Dasatinib reverses Cancer-associated Fibroblasts (CAFs) from primary Lung Carcinomas to a Phenotype comparable to that of normal Fibroblasts

Cancer associated fibroblasts (CAFs) play a critical role for growth, invasion, and metastasis of cancer. Therefore, targeting CAFs with small molecule inhibitors may be an attractive anti-tumor strategy. The current study aims to identify small molecule kinase inhibitors affecting CAF's growth and to characterize the biological effects of active compounds on primary CAFs from lung cancer. We screened two individual CAF strains for their sensitivity to a panel of 160 kinase inhibitors. Five kinase inhibitors were identified inhibiting more than 50% of the growth of both cell lines. Three of them were inhibitors of PDGFR at nanomolar concentrations. Therefore, we further tested the FDA approved PDGFR inhibitors Dasatinib, Nilotinib, Sorafenib, and Imatinib. All 37 CAF strains investigated were highly sensitive to Dasatinib at clinically relevant concentrations. Imatinib was slightly less effective, whereas the inhibitory effects of Nilotinib and Sorafenib were significantly less pronounced

Stress-induced TRAILR2 expression overcomes TRAIL resistance in cancer cell spheroids

The influence of 3D microenvironments on apoptosis susceptibility remains poorly understood. Here, we studied the susceptibility of cancer cell spheroids, grown to the size of micrometastases, to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Interestingly, pronounced, spatially coordinated response heterogeneities manifest within spheroidal microenvironments: In spheroids grown from genetically identical cells, TRAIL-resistant subpopulations enclose, and protect TRAIL-hypersensitive cells, thereby increasing overall treatment resistance. TRAIL-resistant layers form at the interface of proliferating and quiescent cells and lack both TRAILR1 and TRAILR2 protein expression. In contrast, oxygen, and nutrient deprivation promote high amounts of TRAILR2 expression in TRAIL-hypersensitive cells in inner spheroid layers. COX-II inhibitor celecoxib further enhanced TRAILR2 expression in spheroids, likely resulting from increased ER stress, and thereby re-sensitized TRAIL-resistant cell layers to treatment. Our analyses explain how TRAIL response heterogeneities manifest within well-defined multicellular environments, and how spatial barriers of TRAIL resistance can be minimized and eliminated

Ab initio van der Waals interactions in simulations of water alter structure from mainly tetrahedral to high-density-like

The structure of liquid water at ambient conditions is studied in ab initio molecular dynamics simulations using van der Waals (vdW) density-functional theory, i.e. using the new exchange-correlation functionals optPBE-vdW and vdW-DF2. Inclusion of the more isotropic vdW interactions counteracts highly directional hydrogen-bonds, which are enhanced by standard functionals. This brings about a softening of the microscopic structure of water, as seen from the broadening of angular distribution functions and, in particular, from the much lower and broader first peak in the oxygen-oxygen pair-correlation function (PCF), indicating loss of structure in the outer solvation shells. In combination with softer non-local correlation terms, as in the new parameterization of vdW-DF, inclusion of vdW interactions is shown to shift the balance of resulting structures from open tetrahedral to more close-packed. The resulting O-O PCF shows some resemblance with experiment for high-density water (A. K. Soper and M. A. Ricci, Phys. Rev. Lett., 84:2881, 2000), but not directly with experiment for ambient water. However, an O-O PCF consisting of a linear combination of 70% from vdW-DF2 and 30% from experiment on low-density liquid water reproduces near-quantitatively the experimental O-O PCF for ambient water, indicating consistency with a two-liquid model with fluctuations between high- and low-density regions

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Density-Independent Mortality and Increasing Plant Diversity Are Associated with Differentiation of Taraxacum officinale into r- and K-Strategists

Background: Differential selection between clones of apomictic species may result in ecological differentiation without mutation and recombination, thus offering a simple system to study adaptation and life-history evolution in plants. Methodology/Principal Findings: We caused density-independent mortality by weeding to colonizer populations of the largely apomictic Taraxacum officinale (Asteraceae) over a 5-year period in a grassland biodiversity experiment (Jena Experiment). We compared the offspring of colonizer populations with resident populations deliberately sown into similar communities. Plants raised from cuttings and seeds of colonizer and resident populations were grown under uniform conditions. Offspring from colonizer populations had higher reproductive output, which was in general agreement with predictions of r-selection theory. Offspring from resident populations had higher root and leaf biomass, fewer flower heads and higher individual seed mass as predicted under K-selection. Plants grown from cuttings and seeds differed to some degree in the strength, but not in the direction, of their response to the r- vs. K-selection regime. More diverse communities appeared to exert stronger K-selection on resident populations in plants grown from cuttings, while we did not find significant effects of increasing species richness on plants grown from seeds. Conclusions/Significance: Differentiation into r- and K-strategists suggests that clones with characteristics of r-strategists were selected in regularly weeded plots through rapid colonization, while increasing plant diversity favoured the selection of clones with characteristics of K-strategists in resident populations. Our results show that different selection pressures may result in a rapid genetic differentiation within a largely apomictic species. Even under the assumption that colonizer and resident populations, respectively, happened to be r- vs. K-selected already at the start of the experiment, our results still indicate that the association of these strategies with the corresponding selection regimes was maintained during the 5-year experimental period

