There is an ongoing discussion whether floods occur more frequently today than in the past, and whether they will increase in number and magnitude in the future. To explore this issue in Sweden, we ...merged observed time series for the past century from 69 gauging sites throughout the country (450 000 km2) with high-resolution dynamic model projections of the upcoming century. The results show that the changes in annual maximum daily flows in Sweden oscillate between dry and wet periods but exhibit no significant trend over the past 100 years. Temperature was found to be the strongest climate driver of changes in river high flows, which are related primarily to snowmelt in Sweden. Annual daily high flows may decrease by on average -1% per decade in the future, mainly due to lower peaks from snowmelt in the spring (-2% per decade) as a result of higher temperatures and a shorter snow season. In contrast, autumn flows may increase by 3% per decade due to more intense rainfall. This indicates a shift in flood-generating processes in the future, with greater influence of rain-fed floods. Changes in climate may have a more significant impact on some specific rivers than on the average for the whole country. Our results suggest that the temporal pattern in future daily high flow in some catchments will shift in time, with spring floods in the northern-central part of Sweden occurring about 1 month earlier than today. High flows in the southern part of the country may become more frequent. Moreover, the current boundary between snow-driven floods in northern-central Sweden and rain-driven floods in the south may move toward higher latitudes due to less snow accumulation in the south and at low altitudes. The findings also indicate a tendency in observations toward the modeled projections for timing of daily high flows over the last 25 years. Uncertainties related to both the observed data and the complex model chain of climate impact assessments in hydrology are discussed.
River flow is mainly controlled by climate, physiography and regulations, but their relative importance over large landmasses is poorly understood. Here we show from computational modelling that ...hydropower regulation is a key driver of flow regime change in snow-dominated regions and is more important than future climate changes. This implies that climate adaptation needs to include regulation schemes. The natural river regime in snowy regions has low flow when snow is stored and a pronounced peak flow when snow is melting. Global warming and hydropower regulation change this temporal pattern similarly, causing less difference in river flow between seasons. We conclude that in snow-fed rivers globally, the future climate change impact on flow regime is minor compared to regulation downstream of large reservoirs, and of similar magnitude over large landmasses. Our study not only highlights the impact of hydropower production but also that river regulation could be turned into a measure for climate adaptation to maintain biodiversity on floodplains under climate change.Global warming and hydropower regulations are major threats to future fresh-water availability and biodiversity. Here, the authors show that their impact on flow regime over a large landmass result in similar changes, but hydropower is more critical locally and may have potential for climate adaptation in floodplains.
Targeted therapies for chronic myeloid leukaemia (CML) are effective, but rarely curative. Patients typically require treatment indefinitely, which gives ample time for drug resistance to evolve. ...Drug resistance issues are one of the main causes of death owing to CML, thus any means of preventing resistance are of importance. Drug rotations, wherein treatment is switched periodically between different drugs are one such option, and have been theorized to delay the onset of resistance. In vitro testing of drug rotation therapy is a first step towards applying it in animal or human trials. We developed a method for testing drug rotation protocols in CML cell lines based around culturing cells with a moderate amount of inhibitors interspersed with washing procedures and drug swaps. Drug rotations of imatinib and ponatinib were evaluated in a CML specific cell line, KCL-22. The growth of KCL-22 cells was initially reduced by a drug rotation, but the cells eventually adapted to the protocol. Our results show that ponatinib in a drug rotation temporarily sensitizes the cells to imatinib, but the effect is short-lived and is eventually lost after a few treatment cycles. Possible explanations for this observation are discussed.
A total of 27 per- and polyfluorinated compounds (PFCs) were determined in both house dust (n
=
10) and indoor air (n
=
10) from selected homes in Catalonia, Spain. Concentrations were found to be ...similar or lower than those previously reported for household microenvironments in other countries. Ten PFCs were detected in all house dust samples. The highest mean concentrations corresponded to perfluorodecanoic acid (PFDA) and perfluorononanoic acid (PFNA), 10.7
ng/g (median: 1.5
ng/g) and 10.4
ng/g (median: 5.4
ng/g), respectively, while the 8:2 fluorotelomer alcohol (FTOH) was the dominating neutral PFC at a concentration of 0.41
ng/g (median: 0.35
ng/g). The indoor air was dominated by the FTOHs, especially the 8:2 FTOH at a mean (median) concentration of 51
pg/m
3 (median: 42
pg/m
3). A limited number of ionic PFCs were also detected in the indoor air samples. Daily intakes of PFCs were estimated for average and worst case scenarios of human exposure from indoor sources. For toddlers, this resulted in average intakes of ∑
ionic PFCs of 4.9
ng/day (0.33
ng/kg
bw/day for a 15
kg toddlers) and ∑
neutral PFCs of 0.072
ng/day (0.005
ng/kg
bw/day) from house dust. For adults, the average daily intakes of dust were 3.6 and 0.053
ng/day (0.05 and 0.001
ng/kg
bw/day for a 70
kg adult) for ∑
ionic and ∑
neutral PFCs, respectively. The average daily inhalation of ∑
neutral PFCs was estimated to be 0.9 and 1.3
ng/day (0.06 and 0.02
ng/kg
bw/day) for toddlers and adults, respectively. For PFOS, the main ionic PFC detected in indoor air samples, the median intakes (based on those samples where PFOS was detected), resulted in indoor exposures of 0.06 and 0.11
ng/day (0.004 and 0.002
ng/kg
bw/day) for toddlers and adults, respectively. Based on previous studies on dietary intake and drinking water consumption, both house dust and indoor air contribute significantly less to PFC exposure within this population.
