Autophagy is increasingly recognized for its active role in development and differentiation. In particular, its role in the differentiation of hematopoietic cells has been extensively studied, likely ...because blood cells are accessible, easy to identify and purify, and their progenitor tree is well defined. This review aims to discuss the mechanisms by which autophagy impacts on differentiation, using hematopoietic cell types as examples. Autophagy's roles include the remodeling during terminal differentiation, the maintenance of a long‐lived cell type, and the regulation of the balance between self‐renewal and quiescence in stem‐like cells. We discuss and compare the mechanistic roles of autophagy, such as prevention of apoptosis, supply of energy metabolites and metabolic adaption, and selective degradation of organelles and of regulatory factors.
Autophagy is a conserved cellular degradation pathway that recycles cytoplasmic content for new anabolic processes. It is increasingly recognized for its active role in development and differentiation. This review aims to discuss the mechanisms by which autophagy impacts on differentiation of hematopoietic cells. Mechanisms like apoptosis prevention, metabolic adaption, or organelle maintenance are discussed using hematopoietic cell types as examples.
Synthetic evolution Simon, Anna J; d'Oelsnitz, Simon; Ellington, Andrew D
Nature biotechnology,
07/2019, Letnik:
37, Številka:
7
Journal Article
Recenzirano
The combination of modern biotechnologies such as DNA synthesis, λ red recombineering, CRISPR-based editing and next-generation high-throughput sequencing increasingly enables precise manipulation of ...genes and genomes. Beyond rational design, these technologies also enable the targeted, and potentially continuous, introduction of multiple mutations. While this might seem to be merely a return to natural selection, the ability to target evolution greatly reduces fitness burdens and focuses mutation and selection on those genes and traits that best contribute to a desired phenotype, ultimately throwing evolution into fast forward.
The article explains how populists have exploited the weaknesses of liberal constitutionalism and the public-private divide. It argues that populists have not rejected constitutionalism as a project ...but a negative version of it. In its place, they incorporated their vision of a government unrestricted by individual rights and entered the private sphere with their doctrines. The lesson from the victories of populism is therefore to move toward positive constitutionalism that ensures the well-being of all. Drawing on the concept of relational autonomy, the article explains what this shift consists of in the areas of reproductive rights and gender-based violence. The conclusions outline a shift in the operation of the basic principles of constitutionalism, focusing on the relational nature of rights understood not only as shields, but also as claims to positive state action.
Across all branches of the immune system, the process of autophagy is fundamentally important in cellular development, function and homeostasis. Strikingly, this evolutionarily ancient pathway for ...intracellular recycling has been adapted to enable a high degree of functional complexity and specialization. However, although the requirement for autophagy in normal immune cell function is clear, the mechanisms involved are much less so and encompass control of metabolism, selective degradation of substrates and organelles and participation in cell survival decisions. We review here the crucial functions of autophagy in controlling the differentiation and homeostasis of multiple immune cell types and discuss the potential mechanisms involved.