Diversity Promotes Temporal Stability across Levels of Ecosystem Organization in Experimental Grasslands

The diversity–stability hypothesis states that current losses of biodiversity can impair the ability of an ecosystem to dampen the effect of environmental perturbations on its functioning. Using data from a long-term and comprehensive biodiversity experiment, we quantified the temporal stability of 42 variables characterizing twelve ecological functions in managed grassland plots varying in plant species richness. We demonstrate that diversity increases stability i) across trophic levels (producer, consumer), ii) at both the system (community, ecosystem) and the component levels (population, functional group, phylogenetic clade), and iii) primarily for aboveground rather than belowground processes. Temporal synchronization across studied variables was mostly unaffected with increasing species richness. This study provides the strongest empirical support so far that diversity promotes stability across different ecological functions and levels of ecosystem organization in grasslands

Using Plant Functional Traits to Explain Diversity–Productivity Relationships

Background: The different hypotheses proposed to explain positive species richness–productivity relationships, i.e. selection effect and complementarity effect, imply that plant functional characteristics are at the core of a mechanistic understanding of biodiversity effects. Methodology/Principal Findings: We used two community-wide measures of plant functional composition, (1) community- weighted means of trait values (CWM) and (2) functional trait diversity based on Rao’s quadratic diversity (FDQ) to predict biomass production and measures of biodiversity effects in experimental grasslands (Jena Experiment) with different species richness (2, 4, 8, 16 and 60) and different functional group number and composition (1 to 4; legumes, grasses, small herbs, tall herbs) four years after establishment. Functional trait composition had a larger predictive power for community biomass and measures of biodiversitity effects (40–82% of explained variation) than species richness per se (,1–13% of explained variation). CWM explained a larger amount of variation in community biomass (80%) and net biodiversity effects (70%) than FDQ (36 and 38% of explained variation respectively). FDQ explained similar proportions of variation in complementarity effects (24%, positive relationship) and selection effects (28%, negative relationship) as CWM (27% of explained variation for both complementarity and selection effects), but for all response variables the combination of CWM and FDQ led to significant model improvement compared to a separate consideration of different components of functional trait composition. Effects of FDQ were mainly attributable to diversity in nutrient acquisition and life-history strategies. The large spectrum of traits contributing to positive effects of CWM on biomass production and net biodiversity effects indicated that effects of dominant species were associated with different trait combinations. Conclusions/Significance: Our results suggest that the identification of relevant traits and the relative impacts of functional identity of dominant species and functional diversity are essential for a mechanistic understanding of the role of plant diversity for ecosystem processes such as aboveground biomass production

Shaping a screening file for maximal lead discovery efficiency and effectiveness: elimination of molecular redundancy

High Throughput Screening (HTS) is a successful strategy for finding hits and leads that have the opportunity to be converted into drugs. In this paper we highlight novel computational methods used to select compounds to build a new screening file at Pfizer and the analytical methods we used to assess their quality. We also introduce the novel concept of molecular redundancy to help decide on the density of compounds required in any region of chemical space in order to be confident of running successful HTS campaigns

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Amyloid-beta 42 (A beta 42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for A beta 42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple A beta 42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.Peer reviewe

