Since 2003, rare inborn errors of human type I IFN immunity have been discovered, each underlying a few severe viral illnesses. Autoantibodies neutralizing type I IFNs due to rare inborn errors of ...autoimmune regulator (AIRE)-driven T cell tolerance were discovered in 2006, but not initially linked to any viral disease. These two lines of clinical investigation converged in 2020, with the discovery that inherited and/or autoimmune deficiencies of type I IFN immunity accounted for approximately 15%-20% of cases of critical COVID-19 pneumonia in unvaccinated individuals. Thus, insufficient type I IFN immunity at the onset of SARS-CoV-2 infection may be a general determinant of life-threatening COVID-19. These findings illustrate the unpredictable, but considerable, contribution of the study of rare human genetic diseases to basic biology and public health.
Conservationists have proposed methods for adapting to climate change that assume species distributions are primarily explained by climate variables. The key idea is to use the understanding of ...species-climate relationships to map corridors and to identify regions of faunal stability or high species turnover. An alternative approach is to adopt an evolutionary timescale and ask ultimately what factors control total diversity, so that over the long run the major drivers of total species richness can be protected. Within a single climatic region, the temperate area encompassing all of the Northeastern U.S. and Maritime Canada, we hypothesized that geologic factors may take precedence over climate in explaining diversity patterns. If geophysical diversity does drive regional diversity, then conserving geophysical settings may offer an approach to conservation that protects diversity under both current and future climates. Here we tested how well geology predicts the species diversity of 14 US states and three Canadian provinces, using a comprehensive new spatial dataset. Results of linear regressions of species diversity on all possible combinations of 23 geophysical and climatic variables indicated that four geophysical factors; the number of geological classes, latitude, elevation range and the amount of calcareous bedrock, predicted species diversity with certainty (adj. R(2) = 0.94). To confirm the species-geology relationships we ran an independent test using 18,700 location points for 885 rare species and found that 40% of the species were restricted to a single geology. Moreover, each geology class supported 5-95 endemic species and chi-square tests confirmed that calcareous bedrock and extreme elevations had significantly more rare species than expected by chance (P<0.0001), strongly corroborating the regression model. Our results suggest that protecting geophysical settings will conserve the stage for current and future biodiversity and may be a robust alternative to species-level predictions.
Abstract CaMKII is activated by oxidation of methionine residues residing in the regulatory domain. Oxidized CaMKII (ox-CaMKII) is now thought to participate in cardiovascular and pulmonary diseases ...and cancer. This invited review summarizes current evidence for the role of ox-CaMKII in disease, considers critical knowledge gaps and suggests new areas for inquiry.
Although the thymus has long been recognized as a key organ for T cell selection, the intricate details linking these selection events to human autoimmunity have been challenging to decipher. Over ...the last two decades, there has been rapid progress in understanding the role of thymic tolerance mechanisms in autoimmunity through genetics. Here we review some of the recent progress in understanding key thymic tolerance processes that are critical for preventing autoimmune disease.
In school and out of trouble? Anderson, D. Mark
The review of economics and statistics,
05/2014, Letnik:
96, Številka:
2
Journal Article
Recenzirano
This paper examines the relationship between the minimum high school dropout age and juvenile arrest rates by exploiting state-level variation in dropout age laws. County-level arrest data for the ...period 1980 to 2008 and difference-in-difference-in-difference-type empirical strategy are used to compare the arrest rates over time of various age groups within counties that differ by their state's minimum dropout age. The evidence suggests that minimum dropout age requirements have a significant and negative effect on property and violent crime arrest rates for individuals 16 to 18 years old. The results are consistent with an incapacitation effect of schooling.
