Molecular profiling of NSCLC is essential for optimising treatment decisions, but often incomplete. We assessed the efficacy of protocolised molecular profiling in the current standard-of-care (SoC) ...in a prospective observational study in the Netherlands and measured the effect of providing standardised diagnostic procedures. We also explored the potential of plasma-based molecular profiling in the primary diagnostic setting. This multi-centre prospective study was designed to explore the performance of current clinical practice during the run-in phase using local SoC tissue profiling procedures. The subsequent phase was designed to investigate the extent to which comprehensive molecular profiling (CMP) can be maximized by protocolising tumour profiling. Successful molecular profiling was defined as completion of at least EGFR and ALK testing. Additionally, PD-L1 tumour proportions scores were explored. Lastly, the additional value of centralised plasma-based testing for EGFR and KRAS mutations using droplet digital PCR was evaluated. Total accrual was 878 patients, 22.0% had squamous cell carcinoma and 78.0% had non-squamous NSCLC. Stage I-III was seen in 54.0%, stage IV in 46.0%. Profiling of EGFR and ALK was performed in 69.9% of 136 patients included in the run-in phase, significantly more than real-world data estimates of 55% (p<0.001). Protocolised molecular profiling increased the rate to 77.0% (p = 0.049). EGFR and ALK profiling rates increased from 77.9% to 82.1% in non-squamous NSCLC and from 43.8% to 57.5% in squamous NSCLC. Plasma-based testing was feasible in 98.4% and identified oncogenic driver mutations in 7.1% of patients for whom tissue profiling was unfeasible. This study shows a high success rate of tissue-based molecular profiling that was significantly improved by a protocolised approach. Tissue-based profiling remains unfeasible for a substantial proportion of patients. Combined analysis of tumour tissue and circulating tumour DNA is a promising approach to allow adequate molecular profiling of more patients.
An aerobic granular sludge (AGS) reactor was run for 280 days to study the competition between Phosphate and Glycogen Accumulating Organisms (PAOs and GAOs) at high temperatures. Numerous researches ...have proven that in suspended sludge systems PAOs are outcompeted by GAOs at higher temperatures. In the following study a reactor was operated at 30 °C in which the P-removal efficiency declined from 79% to 32% after 69 days of operation when biomass removal for sludge retention time (SRT) control was established by effluent withdrawal. In a second attempt at 24 °C, efficiency of P-removal remained on average at 71 ± 5% for 76 days. Samples taken from different depths of the sludge bed analysed using
Fluorescent in situ hybridization (FISH) microscopy techniques revealed a distinctive microbial community structure: bottom granules contained considerably more
Accumulibacter (PAOs) compared to top granules that were dominated by
Competibacter (GAOs). In a third phase the SRT was controlled by discharging biomass exclusively from the top of the sludge bed. The application of this method increased the P-removal efficiency up to 100% for 88 days at 30 °C. Granules selected near the bottom of the sludge bed increased in volume, density and overall ash content; resulting in significantly higher settling velocities. With the removal of exclusively bottom biomass in phase four, P-removal efficiency decreased to 36% within 3 weeks. This study shows that biomass segregation in aerobic granular sludge systems offers an extra possibility to influence microbial competition in order to obtain a desired population.
► Segregation of granular biomass occurred along the settled sludge bed. ► PAOs were prevalent at the bottom, whereas GAOs dominated at the top of the sludge bed. ► Removal of GAO dominated sludge resulted in 100% P-removal efficiencies at 30 °C. ► Selective sludge withdrawal can be used to engineer the microbial population in the reactor.
The swine-origin A(H1N1) influenza virus that has emerged in humans in early 2009 has raised concerns about pandemic developments. In a ferret pathogenesis and transmission model, the 2009 A(H1N1) ...influenza virus was found to be more pathogenic than a seasonal A(H1N1) virus, with more extensive virus replication occurring in the respiratory tract. Replication of seasonal A(H1N1) virus was confined to the nasal cavity of ferrets, but the 2009 A(H1N1) influenza virus also replicated in the trachea, bronchi, and bronchioles. Virus shedding was more abundant from the upper respiratory tract for 2009 A(H1N1) influenza virus as compared with seasonal virus, and transmission via aerosol or respiratory droplets was equally efficient. These data suggest that the 2009 A(H1N1) influenza virus has the ability to persist in the human population, potentially with more severe clinical consequences.