► A wide range of per- and polyfluorinated compounds (PFCs) were determined in both house dust and indoor air samples. ► Ionic PFCs were dominating in the house dust samples, although at lower concentrations than previously reported. ► For indoor air, the 8:2 telomer alcohol was the major compound detected. ► Daily intakes of PFCs were estimated for mean and worst case scenarios of human exposure from indoor sources. ► House dust and indoor air are of minor importance for the total exposure to PFCs compared to dietary intake.
The population growth rate is an important characteristic of any cell culture. During sustained experiments, the growth rate may vary due to competition or adaptation. For instance, in presence of a ...toxin or a drug, an increasing growth rate indicates that the cells adapt and become resistant. Consequently, time-dependent growth rates are fundamental to follow on the adaptation of cells to a changing evolutionary landscape. However, as there are no tools to calculate the time-dependent growth rate directly by cell counting, it is common to use only end point measurements of growth rather than tracking the growth rate continuously.
We present a computer program for inferring the growth rate over time in suspension cells using nothing but cell counts, which can be measured non-destructively. The program was tested on simulated and experimental data. Changes were observed in the initial and absolute growth rates, betraying resistance and adaptation.
For experiments where adaptation is expected to occur over a longer time, our method provides a means of tracking growth rates using data that is normally collected anyhow for monitoring purposes. The program and its documentation are freely available at https://github.com/Sandalmoth/ratrack under the permissive zlib license.
Human breast milk samples from primipara women from Northern (Tromsø) (
N
=
10) and Southern Norway (Oslo) (
N
=
19) collected in 2000–2001 were analysed with respect to hexachlorobenzene (HCB), ...hexachlorocyclohexane (HCHs), chlordanes (CHLs), DDTs, mirex, toxaphenes (CHBs), polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and hexabromocyclododecane (HBCD). CHBs, PBDEs and HBCD were only analysed in the Tromsø samples. Sum-PCBs and sum-DDTs were the major organochlorines (OCs) (170 and 110
ng
g
−1 lipid weight (lw), respectively). Other OCs were found in levels of approximately 10- to 300-fold lower than sum-PCBs. Overall, the concentrations of OCs followed the decreasing order of PCBs
>
DDTs
>
HCB
>
HCHs
≈
CHLs
>
CHBs
>
mirex. Concentrations of sum-HCHs were significantly higher in breast milk from Oslo compared to Tromsø (
p
<
0.05). The PCB profile was dominated by PCB-153, -138 and -180. The PBDE pattern was dominated by PBDE-47 and PBDE-153. The median level of sum-PBDEs was 4.1
ng
g
−1
lw. PBDE-209 was detected in all analysed samples (median 0.13
ng
g
−1
lw). The estimated daily intake (EDI) for the median (range) of sum mono-
ortho (mo) PCBs
8 was 3.7 (1–9) pg TEQ kg
−1 body weight per day for breast fed infants in Norway. This exceeded the TDI by a factor of 1.8 (1–4) based only on intake of mono-
ortho PCBs. The present study shows that concentrations of OCs in primipara breast milk have decreased 50–60% since 1991, and that this trend is continuing.
Acute myeloid leukaemia (AML) is an aggressive blood cancer. In approximately 30% of the cases, driver mutations in the FLT3 gene are identified. FLT3 inhibitors are used in treatment of such ...patients together with cytotoxic drugs or (in refractory AML) as single agents. Unfortunately, resistance to FLT3 inhibitors limits their efficacy. Resistance is often due to secondary mutations in the gene encoding the molecular target. The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations. In chronic myeloid leukaemia (CML), it has been suggested that rotation between drugs with a different landscape of resistance mutations might postpone the emergence of resistance.
