Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive ...therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients.
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•Loss of EGFR signaling leads to senescence-like dormancy in EGFR-mutant lung cancer•YAP promotes survival and dormancy in the absence of EGFR downstream signaling•YAP/TEAD/SLUG suppress apoptosis through transcriptional repression of BMF•A TEAD inhibitor enhances EGFR inhibitor-mediated apoptosis and prevents dormancy
Kurppa et al. show that YAP activation mediates resistance to combined EGFR/MEK inhibition by inducing dormancy in non-small-cell lung cancer cells. Targeting the YAP pathway, in part by using a newly developed covalent TEAD inhibitor, promotes apoptosis of the dormant therapy-resistant cancer cells.
Distillers' dry grain (DDG) was derivatized either by carboxymethylation, glutaration, maleiation, phthallation, or succination in order to produce anionic materials suitable for complexation with ...soy protein isolate. Infrared spectroscopy confirmed that derivatization of DDG by all reagents was successful. Blending of derivatized anionic products with soy protein resulted in instant precipitation of gels. The gels were centrifuged, molded, and dried into solid pellets with tensile strengths as high as 1.67MPa, suggesting that these materials could be promising as biodegradable structural materials. Infrared spectroscopy suggested the possibility of complexes forming between soy protein isolate and each of the derivatized DDG samples.
Hardwood sawdust was derivatized either by carboxymethylation, glutaration, maleiation, phthallation, or succination in order to produce anionic materials suitable for complexation with soy protein ...isolate. Blending each derivative with soy protein isolate resulted in instant precipitation of gels. Infrared spectroscopy and differential scanning calorimetry suggested that each derivative formed a complex with protein. Reaction products could be dried into pellets exhibiting tensile strengths between 0.9-2.4 MPa, suggested that these materials could be promising candidates for biodegradable structural materials.
Beyond providing food, livestock species are linked to a wide range of uses and ecosystem services (ESs). Based on information reported by 41 countries on 3 361 national breed populations to the ...Domestic Animal Diversity Information System of the Food and Agriculture Organization of the United Nations, we investigated how factors such as species, region, breed adaptedness, or management system associate with the recognition of provision of a set of 52 ESs. Among species, a greater number of cultural ESs were reported for horses (2.47 for horses vs 0.75 on average across all species), while the major ruminant species (cattle, goats and sheep) were on average associated with more provisioning ESs (2.99 vs 2.39), and more regulating and maintenance ESs (1.86 vs 1.32). Compared to European breeds, African livestock contribute more provisioning ES (3.95 vs 1.88). Native breeds and, to a lesser extent, locally adapted breeds, were linked to more ESs than were exotic breeds (5.97 and 4.10 vs 2.90, respectively), regardless of the ES category considered. The total number of ES reported was greater for breeds primarily kept under Back Yard/Farm Yard and extensive management systems than in other production environments. Different "bundles" of ES were identified in relation to the interdependence among themselves, or according to species or regional specificities. Overall, our results highlight that native and locally adapted breeds, which tend to be raised in less specialized production systems than exotic breeds, are reported to play multiple roles contributing to rural community livelihoods and environmental sustainability of food systems.
Sufficient genetic variation in livestock populations is necessary both for adaptation to future changes in climate and consumer demand, and for continual genetic improvement of economically ...important traits. Unfortunately, the current trend is for reduced genetic variation, both within and across breeds. The latter occurs primarily through the loss of small, local breeds. Inferior production is a key driver for loss of small breeds, as they are replaced by high-output international transboundary breeds. Selection to improve productivity of small local breeds is therefore critical for their long term survival. The objective of this paper is to review the technology options available for the genetic improvement of small local breeds and discuss their feasibility. Most technologies have been developed for the high-input breeds and consequently are more favorably applied in that context. Nevertheless, their application in local breeds is not precluded and can yield significant benefits, especially when multiple technologies are applied in close collaboration with farmers and breeders. Breeding strategies that require cooperation and centralized decision-making, such as optimal contribution selection, may in fact be more easily implemented in small breeds.
To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high ...risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
Electrochemistry is an established discipline with modern frontiers spanning energy conversion and storage, neuroscience, and organic synthesis. In spite of the expanding opportunities for academic ...and industrial electrochemists, particularly in the growing energy-storage sector, rigorous training of electrochemists is generally lacking at academic institutions in the United States. In this perspective, we highlight the core concepts of electrochemistry and discuss ways in which it has been historically taught. We identify challenges faced when teaching inherently interdisciplinary electrochemical concepts and discuss how technology provides new tools for teaching, such as inexpensive electronics and open-source software, to help address these challenges. Finally, we outline example programs and discuss how new tools and approaches can be brought together to prepare scientists and engineers for careers in electrochemical technology where they can accelerate the research, development, and deployment of the clean energy technology essential to combat climate change in the coming decades.
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Applied sciences; Education; Electrochemical materials science; Electrochemistry; Electrochemistry experimental methods; Engineering
The selective synthesis and in situ characterization of aqueous Al-containing clusters is a long-standing challenge. We report a newly developed integrated platform that combines (i) a selective, ...atom-economical, step-economical, scalable synthesis of Al-containing nanoclusters in water via precision electrolysis with strict pH control and (ii) an improved femtosecond stimulated Raman spectroscopic method covering a broad spectral range of ca. 350–1,400 cm ⁻¹ with high sensitivity, aided by ab initio computations, to elucidate Al aqueous cluster structures and formation mechanisms in real time. Using this platform, a unique view of flat Al ₁₃(μ ₃-OH) ₆(μ ₂-OH) ₁₈(H ₂O) ₂₄(NO ₃) ₁₅ nanocluster formation is observed in water, in which three distinct reaction stages are identified. The initial stage involves the formation of an Al ₇(μ ₃-OH) ₆(μ ₂-OH) ₆(H ₂O) ₁₂ ⁹⁺ cluster core as an important intermediate toward the flat Al ₁₃ aqueous cluster.
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