The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is activated constitutively in a wide array of human cancers. It is an appealing molecular target for ...novel therapy as it directly regulates expression of genes involved in cell proliferation, survival, angiogenesis, chemoresistance and immune responsiveness. In addition to these well-established oncogenic roles, STAT3 has also been found to mediate a wide array of functions in modulating cellular behavior. The transcriptional function of STAT3 is canonically regulated through tyrosine phosphorylation. However, STAT3 phosphorylated at a single serine residue can allow incorporation of this protein into the inner mitochondrial membrane to support oxidative phosphorylation (OXPHOS) and maximize the utility of glucose sources. Conflictingly, its canonical transcriptional activity suppresses OXPHOS and favors aerobic glycolysis to promote oncogenic behavior. Apart from mediating the energy metabolism and controversial effects on ATP production, STAT3 signaling modulates lipid metabolism of cancer cells. By mediating fatty acid synthesis and beta oxidation, STAT3 promotes employment of available resources and supports survival in the conditions of metabolic stress. Thus, the functions of STAT3 extend beyond regulation of oncogenic genes expression to pleiotropic effects on a spectrum of essential cellular processes. In this review, we dissect the current knowledge on activity and mechanisms of STAT3 involvement in transcriptional regulation, mitochondrial function, energy production and lipid metabolism of malignant cells, and its implications to cancer pathogenesis and therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Cyclin-dependent kinases (CDK), such as CDK4 and CDK6, phosphorylate RB1 to release the transcription factor E2F and drive the transition from G1 to S-phase of the cell cycle. Inhibitors of these ...kinases thereby block cell-cycle progression and presumably exert their therapeutic effect. While this mechanism is straight forward, several aspects have seemed problematic, not the least of which is that these drugs seem to have therapeutic effects on a relatively small number of human cancers. Tong and colleagues took an open-ended approach to this mechanistic question, and their results raise the possibility that inhibition of phosphorylation of the transcription factor p73 is a key mechanism of action of these drugs. They show that p73 inhibition and the resultant upregulation of the cell surface receptor DR5 are necessary for the anticancer effects of CDK4/6 inhibitors, including enhancement of immune-mediated cell killing, and that therapeutic benefit relies largely on their use in conjunction with other agents. While many questions remain to be answered, these findings demonstrate the importance of keeping an open mind to mechanistic aspects of therapeutic agents already in clinical use and highlight how rigorous mechanistic studies can answer both basic and translational questions. See related article by Tong et al., p. 1340.
The terrestrial biosphere is a key component of the global carbon cycle and its carbon balance is strongly influenced by climate. Continuing environmental changes are thought to increase global ...terrestrial carbon uptake. But evidence is mounting that climate extremes such as droughts or storms can lead to a decrease in regional ecosystem carbon stocks and therefore have the potential to negate an expected increase in terrestrial carbon uptake. Here we explore the mechanisms and impacts of climate extremes on the terrestrial carbon cycle, and propose a pathway to improve our understanding of present and future impacts of climate extremes on the terrestrial carbon budget.
Abstract Much of the focus in understanding the molecular pathogenesis of tumors has centered on kinases that are activated in cancer. However, cancers driven by a diversity of activated kinases may ...have very similar pathological and clinical properties. This likely relates to the fact that the biological characteristics of a tumor are driven by the pattern of gene expression in that tumor, and that a wide spectrum of activating events at the cell surface and in the cytoplasm converge on a relatively small number of transcription factors that regulate the expression of key target genes. One transcription factor that has been found to be activated inappropriately in a wide range of human cancers is STAT3. STAT3 target genes are involved in fundamental events of tumor development including proliferation, survival, self-renewal, invasion, and angiogenesis. Furthermore, there is strong evidence that STAT3 is critical for these processes, in that inhibition of STAT3 by a variety of means can exert an anti-cancer effect. Since normal cells are relatively tolerant of interruption in STAT3 signaling, these findings suggest that STAT3 may also be an excellent target for the molecular therapy of cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Stir bar sorptive extraction (SBSE) has been developed nearly 20 years ago and was commercialized as Twister very soon after its introduction. Main appreciated features by its users are the ...solventless extraction, predictable extraction efficiencies, very high sensitivities when applied in combination with thermal desorption (TD) - GC-MS, multiple use for determinations in gaseous and aqueous matrices and excellent repeatability and reproducibility when polydimethylsiloxane (PDMS) is applied as sorptive phase. These features originate from the unique characteristics of PDMS, with low glass transition temperature, very low bleeding profile at high temperatures after appropriate conditioning, and excellent diffusivity and permeability. PDMS-SBSE is intensively applied in different areas (environmental, food, biofluids, drugs, etc.) for sensitive determinations of solutes with a log P larger than 3. Of utmost importance for routine application of SBSE are its figures of merit and several studies have illustrated that SBSE on PDMS can be validated and standard operating procedures developed.
For more polar solutes, different derivatization methods have been applied to enhance the hydrophobicity of the solutes and thus increasing the log P value. Over the years, other coating materials have been evaluated and/or developed for enhanced extraction of more polar compounds. Only a limited number, however, are operating in the sorptive or partitioning mode while only few of them have favorable thermal characteristics to be used in TD-GC-MS applications. To the best of our knowledge, only one has been commercialized namely a PDMS/ethylene glycol (EG) copolymer placed on an inert metal grid for mechanical stabilization. Other home-made coatings, such as monoliths, polyurethane foams or other polymers are mostly used in combination with liquid desorption, are not commercially available in ready-to-use stir bar format and, therefore, not accessible for independent in-depth testing. Alternatively, two other methods applying PDMS stir bars were recently developed to extend SBSE to more polar solutes: solvent assisted SBSE (SA-SBSE) and ice concentration linked with extractive stirrer (ICECLES) that is based on freeze concentration. This review on SBSE is highlighting both developments and future perspectives of SBSE are outlined.
