Browsing by Subject "SENSITIVITY"
Now showing items 1-20 of 111
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(2022)Empirical evidence demonstrates that lakes and reservoirs are warming across the globe. Consequently, there is an increased need to project future changes in lake thermal structure and resulting changes in lake biogeochemistry in order to plan for the likely impacts. Previous studies of the impacts of climate change on lakes have often relied on a single model forced with limited scenario-driven projections of future climate for a relatively small number of lakes. As a result, our understanding of the effects of climate change on lakes is fragmentary, based on scattered studies using different data sources and modelling protocols, and mainly focused on individual lakes or lake regions. This has precluded identification of the main impacts of climate change on lakes at global and regional scales and has likely contributed to the lack of lake water quality considerations in policy-relevant documents, such as the Assessment Reports of the Intergovernmental Panel on Climate Change (IPCC). Here, we describe a simulation protocol developed by the Lake Sector of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) for simulating climate change impacts on lakes using an ensemble of lake models and climate change scenarios for ISIMIP phases 2 and 3. The protocol prescribes lake simulations driven by climate forcing from gridded observations and different Earth system models under various representative greenhouse gas concentration pathways (RCPs), all consistently bias-corrected on a 0.5 degrees x 0.5 degrees global grid. In ISIMIP phase 2, 11 lake models were forced with these data to project the thermal structure of 62 well-studied lakes where data were available for calibration under historical conditions, and using uncalibrated models for 17 500 lakes defined for all global grid cells containing lakes. In ISIMIP phase 3, this approach was expanded to consider more lakes, more models, and more processes. The ISIMIP Lake Sector is the largest international effort to project future water temperature, thermal structure, and ice phenology of lakes at local and global scales and paves the way for future simulations of the impacts of climate change on water quality and biogeochemistry in lakes.
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(2018)Rapid environmental fluctuations are ubiquitous in the wild, yet majority of experimental studies mostly consider effects of slow fluctuations on organism. To test the evolutionary consequences of fast fluctuations, we conducted nine independent experimental evolution experiments with bacteria. Experimental conditions were same for all species, and we allowed them to evolve either in fluctuating temperature alternating rapidly between 20°C and 40°C or at constant 30°C temperature. After experimental evolution, we tested the performance of the clones in both rapid fluctuation and in constant environments (20°C, 30°C and 40°C). Results from experiments on these nine species were combined meta-analytically. We found that overall the clones evolved in the fluctuating environment had evolved better efficiency in tolerating fluctuations (i.e., they had higher yield in fluctuating conditions) than the clones evolved in the constant environment. However, we did not find any evidence that fluctuation-adapted clones would have evolved better tolerance to any measured constant environments (20°C, 30°C, and 40°C). Our results back up recent empirical findings reporting that it is hard to predict adaptations to fast fluctuations using tolerance curves.
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(2022)Predicting areas of severe biomass loss and increased N leaching risk under climate change is critical for applying appropriate adaptation measures to support more sustainable agricultural systems. The frequency of annual severe biomass loss for winter wheat and its coincidence with an increase in N leaching in a temperate region in Germany was estimated including the error from using soil and climate input data at coarser spatial scales, using the soil-crop model CoupModel. We ran the model for a reference period (1980–2010) and used climate data predicted by four climate model(s) for the Representative Concentration Pathways (RCP) 2.6, 4.5 and 8.5. The annual median biomass estimations showed that for the period 2070–2100, under the RCP8.5 scenario, the entire region would suffer from severe biomass loss almost every year. Annual incidence of severe biomass loss and increased N leaching was predicted to increase from RCP4.5 to the 8.5 scenario. During 2070–2100 for RCP8.5, in more than half of the years an area of 95% of the region was projected to suffer from both severe biomass loss and increased N leaching. The SPEI3 predicted a range of 32 (P3 RCP4.5) to 55% (P3 RCP8.5) of the severe biomass loss episodes simulated in the climate change scenarios. The simulations predicted more severe biomass losses than by the SPEI index which indicates that soil water deficits are important in determining crop losses in future climate scenarios. There was a risk of overestimating the area where “no severe biomass loss + increased N leaching” occurred when using coarser aggregated input data. In contrast, underestimation of situations where “severe biomass loss + increased N leaching” occurred when using coarser aggregated input data. Larger annual differences in biomass estimations compared to the finest resolution of input data occurred when aggregating climate input data rather than soil data. The differences were even larger when aggregating both soil and climate input data. In half of the region, biomass could be erroneously estimated in a single year by more than 40% if using soil and climate coarser input data. The results suggest that a higher spatial resolution of especially climate input data would be needed to predict reliably annual estimates of severe biomass loss and N leaching under climate change scenarios.
