Browsing by Subject "DRIVEN"

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  • Li, Shiqian; Prasanna, Xavier; Salo, Veijo T.; Vattulainen, Ilpo; Ikonen, Elina (2019)
    Auxin-inducible degron technology allows rapid and controlled protein depletion. However, basal degradation without auxin and inefficient auxin-inducible depletion have limited its utility. We have identified a potent auxin-inducible degron system composed of auxin receptor F-box protein AtAFB2 and short degron minilAA7. The system showed minimal basal degradation and enabled rapid auxin-inducible depletion of endogenous human transmembrane, cytoplasmic and nuclear proteins in 1 h with robust functional phenotypes.
  • Liu, Hong-Li; Tej, Anandmayee; Liu, Tie; Issac, Namitha; Saha, Anindya; Goldsmith, Paul F.; Wang, Jun-Zhi; Zhang, Qizhou; Qin, Sheng-Li; Wang, Ke; Li, Shanghuo; Soam, Archana; Dewangan, Lokesh; Lee, Chang Won; Li, Pak-Shing; Liu, Xun-Chuan; Zhang, Yong; Ren, Zhiyuan; Juvela, Mika; Bronfman, Leonardo; Wu, Yue-Fang; Tatematsu, Ken'ichi; Chen, Xi; Li, Di; Stutz, Amelia; Zhang, Siju; Tóth, L. Viktor; Luo, Qiu-Yi; Xu, Feng-Wei; Li, Jinzeng; Liu, Rong; Zhou, Jianwen; Zhang, Chao; Tang, Mengyao; Zhang, Chao; Baug, Tapas; Mannfors, Emma Elisa; Chakali, Eswaraiah; Dutta, Somnath (2022)
    We present new 3-mm continuum and molecular lines observations from the ATOMS survey towards the massive protostellar clump, MM1, located in the filamentary infrared dark cloud (IRDC), G034.43+00.24 (G34). The lines observed are the tracers of either dense gas (e.g. HCO+/(HCO+)-C-13 J= 1-0) or outflows (e.g. CS J = 2-1). The most complete picture to date of seven cores in MM1 is revealed by dust continuum emission. These cores are found to be gravitationally bound, with virial parameter, alpha(vir) < 2. At least four outflows are identified in MM1 with a total outflowing mass of similar to 45 M-circle dot, and a total energy of 1 x 10(47) erg, typical of outflows from a B0-type star. Evidence of hierarchical fragmentation, where turbulence dominates over thermal pressure, is observed at both the cloud and the clump scales. This could be linked to the scale-dependent, dynamical mass inflow/accretion on clump and core scales. We therefore suggest that the G34 cloud could be undergoing a dynamical mass inflow/accretion process linked to the multiscale fragmentation, which leads to the sequential formation of fragments of the initial cloud, clumps, and ultimately dense cores, the sites of star formation.
  • Ren, Hao; Yang, Peng; Winnik, Francoise M. (2020)
    Azo dyes, such as azobenzene, are able to convert absorbed light into motion or deformation on the macroscopic scale on the basis of their remarkable ability to undergo repeatedly and in 100% yield reversibletrans-to-cisphotoisomerization. Current needs for multiresponsive and fast photoswitches have led to the development of heteroaryl azo dyes, such as azopyridine. This remarkable azo compound combines the photoresponse of the azo chromophore with the chemistry of the pyridine ring, in particular its responsiveness to changes in pH and its ability to form hydrogen- and halogen-bonds. This mini-review summarizes key features of the photoisomerization of polymer-tethered azopyridine in aqueous media and describes a few recent research accomplishments in emerging areas that have benefited of the fast thermalcis-to-transrelaxation characteristics of azopyridinium or H-bonded azopyridine. It also discusses the effects of the photoisomerization of azopyridine on the thermoresponsive properties of azopyridine-tethered heat-sensitive polymers. Overall, azopyridine is a highly versatile actuator to consider when designing photo/multiresponsive polymeric materials.
