Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.     

Greenhouse Effects in Global Warming based on Analogical Reasoning

Using an analogy in science and everyday life is a double-edged sword because they are accompanied by alternative ideas, in addition to scientific concepts. Schools and public education explain global warming by making a common analogy between this phenomenon and greenhouse effects (Chen in Philos Cogn Sci 105–114, 2012). Unfortunately, this analogy sometimes produces various incorrect explanatory mental models. To construct a correct understanding of global warming, it is necessary: first, to investigate the attributes of analogical reasoning; second, to understand these features by restructuring the greenhouse analogy; and third, to explore the problems and benefits of the greenhouse analogy. The characteristics of relations, rather than objects, must be mapped according to the principle of systematicity, but the public tends to preserve the attributes of the base domain, which is mapped relatively easily. In conclusion, certain facets of the prevailing greenhouse analogy cause a distorted public view of climate change. We must use the greenhouse analogy and yet simultaneously emphasize the relations and attributes highlighted and hidden in the analogy during evaluation.     

Love and Realism

In this reply I try to show that, contrary to Milberry’s apparent assertion, the general intellect of the multitude does not have the explanatory robustness she accredits to it (following both Virno and the Hardt and Negri of the Empire trilogy). Digital network technologies are currently overwhelmingly effective in proletarianizing and disempowering the cognitariat and only an active technopolitics of deproletarianization could reverse this hegemonic situation. In my response to Verbeek, I attempt to correct his misinterpretation (shared by Milberry) of the Stieglerian approach as being dialectical in nature and show that, far from reinstating the humanist dichotomy between human beings and technologies, my analysis assumes their original, albeit fundamentally ambiguous and even ‘uncanny’ [unheimlich] interconnection. I conclude with pointing out some implications of this view for a ‘really realistic’ political theory of technology.     

The Struggle for Technology: Towards a Realistic Political Theory of Technology

Pieter Lemmens’ neo-Marxist approach to technology urges us to rethink how to do political philosophy of technology. First, Lemmens’ high level of abstraction raises the question of how empirically informed a political theory of technology needs to be. Second, his dialectical focus on a “struggle” between humans and technologies reveals the limits of neo-Marxism. Political philosophy of technology needs to return “to the things themselves”. The political significance of technologies cannot be reduced to its origins in systems of production or social organization, but requires study at the micro-level, where technologies help to shape engagement, interaction, power, and social awareness.     

Metabolic changes during B cell differentiation for the production of intestinal IgA antibody

To sustain the bio-energetic demands of growth, proliferation, and effector functions, the metabolism of immune cells changes dramatically in response to immunologic stimuli. In this review, I focus on B cell metabolism, especially regarding the production of intestinal IgA antibody. Accumulating evidence has implicated not only host-derived factors (e.g., cytokines) but also gut environmental factors, including the possible involvement of commensal bacteria and diet, in the control of B cell metabolism during intestinal IgA antibody production. These findings yield new insights into the regulation of immunosurveillance and homeostasis in the gut.     

Proliferation status defines functional properties of endothelial cells

Homeostasis of solid tissue is characterized by a low proliferative activity of differentiated cells while special conditions like tissue damage induce regeneration and proliferation. For some cell types it has been shown that various tissue-specific functions are missing in the proliferating state, raising the possibility that their proliferation is not compatible with a fully differentiated state. While endothelial cells are important players in regenerating tissue as well as in the vascularization of tumors, the impact of proliferation on their features remains elusive. To examine cell features in dependence of proliferation, we established human endothelial cell lines in which proliferation is tightly controlled by a doxycycline-dependent, synthetic regulatory unit. We observed that uptake of macromolecules and establishment of cell–cell contacts was more pronounced in the growth-arrested state. Tube-like structures were formed in vitro in both proliferating and non-proliferating conditions. However, functional vessel formation upon transplantation into immune-compromised mice was restricted to the proliferative state. Kaposi’s sarcoma-associated herpes virus (KSHV) infection resulted in reduced expression of endothelial markers. Upon transplantation of infected cells, drastic differences were observed: proliferation arrested cells acquired a high migratory activity while the proliferating counterparts established a tumor-like phenotype, similar to Kaposi Sarcoma lesions. The study gives evidence that proliferation governs endothelial functions. This suggests that several endothelial functions are differentially expressed during angiogenesis. Moreover, since proliferation defines the functional properties of cells upon infection with KSHV, this process crucially affects the fate of virus-infected cells.     

Assembly and regulation of ASC specks

The inflammasome adapter ASC links activated inflammasome sensors to the effector molecule pro-caspase-1. Recruitment of pro-caspase-1 to ASC promotes the autocatalytic activation of caspase-1, which leads to the release of pro-inflammatory cytokines, such as IL-1β. Upon triggering of inflammasome sensors, ASC assembles into large helical fibrils that interact with each other serving as a supramolecular signaling platform termed the ASC speck. Alternative splicing, post-translational modifications of ASC, as well as interaction with other proteins can perturb ASC function. In several inflammatory diseases, ASC specks can be found in the extracellular space and its presence correlates with poor prognosis. Here, we review the role of ASC in inflammation, and focus on the structural mechanisms that lead to ASC speck formation, the regulation of ASC function during inflammasome assembly, and the importance of ASC specks in disease.     

Assessing heterogeneity in oligomeric AAA+ machines

ATPases Associated with various cellular Activities (AAA+ ATPases) are molecular motors that use the energy of ATP binding and hydrolysis to remodel their target macromolecules. The majority of these ATPases form ring-shaped hexamers in which the active sites are located at the interfaces between neighboring subunits. Structural changes initiate in an active site and propagate to distant motor parts that interface and reshape the target macromolecules, thereby performing mechanical work. During the functioning cycle, the AAA+ motor transits through multiple distinct states. Ring architecture and placement of the catalytic sites at the intersubunit interfaces allow for a unique level of coordination among subunits of the motor. This in turn results in conformational differences among subunits and overall asymmetry of the motor ring as it functions. To date, a large amount of structural information has been gathered for different AAA+ motors, but even for the most characterized of them only a few structural states are known and the full mechanistic cycle cannot be yet reconstructed. Therefore, the first part of this work will provide a broad overview of what arrangements of AAA+ subunits have been structurally observed focusing on diversity of ATPase oligomeric ensembles and heterogeneity within the ensembles. The second part of this review will concentrate on methods that assess structural and functional heterogeneity among subunits of AAA+ motors, thus bringing us closer to understanding the mechanism of these fascinating molecular motors.     

Profilin1 biology and its mutation,actin(g) in disease

Profilins were discovered in the 1970s and were extensively studied for their significant physiological roles. Profilin1 is the most prominent isoform and has drawn special attention due to its role in the cytoskeleton, cell signaling, and its link to conditions such as cancer and vascular hypertrophy. Recently, multiple mutations in the profilin1 gene were linked to amyotrophic lateral sclerosis (ALS). In this review, we will discuss the physiological and pathological roles of profilin1. We will further highlight the cytoskeletal function and dysfunction caused by profilin1 dysregulation. Finally, we will discuss the implications of mutant profilin1 in various diseases with an emphasis on its contribution to the pathogenesis of ALS.