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(2019)A new heated capillary photoionization (CPI) ion source design was developed to photoionize analytes inside a transfer capillary between a gas chromatograph (GC) and a mass spectrometer (MS). The CPI setup included a wide, oval-shaped vacuum-ultraviolet (VUV) transparent magnesium fluoride (MgF2) window to maximize photoionization efficiency and thus sensitivity. The source contained a nitrogen housing around the ionization chamber inlet to avoid undesirable hydrolysis and oxidation reactions with ambient air and to maximize the proportion of formed molecular radical cations of analytes. The feasibility of the ion source was studied by analyzing 18 endogenous steroids in urine as their trimethylsilyl (TMS) derivatives with gas chromatography-tandem mass spectrometry (GC-MS/MS). The method was validated and applied to human urine samples. To our best knowledge, this is the first time that a capillary photoionization ion source has been applied for quantitative analysis of biological samples. The GC-CPI-MS/MS method showed good chromatographic resolution (peak half-widths between 3.1 to 5.3 s), acceptable linearity (coefficient of determination between 0.981 to 0.996), and repeatability (relative standard deviation (RSD%) between 5 to 18%). Limits of detection (LOD) were between 2 to 100 pg mL(-1) and limits of quantitation (LOQ) were between 0.05 to 2 ng mL(-1). In total, 15 steroids were quantified either as a free steroid or glucuronide conjugate from the urine of volunteers. The new CPI source design showed excellent sensitivity for analysis of steroids in complex biological samples. (C) 2019 Elsevier B.V. All rights reserved.
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(2019)This study assesses the change in anthropogenic aerosol forcing from the mid-1970s to the mid-2000s. Both decades had similar global-mean anthropogenic aerosol optical depths but substantially different global distributions. For both years, we quantify (i) the forcing spread due to model-internal variability and (ii) the forcing spread among models. Our assessment is based on new ensembles of atmosphere-only simulations with five state-of-the-art Earth system models. Four of these models will be used in the sixth Coupled Model Intercomparison Project (CMIP6; Eyring et al., 2016). Here, the complexity of the anthropogenic aerosol has been reduced in the participating models. In all our simulations, we prescribe the same patterns of the anthropogenic aerosol optical properties and associated effects on the cloud droplet number concentration. We calculate the instantaneous radiative forcing (RF) and the effective radiative forcing (ERF). Their difference defines the net contribution from rapid adjustments. Our simulations show a model spread in ERF from -0.4 to -0.9 W m(-2). The standard deviation in annual ERF is 0.3 W m(-2), based on 180 individual estimates from each participating model. This result implies that identifying the model spread in ERF due to systematic differences requires averaging over a sufficiently large number of years. Moreover, we find almost identical ERFs for the mid-1970s and mid-2000s for individual models, although there are major model differences in natural aerosols and clouds. The model-ensemble mean ERF is -0.54 W m(-2) for the pre-industrial era to the mid-1970s and -0.59 W m(-2) for the pre-industrial era to the mid-2000s. Our result suggests that comparing ERF changes between two observable periods rather than absolute magnitudes relative to a poorly constrained pre-industrial state might provide a better test for a model's ability to represent transient climate changes.