  • Miliutina, Elena; Guselnikova, Olga; S. Soldatova, Natalia; Bainova, Polina; Elashnikov, Roman; Fitl, Přemysl; Kurten, Theo; S. Yusubov, Mekhman; Švorčík, Václav; Valiev, Rashid; M. Chehimi, Mohamed; Lyutakov, Oleksiy; S. Postnikov, Pavel (2020)
    Plasmon-assisted transformations of organic compounds represent a novel opportunity for conversion of light to chemical energy at room temperature. However, the mechanistic insights of interaction between plasmon energy and organic molecules is still under debate. Herein, we proposed a comprehensive study of the plasmon-assisted reaction mechanism using unsymmetric iodonium salts (ISs) as an organic probe. The experimental and theoretical analysis allow us to exclude the possible thermal effect or hot electron transfer. We found that plasmon interaction with unsymmetrical ISs led to the intramolecular excitation of electron followed by the regioselective cleavage of C–I bond with the formation of electron-rich radical species, which cannot be explained by the hot electron excitation or thermal effects. The high regioselectivity is explained by the direct excitation of electron to LUMO with the formation of a dissociative excited state according to quantum-chemical modeling, which provides novel opportunities for the fine control of reactivity using plasmon energy.
  • Breneman, A. W.; Halford, A. J.; Millan, R. M.; Woodger, L. A.; Zhang, X. -J.; Sandhu, J. K.; Capannolo, L.; Li, W.; Ma, Q.; Cully, C. M.; Murphy, K. R.; Brito, T.; Elliott, S. S. (2020)
    We present observations of similar to 10-60 min solar wind dynamic pressure structures that drive large-scale coherent similar to 20-100 keV electron loss from the outer radiation belt. A combination of simultaneous satellite and Balloon Array for Radiation-belt Relativistic Electron Losses (BARREL) observations on 11-12 January 2014 shows a close association between the pressure structures and precipitation as inferred from BARREL X-rays. Specifically, the structures drive radial ExB transport of electrons up to 1 Earth radii, modulating the free electron energy available for low-frequency plasmaspheric hiss growth, and subsequent hiss-induced loss cone scattering. The dynamic pressure structures, originating near the Sun and commonly observed advecting with the solar wind, are thus able to switch on scattering loss of electrons by hiss over a large spatial scale. Our results provide a direct link between solar wind pressure fluctuations and modulation of electron loss from the outer radiation belt and may explain long-period modulations and large-scale coherence of X-rays commonly observed in the BARREL data set. Plain Language Summary The Earth's low-density magnetosphere is a region of enclosed magnetic field lines that contains energetic electrons ranging from eV to MeV energies. These populations can be greatly enhanced in response to solar driving. Following enhancements, energetic electron populations are depleted on timescales of hours to days by various processes. One important depletion process occurs when an electromagnetic plasma wave called plasmaspheric hiss, which exists within a high plasma density region called the plasmasphere and its (occasional) radial extension called the plume, scatters energetic electrons into the atmosphere. In this paper, we show that these hiss waves can be switched on by compressions of the magnetosphere which occur in response to similar to 1 hr long pressure structures in the solar wind. These structures originate at or near the Sun and are very common in the solar wind at 1 AU. The newly excited hiss waves scatter electrons into the atmosphere where they are observed on balloon-borne X-ray detectors. Our results suggest that magnetospheric models that predict the loss of electrons from hiss waves may be improved by consideration of solar wind pressure-driven dynamics.