•A historical review of SBSE is presented.•The fundamentals and application areas are discussed.•New coatings are discussed.•New SBSE methods ICECLES and SA-SBSE are discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
The lung is an architecturally complex organ comprising a heterogeneous mixture of various epithelial and mesenchymal lineages. We use single-cell RNA sequencing and signaling lineage reporters to ...generate a spatial and transcriptional map of the lung mesenchyme. We find that each mesenchymal lineage has a distinct spatial address and transcriptional profile leading to unique niche regulatory functions. The mesenchymal alveolar niche cell is Wnt responsive, expresses Pdgfrα, and is critical for alveolar epithelial cell growth and self-renewal. In contrast, the Axin2+ myofibrogenic progenitor cell preferentially generates pathologically deleterious myofibroblasts after injury. Analysis of the secretome and receptome of the alveolar niche reveals functional pathways that mediate growth and self-renewal of alveolar type 2 progenitor cells, including IL-6/Stat3, Bmp, and Fgf signaling. These studies define the cellular and molecular framework of lung mesenchymal niches and reveal the functional importance of developmental pathways in promoting self-renewal versus a pathological response to tissue injury.
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•Single-cell and population-based RNA sequencing stratifies lung mesenchymal subsets•Identification of functionally distinct myofibrogenic and alveolar niche cell types•Enriched Fgf/IL-6/Bmp signaling defines the alveolar niche secretome:receptome
A single-cell approach reveals the functional pathways that define the cellular and molecular framework of lung mesenchymal niches and reveals the functional importance of developmental pathways in promoting self-renewal versus a pathological response to tissue injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Functional tissue regeneration is required for the restoration of normal organ homeostasis after severe injury. Some organs, such as the intestine, harbour active stem cells throughout homeostasis ...and regeneration; more quiescent organs, such as the lung, often contain facultative progenitor cells that are recruited after injury to participate in regeneration. Here we show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the alveolar type 2 cell population acts as a major facultative progenitor cell in the distal lung. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a large proportion of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome and functional phenotype and respond specifically to Wnt and Fgf signalling. In contrast to other proposed lung progenitor cells, human AEPs can be directly isolated by expression of the conserved cell surface marker TM4SF1, and act as functional human alveolar epithelial progenitor cells in 3D organoids. Our results identify the AEP lineage as an evolutionarily conserved alveolar progenitor that represents a new target for human lung regeneration strategies.
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KISLJ, NUK, SBMB, UL, UM, UPUK
Recently, invasion biologists have argued that some of the skepticism expressed in the scientific and lay literatures about the risks of invasive species and other aspects of the consensus within ...invasion biology is a kind of science denialism. This paper presents an argument that, while some claims made by skeptics of invasion biology share important features with paradigm cases of science denialism, others express legitimate ethical concerns that, even if one disagrees, should not be dismissed as denialist. Further, this case illustrates a more general point about ethical disagreement within sciences like invasion biology that constitutively pursue non-epistemic goals and values. While philosophers of science have argued that epistemic disagreement within science can be productive as heterogeneous epistemic communities “hedge their bets,” the case of invasion biology shows how
non
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epistemic
or ethical disagreement within sciences, while carrying significant risks, can also be epistemically and non-epistemically valuable.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aim
Radial growth and foliage dynamics of trees both play a significant role in the terrestrial carbon cycle. Yet, crucial knowledge gaps exist in how these two growth components are linked. Our goal ...is to help bridge these gaps by providing a Northern Hemispheric survey of the connections between, and drivers of, inter‐annual wood and canopy–landscape dynamics and phenology.
Location
Northern (>30° N) forest ecosystems.
Methods
We compared a multispecies network of ca. 700 annually resolved radial tree‐growth records with the global inventory modelling and mapping studies‐normalized difference vegetation index (GIMMS‐NDVI) estimates of foliage greenness between 1982 and 2012. Tree‐ring data were assimilated into the simple process‐based Vaganov–Shashkin Lite model to derive xylem phenology on a monthly basis and were contrasted against NDVI estimates of canopy phenology. We additionally determined the response of all these vegetation measures to temperature and precipitation.
Results
We found broad‐scale agreement in the phenology and growing season climate response between radial tree growth and seasonally integrated canopy–landscape dynamics. On a monthly basis, however, a temporal asynchrony in the climate signals at mid‐ and high latitudes was observed, where the strongest climate response of the NDVI record occurred around leaf flush, whereas an early‐ to mid‐growing season signal dominated the tree‐ring growth.
Main conclusions
Our comprehensive study helps to elucidate the unique contributions of foliar and radial growth to terrestrial carbon cycling and the time‐scales at which they operate. Although we observed that both measures have similar overall climate constraints, these two growth components are sensitive to distinct seasonal windows. Our study suggests that joint assessment of both leaf and stem growth is required to address productivity of forests and demonstrates that these seasonal sensitivities must be considered before combining and interpreting these two metrics.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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