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(2016)Droughts can have an impact on forest functioning and production, and even lead to tree mortality. However, drought is an elusive phenomenon that is difficult to quantify and define universally. In this study, we assessed the performance of a set of indicators that have been used to describe drought conditions in the summer months (June, July, August) over a 30-year period (1981-2010) in Finland. Those indicators include the Standardized Precipitation Index (SPI), the Standardized Precipitation-Evapotranspiration Index (SPEI), the Soil Moisture Index (SMI), and the Soil Moisture Anomaly (SMA). Herein, regional soil moisture was produced by the land surface model JSBACH of the Max Planck Institute for Meteorology Earth System Model (MPI-ESM). Results show that the buffering effect of soil moisture and the associated soil moisture memory can impact on the onset and duration of drought as indicated by the SMI and SMA, while the SPI and SPEI are directly controlled by meteorological conditions. In particular, we investigated whether the SMI, SMA and SPEI are able to indicate the Extreme Drought affecting Forest health (EDF), which we defined according to the extreme drought that caused severe forest damages in Finland in 2006. The EDF thresholds for the aforementioned indicators are suggested, based on the reported statistics of forest damages in Finland in 2006. SMI was found to be the best indicator in capturing the spatial extent of forest damage induced by the extreme drought in 2006. In addition, through the application of the EDF thresholds over the summer months of the 30-year study period, the SPEI and SMA tended to show more frequent EDF events and a higher fraction of influenced area than SMI. This is because the SPEI and SMA are standardized indicators that show the degree of anomalies from statistical means over the aggregation period of climate conditions and soil moisture, respectively. However, in boreal forests in Finland, the high initial soil moisture or existence of peat often prevent the EDFs indicated by the SPEI and SMA to produce very low soil moisture that could be indicated as EDFs by the SMI. Therefore, we consider SMI is more appropriate for indicating EDFs in boreal forests. The selected EDF thresholds for those indicators could be calibrated when there are more forest health observation data available. Furthermore, in the context of future climate scenarios, assessments of EDF risks in northern areas should, in addition to climate data, rely on a land surface model capable of reliable prediction of soil moisture.
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(2018)Objective: To study the association between perceptions of various triggers of asthma and employment status. Methods: A questionnaire was administered to all those adults living in the city of Tampere, Finland, who were entitled to special reimbursement for asthma medication by the Social Insurance Institution (n = 2613). The response rate was 79%. The study population (n = 1657) consisted of individuals who worked full-time (n = 967), were unemployed (n = 197), had all-cause work disability (n = 334), or were retired due to old age (n = 159). Given a list of potential asthma triggers, the respondents were asked how often (never/sometimes/often) the trigger caused or worsened their asthma symptoms during leisure time. Results: After adjusting for background variables (age, sex, smoking, and professional status), frequency of asthma symptoms, and the use of asthma medication during the last year, any individual trigger identified as asthma-relevant was associated with having work disability (vs. working full-time). The highest odds ratio (OR) was found for vehicle exhaust (OR 5.0, CI 2.2-11.4). We found similar but less consistent associations between asthma trigger perceptions and unemployment. No elevated ORs were found regarding asthma trigger perceptions for old-age retirement. Conclusions: Perceptions of asthma triggers are associated with all-cause work disability. Our findings suggest that asthmatics have excess trigger perceptions that are not explained by asthma alone. Asthmatics need to be informed that inaccurate trigger perceptions may develop, and how they are induced, because unnecessary trigger avoidance may interfere with work life.
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(2022)Background:Elevated autism spectrum disorder (ASD) traits are associated with anorexia nervosa (AN). Conversely, eating disturbances, which are core characteristics of AN, are common in ASD. Among individuals with ASD, atypical sensory processing is associated with eating disturbance. Because AN and ASD appear to overlap, it would be crucial to understand whether sensory processing atypicality exist also in AN. Further, it would be essential to find if atypical sensory processing is associated with eating disturbances in individuals with AN, since treatment modifications may be needed. We therefore aimed to examine whether atypical sensory processing is associated with AN and its core characteristics. MethodsParticipants of the current study included 42 individuals with AN and 40 healthy controls (HCs). All participants were adult women. Sensory processing, other ASD traits, and eating disorder symptoms were assessed with self-report questionnaires. ResultsIndividuals with AN reported lower registration, decreased sensation seeking, increased sensory sensitivity, and increased sensation avoiding compared to HCs. When analyzing groups with restrictive AN (AN-R) and binge-purge type AN (AN-BP) separately, only individuals with AN-R exhibited decreased sensation seeking, and only those with AN-BP exhibited lower registration. After controlling for body mass index as a covariate, group differences remained significant only in sensory sensitivity between individuals with AN and HCs. Increased atypical sensory processing predicted lower body mass index and increased disordered eating. ConclusionResults suggest that sensory processing appears to differ between AN and HC women, and AN subtypes may exhibit distinct sensory processing atypicality. Sensory sensitivity may be stable traits whereas other aspects of atypical sensory processing may be related to acute AN. Atypical sensory processing may contribute to the severity of AN, and thus it is crucial to recognize sensory processing differences when treating individuals with AN.