We studied the effect of quizartinib and pexidartinib in AML cell lines that express FLT3 (MOLM-14 and MV4-11). Using a rotation protocol, we further examined whether the emergence of resistance could be postponed. Computational modelling was used to analyse the onset of resistance and suggest which mutations are most likely to occur in a quantitative fashion.
The cells were sensitive to both inhibitors but quickly developed resistance that could be inherited, suggesting a genetic origin. Rotation protocols were not useful to postpone the emergence of resistance, which implies that such protocols, or changing from pexidartinib to quizartinib (or vice-versa) should not be used in patients. The computational modelling led to similar conclusions and suggested that F691L is the most common mutation to occur with quizartinib, and also when both drugs are used in rotation.
AML patients are not likely to benefit from a quizartinib/pexidartinib rotation protocol. A combination of tyrosine kinase inhibitors (with different molecular targets) might be more useful in the future. Development of specific FLT3 inhibitors that are less sensitive to resistance mutations might also lead to a better outcome.
Reproducibility and repeatability of experiments are the fundamental prerequisites that allow researchers to validate results and share hydrological knowledge, experience and expertise in the light ...of global water management problems. Virtual laboratories offer new opportunities to enable these prerequisites since they allow experimenters to share data, tools and pre-defined experimental procedures (i.e. protocols). Here we present the outcomes of a first collaborative numerical experiment undertaken by five different international research groups in a virtual laboratory to address the key issues of reproducibility and repeatability. Moving from the definition of accurate and detailed experimental protocols, a rainfall–runoff model was independently applied to 15 European catchments by the research groups and model results were collectively examined through a web-based discussion. We found that a detailed modelling protocol was crucial to ensure the comparability and reproducibility of the proposed experiment across groups. Our results suggest that sharing comprehensive and precise protocols and running the experiments within a controlled environment (e.g. virtual laboratory) is as fundamental as sharing data and tools for ensuring experiment repeatability and reproducibility across the broad scientific community and thus advancing hydrology in a more coherent way.
Chronic myeloid leukaemia is in principle a treatable malignancy but drug resistance is lowering survival. Recent drug discoveries have opened up new options for drug combinations, which is a concept ...used in other areas for preventing drug resistance. Two of these are (I) Axitinib, which inhibits the T315I mutation of BCR-ABL1, a main source of drug resistance, and (II) Asciminib, which has been developed as an allosteric BCR-ABL1 inhibitor, targeting an entirely different binding site, and as such does not compete for binding with other drugs. These drugs offer new treatment options.
We measured the proliferation of KCL-22 cells exposed to imatinib-dasatinib, imatinib-asciminib and dasatinib-asciminib combinations and calculated combination index graphs for each case. Moreover, using the median-effect equation we calculated how much axitinib can reduce the growth advantage of T315I mutant clones in combination with available drugs. In addition, we calculated how much the total drug burden could be reduced by combinations using asciminib and other drugs, and evaluated which mutations such combinations might be sensitive to.
Asciminib had synergistic interactions with imatinib or dasatinib in KCL-22 cells at high degrees of inhibition. Interestingly, some antagonism between asciminib and the other drugs was present at lower degrees on inhibition. Simulations revealed that asciminib may allow for dose reductions, and its complementary resistance profile could reduce the risk of mutation based resistance. Axitinib, however, had only a minor effect on T315I growth advantage.
Given how asciminib combinations were synergistic in vitro, our modelling suggests that drug combinations involving asciminib should allow for lower total drug doses, and may result in a reduced spectrum of observed resistance mutations. On the other hand, a combination involving axitinib was not shown to be useful in countering drug resistance.
► Summary of methods reported for analytical determination of PFAAs in human milk. ► Discussion of trends in the analysis of human milk and need for future development. ► Presentation of the first ...world-wide proficiency testing of PFAAs in human milk. ► Comparing the accuracy of laboratories in the world-wide proficiency testing of PFAAs.
The review describes trends and precision in analytical methods measuring perfluoroalkyl acids (PFAAs) in human milk e.g., perfluorooctane sulfonic acid (PFOS). A worldwide interlaboratory proficiency test with two human milk samples is reported showing a large inter-laboratory variation. High relative standard deviations (RSDs) for the 20 laboratories for PFOS (38, 49%) and perfluorooctanoic acid (PFOA, 53, 71%) indicates that there is a performance variation in the current data.
Assessing the worldwide effectiveness of declining levels as a result of regulations and bans demands analytical precision and accuracy. The Stockholm Convention aims to reduce human levels by 20%. Assessing such a reduction of PFOS levels in human milk is currently impossible due to analytical difficulties. Crucial for improving precision and accuracy is better control of contamination and achieving higher sensitivity and selectivity in quantitative analysis.
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