Current climate change may be a major threat to global biodiversity, but the extent of species loss will depend on the details of how species respond to changing climates. For example, if most ...species can undergo rapid change in their climatic niches, then extinctions may be limited. Numerous studies have now documented shifts in the geographic ranges of species that were inferred to be related to climate change, especially shifts towards higher mean elevations and latitudes. Many of these studies contain valuable data on extinctions of local populations that have not yet been thoroughly explored. Specifically, overall range shifts can include range contractions at the "warm edges" of species' ranges (i.e., lower latitudes and elevations), contractions which occur through local extinctions. Here, data on climate-related range shifts were used to test the frequency of local extinctions related to recent climate change. The results show that climate-related local extinctions have already occurred in hundreds of species, including 47% of the 976 species surveyed. This frequency of local extinctions was broadly similar across climatic zones, clades, and habitats but was significantly higher in tropical species than in temperate species (55% versus 39%), in animals than in plants (50% versus 39%), and in freshwater habitats relative to terrestrial and marine habitats (74% versus 46% versus 51%). Overall, these results suggest that local extinctions related to climate change are already widespread, even though levels of climate change so far are modest relative to those predicted in the next 100 years. These extinctions will presumably become much more prevalent as global warming increases further by roughly 2-fold to 5-fold over the coming decades.
The liberal international order, erected after the Cold War, was crumbling by 2019. It was flawed from the start and thus destined to fail. The spread of liberal democracy around the globe—essential ...for building that order—faced strong resistance because of nationalism, which emphasizes self-determination. Some targeted states also resisted U.S. efforts to promote liberal democracy for security-related reasons. Additionally, problems arose because a liberal order calls for states to delegate substantial decisionmaking authority to international institutions and to allow refugees and immigrants to move easily across borders. Modern nation-states privilege sovereignty and national identity, however, which guarantees trouble when institutions become powerful and borders porous. Furthermore, the hyperglobalization that is integral to the liberal order creates economic problems among the lower and middle classes within the liberal democracies, fueling a backlash against that order. Finally, the liberal order accelerated China's rise, which helped transform the system from unipolar to multipolar. A liberal international order is possible only in unipolarity. The new multipolar world will feature three realist orders: a thin international order that facilitates cooperation, and two bounded orders—one dominated by China, the other by the United States—poised for waging security competition between them.
A major theoretical statement by a distinguished political scholar explains why a policy of liberal hegemony is doomed to failIn this major statement, the renowned international-relations scholar ...John Mearsheimer argues that liberal hegemony, the foreign policy pursued by the United States since the Cold War ended, is doomed to fail. It makes far more sense, he maintains, for Washington to adopt a more restrained foreign policy based on a sound understanding of how nationalism and realism constrain great powers abroad.It is widely believed in the West that the United States should spread liberal democracy across the world, foster an open international economy, and build institutions. This policy of remaking the world in America's image is supposed to protect human rights, promote peace, and make the world safe for democracy. But this is not what has happened. Instead, the United States has ended up as a highly militarized state fighting wars that undermine peace, harm human rights, and threaten liberal values at home. Mearsheimer tells us why this has happened.
The discovery of the Janus kinase (JAK)-signal transducer and activator of transcripton (STAT) signaling pathway, a landmark in cell biology, provided a simple mechanism for gene regulation that ...dramatically advanced our understanding of the action of hormones, interferons, colony-stimulating factors, and interleukins. As we learn more about the complexities of immune responses, new insights into the functions of this pathway continue to be revealed, aided by technology that permits genome-wide views. As we celebrate the 20th anniversary of the discovery of this paradigm in cell signaling, it is particularly edifying to see how this knowledge has rapidly been translated to human immune disease. Not only have genome-wide association studies demonstrated that this pathway is highly relevant to human autoimmunity, but targeting JAKs is now a reality in immune-mediated disease.
Management of COVID-19 Respiratory Distress Marini, John J; Gattinoni, Luciano
JAMA : the journal of the American Medical Association,
06/2020, Letnik:
323, Številka:
22
Journal Article
Signaling pathways are intimately involved in cellular differentiation, allowing cells to respond to their environment by regulating gene expression. Although enhancers are recognized as key elements ...that regulate selective gene expression, the interplay between signaling pathways and actively used enhancer elements is not clear. Here, we use CD4+ T cells as a model of differentiation, mapping the activity of cell-type-specific enhancer elements in T helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the activation of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells.