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(2019)Policy-relevant forest models must be environment and management sensitive and provide unbiased estimates of predicted variables over their intended areas of application. While empirical models derive their structure and parameters from representative data sets, process-based model (PBM) parameters should be evaluated in ranges that have a biological meaning independently of output data. At the same time PBMs should be calibrated against observations in order to obtain unbiased estimates and an understanding of their predictive capability. By means of model data assimilation, we Bayesian calibrated a forest model (PREBAS) using an extensive dataset that covered a wide range of climatic conditions, species composition and management practices. PREBAS was calibrated for three species in Finland: Scots pine (Pinus sylvestris L.), Norway spruce (Picea abies [L.] H. Karst.) and Silver birch (Betula pendula L.). Data assimilation was strongly effective in reducing the uncertainty of PREBAS parameters and predictions. A country-generic calibration showed robust performances in predicting forest variables and the results were consistent with yield tables and national forest statistics. The posterior predictive uncertainty of the model was mainly influenced by the uncertainty of the structural and measurement error.
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(2021)The FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vivo drug response of primary patient samples. We find that ex vivo samples often exhibit a general sensitivity to (any) drug exposure, independent of drug target. We observe that this "general response across drugs" (GRD) is associated with FLT3-ITD mutations, clinical response to standard induction chemotherapy, and overall survival. Further, incorporating GRD into expression-based regression models trained on one of the studies improved their performance in predicting ex vivo response in the second study, thus signifying its relevance to precision oncology efforts. We find that venetoclax response is independent of GRD but instead show that it is linked to expression of monocyte-associated genes by developing and applying a multi-source Bayesian regression approach. The method shares information across studies to robustly identify biomarkers of drug response and is broadly applicable in integrative analyses.
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(2018)Developing reliable mouse models for social behaviour is challenging. Different tests have been proposed, but most of them consist of rather artificial confrontations of unfamiliar mice in novel arenas or are relying on social stress induced by aggressive conspecifics. Natural social interaction in home cage in laboratory has not been investigated well. IntelliCage is a fully automated home-cage system, where activity of the group-housed mice can be monitored along with various cognitive tasks. Here we report the behavioural profile of C57BL/6N (86) and BALB/c (BALB) female mice in IntelliCage when separated by strain, followed by monitoring of activity and formation of 'home-base' after mixing two strains. For that purpose, 3 cages were connected. Significant differences between the strains were established in baseline behaviour in conventional tests and in IntelliCage. The B6 mice showed reduced anxiety-like behaviour in open field and light-dark box, slightly enhanced exploratory activity in IntelliCage during initial adaptation and clearly distinct circadian activity. Mixing of two strains resulted in reduction of body weight and anhedonia in B6 mice. In addition, the B6 mice showed clear preference to previous home-cage, and formed a new home-base faster than BALB mice. In contrast, BALB mice showed enhanced activity and moving between the cages without showing any preference to previous home-cage. It could be argued that social challenge caused changes in both strains and different coping styles are responsible for behavioural manifestations. Altogether, this approach could be useful in modelling and validating mouse models for disorders with disturbed social behaviour.
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(2021)Photoacoustic detection is a sensitive method for measurement of light-absorbing particles directly in the aerosol phase. In this article, we demonstrate a new sensitive technique for photoacoustic aerosol absorption measurements using a cantilever microphone for the detection of the photoacoustic signal. Compared to conventional diaphragm microphones, a cantilever offers increased sensitivity by up to two orders of magnitude. The measurement setup uses a photoacoustic cell from Gasera PA201 gas measurement system, which we have adapted for aerosol measurements. Here we reached a noise level of 0.013 Mm(-1) (one standard deviation) with a sampling time of 20 s, using a simple single-pass design without a need for a resonant acoustic cell. The sampling time includes 10 s signal averaging time and 10 s sample exchange, since the photoacoustic cell is designed for closed cell operation. We demonstrate the method in measurements of size-selected nigrosin particles and ambient black carbon. Due to the exceptional sensitivity, the technique shows great potential for applications where low detection limits are required, for example size-selected absorption measurements and black carbon detection in ultra clean environments.