The biosensor community has long focused on achieving the lowest possible detection limits, with specificity (the ability to differentiate between closely similar target molecules) and sensitivity ...(the ability to differentiate between closely similar target concentrations) largely being relegated to secondary considerations and solved by the inclusion of cumbersome washing and dilution steps or via careful control experimental conditions. Nature, in contrast, cannot afford the luxury of washing and dilution steps, nor can she arbitrarily change the conditions (temperature, pH, ionic strength) under which binding occurs in the homeostatically maintained environment within the cell. This forces evolution to focus at least as much effort on achieving optimal sensitivity and specificity as on achieving low detection limits, leading to the “invention” of a number of mechanisms, such as allostery and cooperativity, by which the useful dynamic range of receptors can be tuned, extended, narrowed, or otherwise optimized by design, rather than by sample manipulation. As the use of biomolecular receptors in artificial technologies matures (i.e., moves away from multistep, laboratory-bound processes and toward, for example, systems supporting continuous in vivo measurement) and these technologies begin to mimic the reagentless single-step convenience of naturally occurring chemoperception systems, the ability to artificially design receptors of enhanced sensitivity and specificity will likely also grow in importance. Thus motivated, we have begun to explore the adaptation of nature’s solutions to these problems to the biomolecular receptors often employed in artificial biotechnologies. Using the population-shift mechanism, for example, we have generated nested sets of receptors and allosteric inhibitors that greatly expanded the normally limited (less than 100-fold) useful dynamic range of unmodified molecular and aptamer beacons, enabling the single-step (e.g., dilution-free) measurement of target concentrations across up to 6 orders of magnitude. Using this same approach to rationally introduce sequestration or cooperativity into these receptors, we have likewise narrowed their dynamic range to as little as 1.5-fold, vastly improving the sensitivity with which they respond to small changes in the concentration of their target ligands. Given the ease with which we have been able to introduce these mechanisms into a wide range of DNA-based receptors and the rapidity with which the field of biomolecular design is maturing, we are optimistic that the use of these and similar naturally occurring regulatory mechanisms will provide viable solutions to a range of increasingly important analytical problems.
Abstract
At the present time, no national constitution expressly guarantees access to abortion as a human right. Yet, despite the absence of explicit constitutional provisions, a growing body of case ...law from countries’ highest courts recognizes abortion as a fundamental, natural right. Judicial interpretations of the right to abortion are evolving, with courts considering it a derivative of the constitutional guarantees of liberty, equality, dignity, or, more recently, the protection of health. Conversely, some courts, notably in the United States and Poland, have ruled out the possibility of such a right having constitutional status. This Reflection outlines current constitutional approaches to the right to abortion. It highlights an important paradigm shift in constitutional law toward framing abortion as part of the right to reproductive health, as already affirmed in international human rights law. Reproductive rights are now defined in relation to the state’s obligation, on the one hand, not to interfere with reproductive choices and, on the other hand, to provide women and girls with conditions ensuring freedom of choice, but also to determine the limits of their choices.
Abstract
Precision genome editing technologies have transformed modern biology. These technologies have arisen from the redirection of natural biological machinery, such as bacteriophage lambda ...proteins for recombineering and CRISPR nucleases for eliciting site-specific double-strand breaks. Less well-known is a widely distributed class of bacterial retroelements, retrons, that employ specialized reverse transcriptases to produce noncoding intracellular DNAs. Retrons’ natural function and mechanism of genetic transmission have remained enigmatic. However, recent studies have harnessed their ability to produce DNA in situ for genome editing and evolution. This review describes retron biology and function in both natural and synthetic contexts. We also highlight areas that require further study to advance retron-based precision genome editing platforms.
The autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago ...with the identification of the genes underlying hereditary periodic fever syndromes. This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex autoinflammatory diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system. Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us. We define six categories of autoinflammatory disease: IL-1beta activation disorders (inflammasomopathies), NF-kappaB activation syndromes, protein misfolding disorders, complement regulatory diseases, disturbances in cytokine signaling, and macrophage activation syndromes. A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside.
The anti–interleukin-1 antibody canakinumab was effective at controlling and preventing recurrence of flares in autoimmune inflammatory diseases: familial Mediterranean fever, mevalonate kinase ...deficiency, and the TNF receptor–associated periodic syndrome.
The WROCLAW COMMENTARIES address legal questions as well as political consequences related to freedom of, and access to, the arts and (old/new) media; questions of religious and language rights; the ...protection of minorities and other vulnerable groups; safeguarding cultural diversity and heritage; and further pertinent issues. Specialists from all over Europe and the world summarise and comment on core messages of legal instruments, the essence of case-law as well as prevailing and important dissenting opinions in the literature, with the aim of providing a user-friendly tool for the daily needs of decision or law-makers at different juridical, administrative and political levels as well as others working in the field of culture and human rights.
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