Ubiquitylation and sumoylation, the covalent attachment of the polypeptides ubiquitin and SUMO, respectively, to target proteins, are pervasive mechanisms for controlling cellular functions. Here, we ...summarize the key steps and enzymes involved in ubiquitin and SUMO conjugation and provide an overview of how they are crucial for maintaining genome stability. Specifically, we review research that has revealed how ubiquitylation and sumoylation regulate and coordinate various pathways of DNA damage recognition, signaling, and repair at the biochemical, cellular, and whole-organism levels. In addition to providing key insights into the control and importance of DNA repair and associated processes, such work has established paradigms for regulatory control that are likely to extend to other cellular processes and that may provide opportunities for better understanding and treatment of human disease.
In vertebrate cells, the DNA damage response is controlled by three related kinases: ATM, ATR, and DNA-PK. It has been 20 years since the cloning of ATR, the last of the three to be identified. ...During this time, our understanding of how these kinases regulate DNA repair and associated events has grown profoundly, although major questions remain unanswered. Here, we provide a historical perspective of their discovery and discuss their established functions in sensing and responding to genotoxic stress. We also highlight what is known regarding their structural similarities and common mechanisms of regulation, as well as emerging non-canonical roles and how our knowledge of ATM, ATR, and DNA-PK is being translated to benefit human health.
In vertebrate cells, the DNA damage response is controlled by three related kinases: ATM, ATR, and DNA-PK. It has been 20 years since the cloning of ATR, the last of the three to be identified. During this time, our understanding of how these kinases regulate DNA repair and associated events has grown profoundly, although major questions remain unanswered. Here, we provide a historical perspective of their discovery and discuss their established functions in sensing and responding to genotoxic stress. We also highlight what is known regarding their structural similarities and common mechanisms of regulation, as well as emerging non-canonical roles and how our knowledge of ATM, ATR, and DNA-PK is being translated to benefit human health.
Thrombosis with associated inflammation (thromboinflammation) occurs commonly in a broad range of human disorders. It is well recognized clinically in the context of superficial thrombophlebitis ...(thrombosis and inflammation of superficial veins); however, it is more dangerous when it develops in the microvasculature of injured tissues and organs. Microvascular thrombosis with associated inflammation is well recognized in the context of sepsis and ischemia-reperfusion injury; however, it also occurs in organ transplant rejection, major trauma, severe burns, the antiphospholipid syndrome, preeclampsia, sickle cell disease, and biomaterial-induced thromboinflammation. Central to thromboinflammation is the loss of the normal antithrombotic and anti-inflammatory functions of endothelial cells, leading to dysregulation of coagulation, complement, platelet activation, and leukocyte recruitment in the microvasculature. α-Thrombin plays a critical role in coordinating thrombotic and inflammatory responses and has long been considered an attractive therapeutic target to reduce thromboinflammatory complications. This review focuses on the role of basic aspects of coagulation and α-thrombin in promoting thromboinflammatory responses and discusses insights gained from clinical trials on the effects of various inhibitors of coagulation on thromboinflammatory disorders. Studies in sepsis patients have been particularly informative because, despite using anticoagulant approaches with different pharmacological profiles, which act at distinct points in the coagulation cascade, bleeding complications continue to undermine clinical benefit. Future advances may require the development of therapeutics with primary anti-inflammatory and cytoprotective properties, which have less impact on hemostasis. This may be possible with the growing recognition that components of blood coagulation and platelets have prothrombotic and proinflammatory functions independent of their hemostatic effects.
The Indignant Generation is the first narrative history of the neglected but essential period of African American literature between the Harlem Renaissance and the civil rights era. The years between ...these two indispensable epochs saw the communal rise of Richard Wright, Gwendolyn Brooks, Ralph Ellison, Lorraine Hansberry, James Baldwin, and many other influential black writers. While these individuals have been duly celebrated, little attention has been paid to the political and artistic milieu in which they produced their greatest works. With this commanding study, Lawrence Jackson recalls the lost history of a crucial era. Looking at the tumultuous decades surrounding World War II, Jackson restores the "indignant" quality to a generation of African American writers shaped by Jim Crow segregation, the Great Depression, the growth of American communism, and an international wave of decolonization. He also reveals how artistic collectives in New York, Chicago, and Washington fostered a sense of destiny and belonging among diverse and disenchanted peoples. As Jackson shows through contemporary documents, the years that brought us Their Eyes Were Watching God, Native Son, and Invisible Man also saw the rise of African American literary criticism--by both black and white critics. Fully exploring the cadre of key African American writers who triumphed in spite of segregation, The Indignant Generation paints a vivid portrait of American intellectual and artistic life in the mid-twentieth century.