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Carbon Dynamics in a Human-Modified Tropical Forest : A Case Study Using Multi-Temporal LiDAR Data (2020)Tropical forests hold significant amounts of carbon and play a critical role on Earth ' s climate system. To date, carbon dynamics over tropical forests have been poorly assessed, especially over vast areas of the tropics that have been affected by some type of disturbance (e.g., selective logging, understory fires, and fragmentation). Understanding the multi-temporal dynamics of carbon stocks over human-modified tropical forests (HMTF) is crucial to close the carbon cycle balance in the tropics. Here, we used multi-temporal and high-spatial resolution airborne LiDAR data to quantify rates of carbon dynamics over a large patch of HMTF in eastern Amazon, Brazil. We described a robust approach to monitor changes in aboveground forest carbon stocks between 2012 and 2018. Our results showed that this particular HMTF lost 0.57 myr(-1) in mean forest canopy height and 1.38 MgCha(-1)yr(-1) of forest carbon between 2012 and 2018. LiDAR-based estimates of Aboveground Carbon Density (ACD) showed progressive loss through the years, from 77.9 MgCha(-1) in 2012 to 53.1 MgCha(-1) in 2018, thus a decrease of 31.8%. Rates of carbon stock changes were negative for all time intervals analyzed, yielding average annual carbon loss rates of -1.34 MgCha(-1)yr(-1). This suggests that this HMTF is acting more as a source of carbon than a sink, having great negative implications for carbon emission scenarios in tropical forests. Although more studies of forest dynamics in HMTFs are necessary to reduce the current remaining uncertainties in the carbon cycle, our results highlight the persistent effects of carbon losses for the study area. HMTFs are likely to expand across the Amazon in the near future. The resultant carbon source conditions, directly associated with disturbances, may be essential when considering climate projections and carbon accounting methods.
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(2019)Objective To evaluate cardiac autonomic function in adults born preterm. Study design We studied the association between prematurity and cardiac autonomic function using heart rate variability measurements in 600 adults (mean age of 23.3 years) from a geographically based cohort in Northern Finland. There were 117 young adults born early preterm (= 37 weeks, controls). Autonomic function was analyzed by calculating time and frequency domain heart rate variability measurements using linear regression. Results Compared with controls, the mean difference in root mean square of successive differences (indicating cardiac vagal activity) was -12.0% (95% CI -22.2%, -0.5%, adjusted for sex, age, source cohort, and season P = .04) for the early preterm group and -7.8% (-16.8%, 2.0%, P = .12) for the late preterm group. Mean differences with controls in low frequency power (indicating cardiac vagal activity, including some sympathetic- and baroreflex-mediated effects) were -13.6% (-26.7%, 1.8%, P = .08) for the early pretermgroup and -16.4% (-27.0%, -4.3%, P = .01) for the late preterm group. Mean differences in high frequency power (quantifying cardiac vagal modulation in respiratory frequency) were -19.2% (-36.6%, 2.9%, P = .09) for the early preterm group and -13.8% (-29.4%, 5.3%, P = .15) for the late preterm group. Differences were attenuated when controlled for body mass index and physical activity. Conclusions Our results suggest altered autonomic regulatory control in adults born preterm, including those born late preterm. Altered autonomic regulatory control may contribute to increased cardiovascular risk in adults born preterm.
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(2017)Background: Despite of the presence of sulfhydryl oxidases (SOXs) in the secretomes of industrially relevant organisms and their many potential applications, only few of these enzymes have been biochemically characterized. In addition, basic functions of most of the SOX enzymes reported so far are not fully understood. In particular, the physiological role of secreted fungal SOXs is unclear. Results: The recently identified SOX from Aspergillus tubingensis (AtSOX) was produced, purified and characterized in the present work. AtSOX had a pH optimum of 6.5, and showed a good pH stability retaining more than 80% of the initial activity in a pH range 4-8.5 within 20 h. More than 70% of the initial activity was retained after incubation at 50 degrees C for 20 h. AtSOX contains a non-covalently bound flavin cofactor. The enzyme oxidised a sulfhydryl group of glutathione to form a disulfide bond, as verified by nuclear magnetic resonance spectroscopy. AtSOX preferred glutathione as a substrate over cysteine and dithiothreitol. The activity of the enzyme was totally inhibited by 10 mM zinc sulphate. Peptide-and protein-bound sulfhydryl groups in bikunin, gliotoxin, holomycin, insulin B chain, and ribonuclease A, were not oxidised by the enzyme. Based on the analysis of 33 fungal genomes, SOX enzyme encoding genes were found close to nonribosomal peptide synthetases (NRPS) but not with polyketide synthases (PKS). In the phylogenetic tree, constructed from 25 SOX and thioredoxin reductase sequences from IPR000103 InterPro family, AtSOX was evolutionary closely related to other Aspergillus SOXs. Oxidoreductases involved in the maturation of nonribosomal peptides of fungal and bacterial origin, namely GliT, HlmI and DepH, were also evolutionary closely related to AtSOX whereas fungal thioreductases were more distant. Conclusions: AtSOX (55 kDa) is a fungal secreted flavin-dependent enzyme with good stability to both pH and temperature. A Michaelis-Menten behaviour was observed with reduced glutathione as a substrate. Based on the location of SOX enzyme encoding genes close to NRPSs, SOXs could be involved in the secondary metabolism and act as an accessory enzyme in the production of nonribosomal peptides.