Environmental conditions during incubation such as temperature and O₂ concentration affect embryo development that may be associated with modifications in nutrient partitioning. Additionally, ...prenatal conditions can affect postnatal nutrient utilization. Using broiler chicken embryos, we studied the effects of eggshell temperature (EST; 37.8 or 38.9°C) and O₂ (17, 21, or 25%) applied from d 7 until 19 of incubation in a 2 x 3 factorial design. Effects of these factors on embryonic survival, development, and nutrient utilization were assessed in the pre- and posthatch period. High EST reduced yolk-free body mass compared with normal EST (36.1 vs. 37.7 g), possibly through reduced incubation duration (479 vs. 487 h) and lower efficiency of protein utilization for growth (83.6 vs. 86.8%). Increasing O₂ increased yolk-free body mass (from 35.7 to 38.3 g) at 12 h after emergence from the eggshell, but differences were larger between the low and normal O₂ than between the normal and high O₂. This might be due to the lower efficiency of nutrient utilization for growth at low O₂. However, the effects of O₂ that were found at 12 h were less pronounced at 48 h posthatch. When O₂ was shifted to 21% for all treatments at d 19 of incubation, embryos incubated at low O₂ used nutrients more efficiently than those incubated at normal or high O₂. An additional negative effect on survival and chick development occurred when embryos were exposed to a combination of high EST and low O₂. Possible explanations include reduced nutrient availability for hatching, decreased body development to fulfill the energy-demanding hatching process, and higher incidence of malpositions. In conclusion, EST and O₂ during incubation affect nutrient utilization for growth, which may explain differences in survival and development. Embryos raised under suboptimal environmental conditions in the prenatal period may develop adaptive mechanisms that still continue in the posthatch period.
•We retrieved 44 publications and 199 observations comparing continuous cereal with grain legume-cereal rotation in SSA.•Cereal after legume yielded on average 0.49t grain ha−1 or 41% more than ...continuous cereal.•Sustained residual benefits of legumes with large N applications indicate the importance of non-N effects.•Relevant non-N effects include improved P availability, changes in SOM, and in pest, disease and striga pressure.
We conducted a systematic review of literature on the residual effects of grain legumes in cereal-based systems of sub-Saharan Africa (SSA) to quantify the magnitude and variability of rotational effects, to explore the importance of environmental and management factors in determining variability and to evaluate the evidence of the different mechanisms that explain rotational effects. We retrieved 44 unique publications providing 199 observations comparing continuous cereal performance with that of a grain legume-cereal rotation. The overall mean yield increase of 0.49t grainha−1, equal to an increase of 41% of the continuous cereal yield, is highly significant, but the variability in residual effects is large. Effects were more pronounced in southern Africa, the highlands of East Africa and the Guinea savannah, and less in the humid forest/derived savannah of West Africa and the Sudano-Sahelian zone. Maize showed stronger yield responses after a legume than millet and sorghum. Agro-ecological zone and cereal type were however confounded. All grain legume types significantly improved cereal yields, with stronger residual effects observed after soybean and groundnut than after cowpea. Fertiliser N application to cereals reduces the residual effects of legumes, but the response at 60–120kgNha−1 still equalled 0.32tha−1 or 59% of the response when no N is applied. The sustained benefits with large N applications indicate the importance of non-N effects. While mechanisms for improved soil P availability after grain legumes have been studied in some detail, it remains uncertain how important these are in farmers’ fields. Grain legumes are unlikely to have a major influence on the availability of nutrients other than N and P, or on soil pH. Beneficial impacts of grain legumes on soil organic matter content can occur if legumes contribute to a greater overall cropping productivity, but studies generally report no such impacts. Evidence of impacts of grain legumes on weeds is limited to striga. Studies on the impacts on nematode pressure in cereals are inconclusive, probably because legumes act as a host for some of the key nematode genera that harm maize. The impact on the pressure of other pests and diseases in cereals is probably important, but evidence on this from SSA is lacking. Future research on N2-fixation by grain legumes and residual N benefits should focus on explaining the wide variability observed among sites. There is a clear need for more detailed mechanistic studies to assess the occurrence and relevance of non-N effects of grain legumes, particularly in relation to common pests and diseases in cereals.
Susceptibility of rabbits to SARS-CoV-2 Mykytyn, Anna Z.; Lamers, Mart M.; Okba, Nisreen M. A. ...