Abstract Sustained Ca 2 + /calmodulin-dependent kinase II (CaMKII) activation plays a central role in the pathogenesis of a variety of cardiac diseases. Emerging evidence suggests CaMKII evoked ...programmed cell death, including apoptosis and necroptosis, is one of the key underlying mechanisms for the detrimental effect of sustained CaMKII activation. CaMKII integrates β-adrenergic, Gq coupled receptor, reactive oxygen species (ROS), hyperglycemia, and pro-death cytokine signaling to elicit myocardial apoptosis by intrinsic and extrinsic pathways. New evidence demonstrates CaMKII is also a key mediator of receptor interacting serine/threonine kinase 3 (RIP3)-induced myocardial necroptosis. The role of CaMKII in cell death is dependent upon subcellular localization and varies across isoforms and splice variants. While CaMKII is now an extensively validated nodal signal for promoting cardiac myocyte death, the upstream and downstream pathways and targets remain incompletely understood, demanding further investigation.
Heterogeneity of reactive astrocytes Anderson, Mark A.; Ao, Yan; Sofroniew, Michael V.
Neuroscience letters,
04/2014, Letnik:
565
Journal Article
Recenzirano
Odprti dostop
•Astrocyte reactivity is not a single stereotypic program.•Reactive astrocytes exhibit substantial heterogeneity at multiple levels.•Heterogeneity includes gene expression, cell morphology and cell ...function.•Astrocyte reactivity varies in a context specific manner.•Astrocyte reactivity occurs in response to many different specific signaling events.
Astrocytes respond to injury and disease in the central nervous system (CNS) with a process referred to as reactive astrogliosis. Recent progress demonstrates that reactive astrogliosis is not a simple all-or-none phenomenon, but is a finely gradated continuum of changes that range from reversible alterations in gene expression and cell hypertrophy, to scar formation with permanent tissue rearrangement. There is now compelling evidence that reactive astrocytes exhibit a substantial potential for heterogeneity at multiple levels, including gene expression, cell morphology, topography (distance from lesions), CNS regions, local (among neighboring cells), cell signaling and cell function. Structural and functional changes are regulated in reactive astrocytes by many different potential signaling events that occur in a context dependent manner. It is noteworthy that different stimuli of astrocyte reactivity can lead to similar degrees of GFAP upregulation while causing substantially different changes in transcriptome profiles and cell function. Thus, it is not possible to equate simple and uniform measures such as cell hypertrophy and upregulation of GFAP expression with a single, uniform concept of astrocyte reactivity. Instead, it is necessary to recognize the considerable potential for heterogeneity and determine the functional implications of astrocyte reactivity in a context specific manner as regulated by specific signaling events.
Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of pancreatic β cells that results in lifelong absolute insulin deficiency. For nearly a century, insulin ...replacement has been the only therapy for most people living with this disease. Recent advances in technology and our understanding of β cell development, glucose metabolism, and the underlying immune pathogenesis of the disease have led to innovative therapeutic and preventative approaches. A paradigm shift in immunotherapy development toward the targeting of islet-specific immune pathways involved in tolerance has driven the development of therapies that may allow for the prevention or reversal of this disease while avoiding toxicities associated with historical approaches that were broadly immunosuppressive. In this review, we discuss successes, failures, and emerging pharmacological therapies for type 1 diabetes that are changing how we approach this disease, from improving glycemic control to developing the “holy grail” of disease prevention.
Type 1 diabetes (T1D) immunotherapies are entering a new era of targeted approaches that take advantage of key mechanistic insights to generate therapies that maintain safety where broadly immunosuppressive approaches have failed. Warshauer et al. discuss successes, failures, and emerging pharmacological therapies for T1D that address the immune and metabolic side of the disease.
More than 15 years ago, mutations in the autoimmune regulator (AIRE) gene were identified as the cause of autoimmune polyglandular syndrome type 1 (APS1). It is now clear that this transcription ...factor has a crucial role in promoting self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery. In this Review, we highlight many of the recent advances in our understanding of the complex biology that is related to AIRE, with a particular focus on advances in genetics, molecular interactions and the effect of AIRE on thymic selection of regulatory T cells. Furthermore, we highlight new areas of biology that are potentially affected by this key regulator of immune tolerance.
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