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(2020)Understanding how conditions experienced during development affect reproductive timing is of considerable cross-disciplinary interest. Life-history theory predicts that organisms will accelerate reproduction when future survival is unsure. In humans, this can be triggered by early exposure to mortality. Previous studies, however, have been inconclusive due to several confounds that are also likely to affect reproduction. Here we take advantage of a natural experiment in which a population is temporarily divided by war to analyze how exposure to mortality affects reproduction. Using records of Finnish women in World War II, we find that young girls serving in a paramilitary organization wait less time to reproduce, have shorter inter-birth intervals, and have more children than their non-serving peers or sisters. These results support the hypothesis that exposure to elevated mortality rates during development can result in accelerated reproductive schedules and adds to our understanding of how participation in warfare affects women.
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(2020)We present an extensive, large-scale, long-term and multitaxon database on phenological and climatic variation, involving 506,186 observation dates acquired in 471 localities in Russian Federation, Ukraine, Uzbekistan, Belarus and Kyrgyzstan. The data cover the period 1890-2018, with 96% of the data being from 1960 onwards. The database is rich in plants, birds and climatic events, but also includes insects, amphibians, reptiles and fungi. The database includes multiple events per species, such as the onset days of leaf unfolding and leaf fall for plants, and the days for first spring and last autumn occurrences for birds. The data were acquired using standardized methods by permanent staff of national parks and nature reserves (87% of the data) and members of a phenological observation network (13% of the data). The database is valuable for exploring how species respond in their phenology to climate change. Large-scale analyses of spatial variation in phenological response can help to better predict the consequences of species and community responses to climate change.
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(2019)While acknowledged as key components in the formation of new particles in the atmosphere, the accurate characterization of gaseous (highly) oxygenated organic compounds remains challenging and requires analytical developments. Earlier studies have successfully used the nitrate ion (NO3) based chemical ionization (CI) coupled to atmospheric pressure interface time-of-flight mass spectrometry (CI-APi-TOF) for monitoring these compounds. Despite many breakthroughs in recent years, the CI-APi-TOF has many limitations, preventing for instance the unambiguous ion identification of overlapping peaks. To tackle this analytical challenge, we developed a CI interface coupled to an ultrahigh-resolution Orbitrap mass spectrometer (CI-Orbitrap). We show that the CI-Orbitrap has similar sensitivity and selectivity as the CI-APi-TOF, but with over an order of magnitude higher mass resolving power (up to 140 000). Equally importantly, the CI-Orbitrap allows tandem mass spectrometry, providing the possibility for structural elucidation of the highly oxygenated organic molecules (HOM). As a proof of concept, we characterized HOM formed during the ozonolysis of two biogenic compounds (alpha-pinene and limonene), under different environmental conditions in a flow reactor. The CI-Orbitrap exhibited high sensitivity to both HOM and radical species, while easily separating ions of different elemental composition in cases where the more common TOF applications would not have been able to distinguish all ions. Our tandem mass spectrometry analyses revealed distinct fingerprint spectra for all the studied HOM. Overall, the CI-Orbitrap is an extremely promising instrument, and it provides a much-needed extension to ongoing research on HOM, with potential to impact also many other fields within atmospheric chemistry.
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(2021)Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage-induced initiation of mouse BLBC-like mammary tumors and for survival of HR-defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNAdamage-induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. Significance: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage-induced G2-M checkpoint and proliferative signaling.