State of the climate in 2018

In 2018, the dominant greenhouse gases released into Earth’s atmosphere—carbon dioxide, methane, and nitrous oxide—continued their increase. The annual global average carbon dioxide concentration at Earth’s surface was 407.4 ± 0.1 ppm, the highest in the modern instrumental record and in ice core records dating back 800 000 years. Combined, greenhouse gases and several halogenated gases contribute just over 3 W m−2 to radiative forcing and represent a nearly 43% increase since 1990. Carbon dioxide is responsible for about 65% of this radiative forcing. With a weak La Niña in early 2018 transitioning to a weak El Niño by the year’s end, the global surface (land and ocean) temperature was the fourth highest on record, with only 2015 through 2017 being warmer. Several European countries reported record high annual temperatures. There were also more high, and fewer low, temperature extremes than in nearly all of the 68-year extremes record. Madagascar recorded a record daily temperature of 40.5°C in Morondava in March, while South Korea set its record high of 41.0°C in August in Hongcheon. Nawabshah, Pakistan, recorded its highest temperature of 50.2°C, which may be a new daily world record for April. Globally, the annual lower troposphere temperature was third to seventh highest, depending on the dataset analyzed. The lower stratospheric temperature was approximately fifth lowest. The 2018 Arctic land surface temperature was 1.2°C above the 1981–2010 average, tying for third highest in the 118-year record, following 2016 and 2017. June’s Arctic snow cover extent was almost half of what it was 35 years ago. Across Greenland, however, regional summer temperatures were generally below or near average. Additionally, a satellite survey of 47 glaciers in Greenland indicated a net increase in area for the first time since records began in 1999. Increasing permafrost temperatures were reported at most observation sites in the Arctic, with the overall increase of 0.1°–0.2°C between 2017 and 2018 being comparable to the highest rate of warming ever observed in the region. On 17 March, Arctic sea ice extent marked the second smallest annual maximum in the 38-year record, larger than only 2017. The minimum extent in 2018 was reached on 19 September and again on 23 September, tying 2008 and 2010 for the sixth lowest extent on record. The 23 September date tied 1997 as the latest sea ice minimum date on record. First-year ice now dominates the ice cover, comprising 77% of the March 2018 ice pack compared to 55% during the 1980s. Because thinner, younger ice is more vulnerable to melting out in summer, this shift in sea ice age has contributed to the decreasing trend in minimum ice extent. Regionally, Bering Sea ice extent was at record lows for almost the entire 2017/18 ice season. For the Antarctic continent as a whole, 2018 was warmer than average. On the highest points of the Antarctic Plateau, the automatic weather station Relay (74°S) broke or tied six monthly temperature records throughout the year, with August breaking its record by nearly 8°C. However, cool conditions in the western Bellingshausen Sea and Amundsen Sea sector contributed to a low melt season overall for 2017/18. High SSTs contributed to low summer sea ice extent in the Ross and Weddell Seas in 2018, underpinning the second lowest Antarctic summer minimum sea ice extent on record. Despite conducive conditions for its formation, the ozone hole at its maximum extent in September was near the 2000–18 mean, likely due to an ongoing slow decline in stratospheric chlorine monoxide concentration. Across the oceans, globally averaged SST decreased slightly since the record El Niño year of 2016 but was still far above the climatological mean. On average, SST is increasing at a rate of 0.10° ± 0.01°C decade−1 since 1950. The warming appeared largest in the tropical Indian Ocean and smallest in the North Pacific. The deeper ocean continues to warm year after year. For the seventh consecutive year, global annual mean sea level became the highest in the 26-year record, rising to 81 mm above the 1993 average. As anticipated in a warming climate, the hydrological cycle over the ocean is accelerating: dry regions are becoming drier and wet regions rainier. Closer to the equator, 95 named tropical storms were observed during 2018, well above the 1981–2010 average of 82. Eleven tropical cyclones reached Saffir–Simpson scale Category 5 intensity. North Atlantic Major Hurricane Michael’s landfall intensity of 140 kt was the fourth strongest for any continental U.S. hurricane landfall in the 168-year record. Michael caused more than 30 fatalities and $25 billion (U.S. dollars) in damages. In the western North Pacific, Super Typhoon Mangkhut led to 160 fatalities and$6 billion (U.S. dollars) in damages across the Philippines, Hong Kong, Macau, mainland China, Guam, and the Northern Mariana Islands. Tropical Storm Son-Tinh was responsible for 170 fatalities in Vietnam and Laos. Nearly all the islands of Micronesia experienced at least moderate impacts from various tropical cyclones. Across land, many areas around the globe received copious precipitation, notable at different time scales. Rodrigues and Réunion Island near southern Africa each reported their third wettest year on record. In Hawaii, 1262 mm precipitation at Waipā Gardens (Kauai) on 14–15 April set a new U.S. record for 24-h precipitation. In Brazil, the city of Belo Horizonte received nearly 75 mm of rain in just 20 minutes, nearly half its monthly average. Globally, fire activity during 2018 was the lowest since the start of the record in 1997, with a combined burned area of about 500 million hectares. This reinforced the long-term downward trend in fire emissions driven by changes in land use in frequently burning savannas. However, wildfires burned 3.5 million hectares across the United States, well above the 2000–10 average of 2.7 million hectares. Combined, U.S. wildfire damages for the 2017 and 2018 wildfire seasons exceeded $40 billion (U.S. dollars)