  • Karcher, Nicolai; Nigro, Eleonora; Puncochar, Michal; Blanco-Miguez, Aitor; Ciciani, Matteo; Manghi, Paolo; Zolfo, Moreno; Cumbo, Fabio; Manara, Serena; Golzato, Davide; Cereseto, Anna; Arumugam, Manimozhiyan; Bui, Thi Phuong Nam; Tytgat, Hanne L. P.; Valles-Colomer, Mireia; de Vos, Willem M.; Segata, Nicola (2021)
    Background Akkermansia muciniphila is a human gut microbe with a key role in the physiology of the intestinal mucus layer and reported associations with decreased body mass and increased gut barrier function and health. Despite its biomedical relevance, the genomic diversity of A. muciniphila remains understudied and that of closely related species, except for A. glycaniphila, unexplored. Results We present a large-scale population genomics analysis of the Akkermansia genus using 188 isolate genomes and 2226 genomes assembled from 18,600 metagenomes from humans and other animals. While we do not detect A. glycaniphila, the Akkermansia strains in the human gut can be grouped into five distinct candidate species, including A. muciniphila, that show remarkable whole-genome divergence despite surprisingly similar 16S rRNA gene sequences. These candidate species are likely human-specific, as they are detected in mice and non-human primates almost exclusively when kept in captivity. In humans, Akkermansia candidate species display ecological co-exclusion, diversified functional capabilities, and distinct patterns of associations with host body mass. Analysis of CRISPR-Cas loci reveals new variants and spacers targeting newly discovered putative bacteriophages. Remarkably, we observe an increased relative abundance of Akkermansia when cognate predicted bacteriophages are present, suggesting ecological interactions. A. muciniphila further exhibits subspecies-level genetic stratification with associated functional differences such as a putative exo/lipopolysaccharide operon. Conclusions We uncover a large phylogenetic and functional diversity of the Akkermansia genus in humans. This variability should be considered in the ongoing experimental and metagenomic efforts to characterize the health-associated properties of A. muciniphila and related bacteria.
  • Berglund, Martin; Adiels, Martin; Taskinen, Marja-Riitta; Boren, Jan; Wennberg, Bernt (2015)
    Context Mathematical models may help the analysis of biological systems by providing estimates of otherwise un-measurable quantities such as concentrations and fluxes. The variability in such systems makes it difficult to translate individual characteristics to group behavior. Mixed effects models offer a tool to simultaneously assess individual and population behavior from experimental data. Lipoproteins and plasma lipids are key mediators for cardiovascular disease in metabolic disorders such as diabetes mellitus type 2. By the use of mathematical models and tracer experiments fluxes and production rates of lipoproteins may be estimated. Results We developed a mixed effects model to study lipoprotein kinetics in a data set of 15 healthy individuals and 15 patients with type 2 diabetes. We compare the traditional and the mixed effects approach in terms of group estimates at various sample and data set sizes. Conclusion We conclude that the mixed effects approach provided better estimates using the full data set as well as with both sparse and truncated data sets. Sample size estimates showed that to compare lipoprotein secretion the mixed effects approach needed almost half the sample size as the traditional method.
  • Yuryev, Mikhail; Pellegrino, Christophe; Jokinen, Ville; Andriichuk, Liliia; Khirug, Stanislav; Khiroug, Leonard; Rivera Baeza, Claudio (2016)
    The dynamics of intracellular calcium fluxes are instrumental in the proliferation, differentiation, and migration of neuronal cells. Knowledge thus far of the relationship between these calcium changes and physiological processes in the developing brain has derived principally from ex vivo and in vitro experiments. Here, we present a new method to image intracellular calcium flux in the cerebral cortex of live rodent embryos, whilst attached to the dam through the umbilical cord. Using this approach we demonstrate induction of calcium waves by laser stimulation. These waves are sensitive to ATP-receptor blockade and are significantly increased by pharmacological facilitation of intracellular-calcium release. This approach is the closest to physiological conditions yet achieved for imaging of calcium in the embryonic brain and as such opens new avenues for the study of prenatal brain development. Furthermore, the developed method could open the possibilities of preclinical translational studies in embryos particularly important for developmentally related diseases such as schizophrenia and autism.
  • Barkovskaya, Anna; Seip, Kotryna; Prasmickaite, Lina; Mills, Ian G; Moestue, Siver A; Itkonen, Harri M. (2020)
    In this study, we probed the importance of O-GlcNAc transferase (OGT) activity for the survival of tamoxifen-sensitive (TamS) and tamoxifen-resistant (TamR) breast cancer cells. Tamoxifen is an antagonist of estrogen receptor (ERa), a transcription factor expressed in over 50% of breast cancers. ERa-positive breast cancers are successfully treated with tamoxifen; however, a significant number of patients develop tamoxifen-resistant disease. We show that in vitro development of tamoxifenresistance is associated with increased sensitivity to the OGT small molecule inhibitor OSMI-1. Global transcriptome profiling revealed that TamS cells adapt to OSMI-1 treatment by increasing the expression of histone genes. This is known to mediate chromatin compaction. In contrast, TamR cells respond to OGT inhibition by activating the unfolded protein response and by significantly increasing ERRFI1 expression. ERRFI1 is an endogenous inhibitor of ERBB-signaling, which is a known driver of tamoxifen-resistance. We show that ERRFI1 is selectively downregulated in ERa-positive breast cancers and breast cancers driven by ERBB2. This likely occurs via promoter methylation. Finally, we show that increased ERRFI1 expression is associated with extended survival in patients with ERa-positive tumors (p = 9.2e-8). In summary, we show that tamoxifen-resistance is associated with sensitivity to OSMI-1, and propose that this is explained in part through an epigenetic activation of the tumor-suppressor ERRFI1 in response to OSMI-1 treatment.