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► Closely related T helper cell subsets have distinct p300 binding profiles ► STATs activate lineage-specific enhancers and suppress those of alternative fates ► Overexpression of master regulators cannot compensate for lack of STATs ► Changes in T cell transcriptome correspond to changes in p300 binding
Responding to environmental cues, STAT proteins direct the establishment of enhancer signatures that promote unique T cell fates. Surprisingly, T cell master regulators cannot compensate for the lack of STATs, suggesting that STATs play an essential and independent role in the activation of lineage-specific enhancers.
The four Janus kinase (JAK) proteins and seven signal transducer and activator of transcription (STAT) transcription factors mediate intracellular signal transduction downstream of cytokine ...receptors, which are implicated in the pathology of autoimmune, allergic and inflammatory diseases. Development of targeted small-molecule therapies such as JAK inhibitors, which have varied selective inhibitory profiles, has enabled a paradigm shift in the treatment of diverse disorders. JAK inhibitors suppress intracellular signalling mediated by multiple cytokines involved in the pathological processes of rheumatoid arthritis and many other immune and inflammatory diseases, and therefore have the capacity to target multiple aspects of those diseases. In addition to rheumatoid arthritis, JAK inhibition has potential for treatment of autoimmune diseases including systemic lupus erythematosus, spondyloarthritis, inflammatory bowel disease and alopecia areata, in which stimulation of innate immunity activates adaptive immunity, leading to generation of autoreactive T cells and activation and differentiation of B cells. JAK inhibitors are also effective in the treatment of allergic disorders, such as atopic dermatitis, and can even be used for the COVID-19-related cytokine storm. Mechanism-based treatments targeting JAK-STAT pathways have the potential to provide positive outcomes by minimizing the use of glucocorticoids and/or non-specific immunosuppressants in the treatment of systemic immune-mediated inflammatory diseases.
This article reviews published data on the mechanical properties of additively manufactured metallic materials. The additive manufacturing techniques utilized to generate samples covered in this ...review include powder bed fusion (e.g., EBM, SLM, DMLS) and directed energy deposition (e.g., LENS, EBF
3
). Although only a limited number of metallic alloy systems are currently available for additive manufacturing (e.g., Ti-6Al-4V, TiAl, stainless steel, Inconel 625 718, and Al-Si-10Mg), the bulk of the published mechanical properties information has been generated on Ti-6Al-4V. However, summary tables for published mechanical properties and or key figures are included for each of the alloys listed above, grouped by the additive technique used to generate the data. Published values for mechanical properties obtained from hardness, tension compression, fracture toughness, fatigue crack growth, and high cycle fatigue are included for as-built, heat-treated, and or HIP conditions, when available. The effects of test orientation build direction on properties, when available, are also provided, along with discussion of the potential source(s) (e.g., texture, microstructure changes, defects) of anisotropy in properties. Recommendations for additional work are also provided.
A key metric to assess molecular docking remains ligand enrichment against challenging decoys. Whereas the directory of useful decoys (DUD) has been widely used, clear areas for optimization have ...emerged. Here we describe an improved benchmarking set that includes more diverse targets such as GPCRs and ion channels, totaling 102 proteins with 22886 clustered ligands drawn from ChEMBL, each with 50 property-matched decoys drawn from ZINC. To ensure chemotype diversity, we cluster each target’s ligands by their Bemis–Murcko atomic frameworks. We add net charge to the matched physicochemical properties and include only the most dissimilar decoys, by topology, from the ligands. An online automated tool (http://decoys.docking.org) generates these improved matched decoys for user-supplied ligands. We test this data set by docking all 102 targets, using the results to improve the balance between ligand desolvation and electrostatics in DOCK 3.6. The complete DUD-E benchmarking set is freely available at http://dude.docking.org.
Progenitor-like CD8
T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory ...precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8
T cells responding to acute and chronic viral infections, we found that progenitor-like CD8
T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8
T cells and was required for the programming of progenitor-like CD8
T cells. Thus, long-term CD8
T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.
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