verifiable, and transparent in-depth echocardiographic investigation might ensure consistent hemodynamic plausibility of the quantitative results in patients with combined aortic and mitral regurgitation.
Graphic abstract
The quantitative approach to assess LV volumes in combined AR and MR patients: explanation and algorithm of how to determine the relevant target parameters. LVSV
eff
—effective left ventricular (LV) stroke volume, LVSV
forward
—forward LV stroke volume through the aortic valve (AV), LVSV
tot
—total LV stroke volume, RegVol
AR
—regurgitant volume through the AV, RegVol
MR
—regurgitant volume through the mitral valve (MV), LV
filling volume
= LV
MV
-Inflow − transmitral LV inflow, LVOT—left ventricular outflow tract, RF
AR
—regurgitant fraction of aortic regurgitation (AR), RF
MR
—regurgitant fraction of mitral regurgitation (MR), RVSV
eff
—effective right ventricular (RV) stroke volume, RVSV
forward
—forward RV stroke volume through the pulmonary valve, RVSV
tot
—total RV stroke volume.
Gnathostomiasis is a foodborne parasitic zoonosis known to be endemic in Southeast Asia, India, Central and South America, with recent cases reported in Zambia, Botswana and South Africa. We report a ...case of gnathostomiasis acquired in Madagascar and alert clinicians of the emerging risk in southern Africa.
This paper investigates the utility of the Lomb-Scargle periodogram for the analysis of biological rhythms. This method is particularly suited to detect periodic components in unequally sampled ...time-series and data sets with missing values, but restricts all calculations to actually measured values. The Lomb-Scargle method was tested on both real and simulated time-series with even and uneven sampling, and compared to a standard method in biomedical rhythm research, the Chi-square periodogram. Results indicate that the Lomb-Scargle algorithm shows a clearly better detection efficiency and accuracy in the presence of noise, and avoids possible bias or erroneous results that may arise from replacement of missing data by interpolation techniques. Hence, the Lomb-Scargle periodogram may serve as a useful method for the study of biological rhythms, especially when applied to telemetrical or observational time-series obtained from free-living animals, i.e., data sets that notoriously lack points.
Summary
Background
The ribosomal protein S6 is part of the translation machinery and is activated by phosphorylation via the mammalian target of rapamycin pathway, which is activated in psoriatic ...skin.
Objectives
To investigate which S6 sites are phosphorylated in psoriasis and atopic dermatitis (AD), and to study whether S6 phosphorylation is associated with inflammation and/or keratinocyte hyperproliferation.
Methods
Healthy skin and skin lesions of patients with psoriasis and AD were investigated by immunostaining using antibodies that stain proliferating cells, leucocytes and distinct phosphorylated sites of S6.
Results
All psoriasis and AD lesions revealed abnormal S6 phosphorylation in the epidermis. The extent of S6 phosphorylation was diverse, generally stronger in psoriasis and correlated, in both diseases, with inflammation. S6 showed differential phosphorylation in distinct epidermal layers, which was most pronounced in hyperproliferative regions.
Conclusions
Differential S6 phosphorylation may have a role in abnormal keratinocyte proliferation/differentiation.
What's already known about this topic?
Phosphorylation of ribosomal protein S6 is important for the initiation of translation.
S6 becomes phosphorylated via the mammalian target of rapamycin pathway, which is activated in psoriatic skin.
What does this study add?
In psoriasis and atopic dermatitis, S6 phosphorylation is associated with inflammation and epidermal hyperproliferation.
S6 is differentially phosphorylated in distinct layers of the diseased epidermis, which may impact on the proliferation/differentiation of keratinocytes.
Edible dormice (Glis glis) reproduce in years with beech mast seeding, but entire populations may skip reproduction in years when tree seeds, a major food resource of this small hibernator, are ...absent. We tested the hypothesis that the year-to-year variability in reproductive effort caused by this breeding strategy should lead to detectable differences in yearly survival rates. Therefore, we analyzed capture-recapture data from animals occupying nest boxes, collected over nine years at two study sites in Germany. Among fully grown adults (aged two years or older), survival probabilities were significantly lower (0.32 ± 0.04) after reproductive years (n = 5) compared to years (n = 4) with absent or below-average reproduction (0.58 ± 0.07) on both study sites. This trade-off between reproduction and subsequent survival was observed in both females and males and appears to be a relatively rare case in which costs of reproduction in terms of longevity are detectable at the population level. Effects of reproduction on survival were less pronounced when yearlings (with a generally lower reproductive effort) were included and were more distinct in a suboptimal habitat. Of those females breeding in nest boxes, 96.5% had only one or two litters within the study period. Considering these and previously published results, including a report of extremely high mean longevities (9-12 years) of dormice in a habitat with infrequent mast seeding, we conclude that edible dormice flexibly adjust life history tactics to local mast patterns. Long stretches of mast failures can in fact lead to relative semelparity, i.e., a strategy in which dormice "sit tight" for several years until environmental conditions are favorable for reproduction.
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