  • Dauner, Ana Lucia Lindroth; Mollenhauer, Gesine; Hefter, Jens; Bicego, Marcia Caruso; de Mahiques, Michel Michaelovitch; Martins, Cesar de Castro (2022)
    Despite the increased number of paleoceanographic studies in the SW Atlantic in recent years, the mechanisms controlling marine productivity and terrestrial material delivery to the South Brazil Bight remain unresolved. Because of its wide continental shelf and abrupt change in coastline orientation, this region is under the influence of several environmental forcings, causing the region to have large variability in primary production. This study investigated terrestrial organic matter (OM) sources and marine OM sources in the South Brazil Bight, as well as the main controls on marine productivity and terrestrial OM export. We analyzed OM geochemical (bulk and molecular) proxies in sediment samples from a core (NAP 63-1) retrieved from the SW Atlantic slope (24.8 degrees S, 44.3 degrees W, 840-m water depth). The organic proxies were classified into "terrestrial-source" and "marine-source" groups based on a cluster analysis. The two sources presented different stratigraphical profiles, indicating distinct mechanisms governing their delivery. Bulk proxies indicate the predominance of marine OM, although terrestrial input also affected the total OM deposition. The highest marine productivity, observed between 50 and 39 ka BP, was driven by the combined effects of the South Atlantic Central Water upwelling promoted by Brazil Current eddies and fluvial nutrient inputs from the adjacent coast. After the last deglaciation, decreased phytoplankton productivity and increased archaeal productivity suggest a stronger oligotrophic tropical water presence. The highest terrestrial OM accumulation occurred between 30 and 20 ka BP, with its temporal evolution controlled mainly by continental moisture evolution. Sea level fluctuations affected the distance between the coastline and the sampling site. In contrast, continental moisture affected the phytogeography, changing from lowlands covered by grasses and saltmarshes to a landscape dominated by mangroves and the Atlantic Forest. Our results suggest how the OM cycle in the South Brazil Bight may respond to warmer and dryer climate conditions.
  • Donvil, Brecht; Muratore-Ginanneschi, Paolo; Pekola, Jukka; Schwieger, Kay (2018)
    We investigate the experimental setup proposed in [New J. Phys., 15, 115006 (2013)] for calorimetric measurements of thermodynamic indicators in an open quantum system. As theoretical model we consider a periodically driven qubit coupled with a large yet finite electron reservoir, the calorimeter. The calorimeter is initially at equilibrium with an infinite phonon bath. As time elapses, the temperature of the calorimeter varies in consequence of energy exchanges with the qubit and the phonon bath. We show how under weak coupling assumptions, the evolution of the qubit-calorimeter system can be described by a generalized quantum jump process including as dynamical variable the temperature of the calorimeter. We study the jump process by numeric and analytic methods. Asymptotically with the duration of the drive, the qubit-calorimeter attains a steady state. In this same limit, we use multiscale perturbation theory to derive a Fokker--Planck equation governing the calorimeter temperature distribution. We inquire the properties of the temperature probability distribution close and at the steady state. In particular, we predict the behavior of measurable statistical indicators versus the qubit-calorimeter coupling constant.