Emerging microbes & infections,
01/2021, Letnik:
10, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Transmission of severe acute respiratory coronavirus-2 (SARS-CoV-2) between livestock and humans is a potential public health concern. We demonstrate the susceptibility of rabbits to SARS-CoV-2, ...which excrete infectious virus from the nose and throat upon experimental inoculation. Therefore, investigations on the presence of SARS-CoV-2 in farmed rabbits should be considered.
CKD: A Call for an Age-Adapted Definition Delanaye, Pierre; Jager, Kitty J; Bökenkamp, Arend ...
Journal of the American Society of Nephrology,
10/2019, Letnik:
30, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m
...This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m
, whereas in elderly people it is increased at levels <45 ml/min per 1.73 m
Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.
Orthology is a central tenet of comparative genomics and ortholog identification is instrumental to protein function prediction. Major advances have been made to determine orthology relations among a ...set of homologous proteins. However, they depend on the comparison of individual sequences and do not take into account divergent orthologs.
We have developed an iterative orthology prediction method, Ortho-Profile, that uses reciprocal best hits at the level of sequence profiles to infer orthology. It increases ortholog detection by 20% compared to sequence-to-sequence comparisons. Ortho-Profile predicts 598 human orthologs of mitochondrial proteins from Saccharomyces cerevisiae and Schizosaccharomyces pombe with 94% accuracy. Of these, 181 were not known to localize to mitochondria in mammals. Among the predictions of the Ortho-Profile method are 11 human cytochrome c oxidase (COX) assembly proteins that are implicated in mitochondrial function and disease. Their co-expression patterns, experimentally verified subcellular localization, and co-purification with human COX-associated proteins support these predictions. For the human gene C12orf62, the ortholog of S. cerevisiae COX14, we specifically confirm its role in negative regulation of the translation of cytochrome c oxidase.
Divergent homologs can often only be detected by comparing sequence profiles and profile-based hidden Markov models. The Ortho-Profile method takes advantage of these techniques in the quest for orthologs.
The mammalian heart is derived from multiple cell lineages; however, our understanding of when and how the diverse cardiac cell types arise is limited. We mapped the origin of the embryonic mouse ...heart at single-cell resolution using a combination of transcriptomic, imaging, and genetic lineage labeling approaches. This mapping provided a transcriptional and anatomic definition of cardiac progenitor types. Furthermore, it revealed a cardiac progenitor pool that is anatomically and transcriptionally distinct from currently known cardiac progenitors. Besides contributing to cardiomyocytes, these cells also represent the earliest progenitor of the epicardium, a source of trophic factors and cells during cardiac development and injury. This study provides detailed insights into the formation of early cardiac cell types, with particular relevance to the development of cell-based cardiac regenerative therapies.
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•p-cresyl sulfate and p-cresyl glucuronide are retained in patients with chronic kidney disease.•Both solutes hamper the functionality of renal efflux transporters.•BCRP is likely ...involved in the urinary excretion of p-cresyl sulfate and p-cresyl glucuronide.•p-cresyl glucuronide induces cell stress in renal tubular cells, while p-cresyl sulfate has no effect.
The uremic solutes p-cresyl sulfate (pCS) and p-cresyl glucuronide (pCG) accumulate in patients with chronic kidney disease (CKD), and might contribute to disease progression. Moreover, retention of these solutes may directly be related to renal tubular function. Here, we investigated the role of the efflux transporters Multidrug Resistance Protein 4 (MRP4) and Breast Cancer Resistance Protein (BCRP) in pCS and pCG excretion, and studied the impact of both solutes on the phenotype of human conditionally immortalized renal proximal tubule epithelial cells (ciPTEC).
Our results show that p-cresol metabolites accumulate during CKD, with a shift from sulfation to glucuronidation upon progression. Moreover, pCS inhibited the activity of MRP4 by 40% and BCRP by 25%, whereas pCG only reduced MRP4 activity by 75%. Moreover, BCRP-mediated transport of both solutes was demonstrated. Exposure of ciPTEC to pCG caused epithelial-to-mesenchymal transition, indicated by increased expression of vimentin and Bcl-2, and diminished E-cadherin. This was associated with altered expression of key tubular transporters.
In conclusion, BCRP is likely involved in the renal excretion of both solutes, and pCG promotes phenotypical changes in ciPTEC, supporting the notion that uremic toxins may be involved in CKD progression by negatively affecting renal tubule cell phenotype and functionality.