The formation of blood clots--thrombosis--at sites of atherosclerotic plaque rupture is a major clinical problem despite ongoing improvements in antithrombotic therapy. Progress in identifying the ...pathogenic mechanisms regulating arterial thrombosis has led to the development of newer therapeutics, and there is general anticipation that these treatments will have greater efficacy and improved safety. However, major advances in this field require the identification of specific risk factors for arterial thrombosis in affected individuals and a rethink of the 'one size fits all' approach to antithrombotic therapy.
Platelet aggregation, the process by which platelets adhere to each other at sites of vascular injury, has long been recognized as critical for hemostatic plug formation and thrombosis. Until ...relatively recently, platelet aggregation was considered a straightforward process involving the noncovalent bridging of integrin αIIbβ3 receptors on the platelet surface by the dimeric adhesive protein fibrinogen. However, with recent technical advances enabling real-time analysis of platelet aggregation in vivo, it has become apparent that this process is much more complex and dynamic than previously anticipated. Over the last decade, it has become clear that platelet aggregation represents a multistep adhesion process involving distinct receptors and adhesive ligands, with the contribution of individual receptor-ligand interactions to the aggregation process dependent on the prevailing blood flow conditions. It now appears that at least 3 distinct mechanisms can initiate platelet aggregation, with each of these mechanisms operating over a specific shear range in vivo. The identification of shear-dependent mechanisms of platelet aggregation has raised the possibility that vascular-bed–specific inhibitors of platelet aggregation may be developed in the future that are safer and more effective than existing antiplatelet agents.
Global warming is expected to drive increasing extreme sea levels (ESLs) and flood risk along the world's coastlines. In this work we present probabilistic projections of ESLs for the present century ...taking into consideration changes in mean sea level, tides, wind-waves, and storm surges. Between the year 2000 and 2100 we project a very likely increase of the global average 100-year ESL of 34-76 cm under a moderate-emission-mitigation-policy scenario and of 58-172 cm under a business as usual scenario. Rising ESLs are mostly driven by thermal expansion, followed by contributions from ice mass-loss from glaciers, and ice-sheets in Greenland and Antarctica. Under these scenarios ESL rise would render a large part of the tropics exposed annually to the present-day 100-year event from 2050. By the end of this century this applies to most coastlines around the world, implying unprecedented flood risk levels unless timely adaptation measures are taken.
Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed the DNA damage response (DDR). A common feature of DDR proteins is their mobilization in response to ...genotoxic stress. Here, we outline how the development of various complementary methodologies has provided valuable insights into the spatiotemporal dynamics of DDR protein assembly/disassembly at sites of DNA strand breaks in eukaryotic cells. Considerable advances have also been made in understanding the underlying molecular mechanisms for these events, with post-translational modifications of DDR factors being shown to play prominent roles in controlling the formation of foci in response to DNA-damaging agents. We review these regulatory mechanisms and discuss their biological significance to the DDR.
Sea-level change is an integrated climate system response due to changes in radiative forcing, anthropogenic land-water use and land-motion. Projecting sea-level at a global and regional scale ...requires a subset of projections - one for each sea-level component given a particular climate-change scenario. We construct relative sea-level projections through the 21st century for RCP 4.5, RCP 8.5 and High-end (RCP 8.5 with increased ice-sheet contribution) scenarios by aggregating spatial projections of individual sea-level components in a probabilistic manner. Most of the global oceans adhere to the projected global average sea level change within 5cm throughout the century for all scenarios; however coastal regions experience localised effects due to the non-uniform spatial patterns of individual components. This can result in local projections that are 10′s of centimetres different from the global average by 2100. Early in the century, RSL projections are consistent across all scenarios, however from the middle of the century the patterns of RSL for RCP scenarios deviate from the High-end where the contribution from Antarctica dominates. Similarly, the uncertainty in projected sea-level is dominated by an uncertain Antarctic fate. We also explore the effect upon projections of, treating CMIP5 model ensembles as normally distributed when they might not be, correcting CMIP5 model output for internal variability using different polynomials and using different unloading patterns of ice for the Greenland and Antarctic ice sheets.
•We construct regional sea-level projections for three climate change scenarios•Projections are derived using a probabilistic method•The bulk of global oceans display close to global average projected sea level (± 5cm)•The pattern of projected sea-level deviates between scenarios – primarily due to the contribution from Antarctic ice sheet•Methodological choices affect projections at cm-scale for ocean volume and up to 10′s of cm for land-ice melt by 2100.
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