  • Morosan, Diana E.; Carley, Eoin P.; Hayes, Laura A.; Murray, Sophie A.; Zucca, Pietro; Fallows, Richard A.; McCauley, Joe; Kilpua, Emilia K. J.; Mann, Gottfried; Vocks, Christian; Gallagher, Peter T. (2019)
    The Sun is an active star that can launch large eruptions of magnetized plasma into the heliosphere, known as corona! mass ejections (CMEs). These can drive shocks that accelerate particles to high energies, often resulting in radio emission at low frequencies (
  • Wijsen, N.; Aran, A.; Scolini, C.; Lario, D.; Afanasiev, A.; Vainio, R.; Sanahuja, B.; Pomoell, J.; Poedts, S. (2022)
    Aims. We model the energetic storm particle (ESP) event of 14 July 2012 using the energetic particle acceleration and transport model named 'PArticle Radiation Asset Directed at Interplanetary Space Exploration' (PARADISE), together with the solar wind and coronal mass ejection (CME) model named 'EUropean Heliospheric FORcasting Information Asset' (EUHFORIA). The simulation results illustrate both the capabilities and limitations of the utilised models. We show that the models capture some essential structural features of the ESP event; however, for some aspects the simulations and observations diverge. We describe and, to some extent, assess the sources of errors in the modelling chain of EUHFORIA and PARADISE and discuss how they may be mitigated in the future. Methods. The PARADISE model computes energetic particle distributions in the heliosphere by solving the focused transport equation in a stochastic manner. This is done using a background solar wind configuration generated by the ideal magnetohydrodynamic module of EUHFORIA. The CME generating the ESP event is simulated by using the spheromak model of EUHFORIA, which approximates the CME's flux rope as a linear force-free spheroidal magnetic field. In addition, a tool was developed to trace CME-driven shock waves in the EUHFORIA simulation domain. This tool is used in PARADISE to (i) inject 50 keV protons continuously at the CME-driven shock and (ii) include a foreshock and a sheath region, in which the energetic particle parallel mean free path, lambda(parallel to), decreases towards the shock wave. The value of lambda(parallel to) at the shock wave is estimated from in situ observations of the ESP event. Results. For energies below similar to 1 MeV, the simulation results agree well with both the upstream and downstream components of the ESP event observed by the Advanced Composition Explorer. This suggests that these low-energy protons are mainly the result of interplanetary particle acceleration. In the downstream region, the sharp drop in the energetic particle intensities is reproduced at the entry into the following magnetic cloud, illustrating the importance of a magnetised CME model.
  • Kalliokoski, Milla M. H.; Kilpua, Emilia K. J.; Osmane, Adnane; Turner, Drew L.; Jaynes, Allison N.; Turc, Lucile; George, Harriet; Palmroth, Minna (2020)
    The energetic electron content in the Van Allen radiation belts surrounding the Earth can vary dramatically at several timescales, and these strong electron fluxes present a hazard for spacecraft traversing the belts. The belt response to solar wind driving is, however, largely unpredictable, and the direct response to specific large-scale heliospheric structures has not been considered previously. We investigate the immediate response of electron fluxes in the outer belt that are driven by sheath regions preceding interplanetary coronal mass ejections and the associated wave activity in the inner magnetosphere. We consider the events recorded from 2012 to 2018 in the Van Allen Probes era to utilise the energy- and radial-distance-resolved electron flux observations of the twin spacecraft mission. We perform a statistical study of the events by using the superposed epoch analysis in which the sheaths are superposed separately from the ejecta and resampled to the same average duration. Our results show that the wave power of ultra-low frequency Pc5 and electromagnetic ion cyclotron waves, as measured by a Geostationary Operational Environmental Satellite (GOES), is higher during the sheath than during the ejecta. However, the level of chorus wave power, as measured by the Van Allen Probes, remains approximately the same due to similar substorm activity during the sheath and ejecta. Electron flux enhancements are common at low energies (<1 MeV) throughout the outer belt (L = 3-6), whereas depletion predominantly occurs at high energies for high radial distances (L > 4). It is distinctive that the depletion extends to lower energies at larger distances. We suggest that this L-shell and energy-dependent depletion results from the magnetopause shadowing that dominates the losses at large distances, while the wave-particle interactions dominate closer to the Earth. We also show that non-geoeffective sheaths cause significant changes in the outer belt electron fluxes.
  • Westerbom, Mats; Mustonen, Olli; Jaatinen, Kim; Kilpi, Mikael; Norkko, Alf (2019)
    Examining changes in abundance and demographic rates at species distribution margins may provide the first signs of broader species responses to environmental change. Still, the joint impact of space and time have remained relatively unstudied in most marginal regions. In order to examine the influence of climate variability on mussel distribution patterns, we monitored three sublittoral and marginal blue mussel (Mytilus trossulus) populations, spaced along a salinity gradient. Densities and biomasses peaked toward the saltier parts of the study area and showed relatively larger variations toward the low saline edge. Temporally, the areas showed a consistent increase in abundance after a synchronized large-scale recruitment event, which was followed by a decline in population size, occurring much faster toward the very range edge. Salinity, temperature, winter severity, and wave exposure explained most of the spatiotemporal variation in mussel abundances and adults showed positive effects on recruit abundance. We show empirically that the dynamics of edge populations are not driven by large changes in climate variables but that small spatial and temporal changes in key environmental variables have large and non-linear population level effects. Our results also show that fluctuating recruitment is a key factor for population stability affecting the storage potential of marginal populations, which dramatically decrease toward the edge. Our study provides a window into future population patterns and processes that drive marginal mussel populations in an altered sea characterized by rising temperature and declining salinity.
  • Daglis, Ioannis A.; Chang, Loren C.; Dasso, Sergio; Gopalswamy, Nat; Khabarova, Olga; Kilpua, Emilia; Lopez, Ramon; Marsh, Daniel; Matthes, Katja; Nandy, Dibyendu; Seppala, Annika; Shiokawa, Kazuo; Thieblemont, Remi; Zong, Qiugang (2021)
    In October 2017, the Scientific Committee on Solar-Terrestrial Physics (SCOSTEP) Bureau established a committee for the design of SCOSTEP's Next Scientific Programme (NSP). The NSP committee members and authors of this paper decided from the very beginning of their deliberations that the predictability of the Sun-Earth System from a few hours to centuries is a timely scientific topic, combining the interests of different topical communities in a relevant way. Accordingly, the NSP was christened PRESTO - PREdictability of the variable Solar-Terrestrial cOupling. This paper presents a detailed account of PRESTO; we show the key milestones of the PRESTO roadmap for the next 5 years, review the current state of the art and discuss future studies required for the most effective development of solar-terrestrial physics.
  • Good, S. W.; Ala-Lahti, M.; Palmerio, E.; Kilpua, E. K. J.; Osmane, A. (2020)
    The sheaths of compressed solar wind that precede interplanetary coronal mass ejections (ICMEs) commonly display large-amplitude magnetic field fluctuations. As ICMEs propagate radially from the Sun, the properties of these fluctuations may evolve significantly. We have analyzed magnetic field fluctuations in an ICME sheath observed by MESSENGER at 0.47 au and subsequently by STEREO-B at 1.08 au while the spacecraft were close to radial alignment. Radial changes in fluctuation amplitude, compressibility, inertial-range spectral slope, permutation entropy, Jensen-Shannon complexity, and planar structuring are characterized. These changes are discussed in relation to the evolving turbulent properties of the upstream solar wind, the shock bounding the front of the sheath changing from a quasi-parallel to quasi-perpendicular geometry, and the development of complex structures in the sheath plasma.
  • Talwelkar, Sarang S.; Nagaraj, Ashwini S.; Devlin, Jennifer R.; Hemmes, Annabrita; Potdar, Swapnil; Kiss, Elina A.; Saharinen, Pipsa; Salmenkivi, Kaisa Maria; Mäyränpää, Mikko I.; Wennerberg, Krister; Verschuren, Emmy (2019)
    Most non-small cell lung cancers (NSCLC) contain nontargetable mutations, including KRAS, TP53, or STK11/LKB1 alterations. By coupling ex viva drug sensitivity profiling with in vivo drug response studies, we aimed to identify drug vulnerabilities for these NSCLC subtypes. Primary adenosquamous carcinoma (ASC) or adenocarcinoma (AC) cultures were established from Kras(G12D/+);Lkb1(fl/fl) (KL) tumors or AC cultures from Kras(G12D/+);p53(fl/fl) (KP) tumors. Although p53-null cells readily propagated as conventional cultures, Lkb1-null cells required conditional reprograming for establishment. Drug response profiling revealed short-term response to MEK inhibition, yet long-term clonogenic assays demonstrated resistance, associated with sustained or adaptive activation of receptor tyrosine kinases (RTK): activation of ERBBs in KL cultures, or FGFR in AC niltures. Furthermore, pan-ERBB inhibition reduced the clonogenidty of KL cultures, which was exacerbated by combinatorial MEK inhibition, whereas combinatorial MEK and FGFR inhibition suppressed clonogenicity of AC cultures. Importantly, in vivo studies confirmed KL-selective sensitivity to pan-ERBB inhibition, which correlated with high ERBB ligand expression and activation of ERBB receptors, implying that ERBB network activity may serve as a predictive biomarker of drug response. Interestingly, in human NSCLCs, phosphorylation of EGFR or ERBB3 was frequently detected in ASCs and squamous cell carcinomas. We conclude that analysis of in situ ERBB signaling networks in conjunction with ex vivo drug response profiling and biochemical dissection of adaptive RTK activities may serve as a valid diagnostic approach to identify tumors sensitive to ERBB network inhibition.
  • Bao, Jie; Walliander, Margarita; Kovacs, Ferenc; Nagaraj, Ashwini S.; Hemmes, Annabrita; Sarhadi, Virinder Kaur; Knuutila, Sakari; Lundin, Johan; Horvath, Peter; Verschuren, Emmy W. (2019)
    To facilitate analysis of spatial tissue phenotypes, we created an open-source tool package named 'Spa-RQ' for 'Spatial tissue analysis: image Registration & Quantification'. Spa-RQ contains software for image registration (Spa-R) and quantitative analysis of DAB staining overlap (Spa-Q). It provides an easy-to-implement workflow for serial sectioning and staining as an alternative to multiplexed techniques. To demonstrate Spa-RQ's applicability, we analysed the spatial aspects of oncogenic KRAS-related signalling activities in non-small cell lung cancer (NSCLC). Using Spa-R in conjunction with ImageJ/Fiji, we first performed annotation-guided tumour-by-tumour phenotyping using multiple signalling markers. This analysis showed histopathology-selective activation of PI3K/AKT and MAPK signalling in Kras mutant murine tumours, as well as high p38MAPK stress signalling in p53 null murine NSCLC. Subsequently, Spa-RQ was applied to measure the co-activation of MAPK, AKT, and their mutual effector mTOR pathway in individual tumours. Both murine and clinical NSCLC samples could be stratified into 'MAPK/mTOR', 'AKT/mTOR', and 'Null' signature subclasses, suggesting mutually exclusive MAPK and AKT signalling activities. Spa-RQ thus provides a robust and easy to use tool that can be employed to identify spatially-distributed tissue phenotypes.
  • Isotalo, Teija; Rottenbiller, Lilla; Candolin, Ulrika (2022)
    The frequency and duration of heatwaves are increasing because of human activities. To cope with the changes, species with longer generation times may have to rely on plastic responses. The probability that their responses are adaptive is higher if the species have experienced temperature fluctuations also in their evolutionary past. However, experimental studies investigating responses to heatwaves often use exposure times that are significantly shorter than recent heatwaves. We show that this can lead to faulty conclusions and that the duration of higher temperature has to be considered in experimental designs. We recorded the response of threespine stickleback to prolonged duration of higher temperature during the breeding season, using a population that has experienced large fluctuations in temperature in its past and, hence, is expected to endure temperature changes well. We found males to adaptively adjust their reproductive behaviours to short periods of higher temperature, but not to longer periods that extended across two breeding cycles. Males initially increased their reproductive activities-nest building, courtship and parental care-which ensured high reproductive success during the first breeding cycle, but decreased their reproductive activities during the second breeding cycle when exposed to sustained high temperature. This reduced their courtship success and resulted in fewer offspring. Thus, a species expected to cope well with higher temperature suffers fitness reductions when the duration of high temperature is prolonged. The results stress the importance of considering the duration of extreme environmental conditions when investigating the impact that human activities have on species. Responses to short-term exposures cannot be extrapolated to assess responses to longer periods of extreme conditions.