Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis

Dysfunction of the intestinal epithelium is believed to result in the excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease, an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum. In healthy individuals, the intestinal epithelium maintains a physical barrier, established by the tight contact of cells. Moreover, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides, which hamper access and survival of bacteria adjacent to the epithelium. Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a possible pathogenic mechanism driving Crohn's disease in humans. However, the regulation of epithelial cell death and its role in intestinal homeostasis remain poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IECs) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8(ΔIEC)) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8(ΔIEC) mice lacked Paneth cells and showed reduced numbers of goblet cells, indicating dysregulated antimicrobial immune cell functions of the intestinal epithelium. Casp8(ΔIEC) mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumour necrosis factor (TNF)-α, was associated with increased expression of receptor-interacting protein 3 (Rip3; also known as Ripk3) and could be inhibited on blockade of necroptosis. Lastly, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IECs from TNF-α-induced necroptotic cell death.     

Collapse of long-range charge order tracked by time-resolved photoemission at high momenta

Intense femtosecond (10(-15)?s) light pulses can be used to transform electronic, magnetic and structural order in condensed-matter systems on timescales of electronic and atomic motion. This technique is particularly useful in the study and in the control of materials whose physical properties are governed by the interactions between multiple degrees of freedom. Time- and angle-resolved photoemission spectroscopy is in this context a direct and comprehensive, energy- and momentum-selective probe of the ultrafast processes that couple to the electronic degrees of freedom. Previously, the capability of such studies to access electron momentum space away from zero momentum was, however, restricted owing to limitations of the available probing photon energy. Here, using femtosecond extreme-ultraviolet pulses delivered by a high-harmonic-generation source, we use time- and angle-resolved photoemission spectroscopy to measure the photoinduced vaporization of a charge-ordered state in the potential excitonic insulator 1T-TiSe(2 )(refs 12, 13). By way of stroboscopic imaging of electronic band dispersions at large momentum, in the vicinity of the edge of the first Brillouin zone, we reveal that the collapse of atomic-scale periodic long-range order happens on a timescale as short as 20?femtoseconds. The surprisingly fast response of the system is assigned to screening by the transient generation of free charge carriers. Similar screening scenarios are likely to be relevant in other photoinduced solid-state transitions and may generally determine the response times. Moreover, as electron states with large momenta govern fundamental electronic properties in condensed matter systems, we anticipate that the experimental advance represented by the present study will be useful to study the ultrafast dynamics and microscopic mechanisms of electronic phenomena in a wide range of materials.     

Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.     

EP4 receptor stimulation down-regulates human eosinophil function

Accumulation of eosinophils in tissue is a hallmark of allergic inflammation. Here we observed that a selective agonist of the PGE₂ receptor EP4, ONO AE1-329, potently attenuated the chemotaxis of human peripheral blood eosinophils, upregulation of the adhesion molecule CD11b and the production of reactive oxygen species. These effects were accompanied by the inhibition of cytoskeletal rearrangement and Ca²⁺ mobilization. The involvement of the EP4 receptor was substantiated by a selective EP4 antagonist, which reversed the inhibitory effects of PGE₂ and the EP4 agonist. Selective kinase inhibitors revealed that the inhibitory effect of EP4 stimulation on eosinophil migration depended upon activation of PI 3-kinase and PKC, but not cAMP. Finally, we found that EP4 receptors are expressed by human eosinophils, and are also present on infiltrating leukocytes in inflamed human nasal mucosa. These data indicate that EP4 agonists might be a novel therapeutic option in eosinophilic diseases.     

Clinical outcome measurement: Models,theory, psychometrics and practice

In the last decade much has been made of the role that models play in the epistemology of measurement. Specifically, philosophers have been interested in the role of models in producing measurement outcomes. This discussion has proceeded largely within the context of the physical sciences, with notable exceptions considering measurement in economics. However, models also play a central role in the methods used to develop instruments that purport to quantify psychological phenomena. These methods fall under the umbrella term ‘psychometrics’. In this paper, we focus on Clinical Outcome Assessments (COAs) and discuss two measurement theories and their associated models: Classical Test Theory (CTT) and Rasch Measurement Theory. We argue that models have an important role to play in coordinating theoretical terms with empirical content, but to do so they must serve: 1) as a representation of the measurement interaction; and 2) in conjunction with a theory of the attribute in which we are interested. We conclude that Rasch Measurement Theory is a more promising approach than CTT in these regards despite the latter's popularity with health outcomes researchers.     

A ubiquitous thermoacidophilic archaeon from deep-sea hydrothermal vents

Deep-sea hydrothermal vents are important in global biogeochemical cycles, providing biological oases at the sea floor that are supported by the thermal and chemical flux from the Earth's interior. As hot, acidic and reduced hydrothermal fluids mix with cold, alkaline and oxygenated sea water, minerals precipitate to form porous sulphide-sulphate deposits. These structures provide microhabitats for a diversity of prokaryotes that exploit the geochemical and physical gradients in this dynamic ecosystem. It has been proposed that fluid pH in the actively venting sulphide structures is generally low (pH < 4.5), yet no extreme thermoacidophile has been isolated from vent deposits. Culture-independent surveys based on ribosomal RNA genes from deep-sea hydrothermal deposits have identified a widespread euryarchaeotal lineage, DHVE2 (deep-sea hydrothermal vent euryarchaeotic 2). Despite the ubiquity and apparent deep-sea endemism of DHVE2, cultivation of this group has been unsuccessful and thus its metabolism remains a mystery. Here we report the isolation and cultivation of a member of the DHVE2 group, which is an obligate thermoacidophilic sulphur- or iron-reducing heterotroph capable of growing from pH 3.3 to 5.8 and between 55 and 75 degrees C. In addition, we demonstrate that this isolate constitutes up to 15% of the archaeal population, providing evidence that thermoacidophiles may be key players in the sulphur and iron cycling at deep-sea vents.     

Synchrotron X-ray tomographic microscopy of fossil embryos

Fossilized embryos from the late Neoproterozoic and earliest Phanerozoic have caused much excitement because they preserve the earliest stages of embryology of animals that represent the initial diversification of metazoans. However, the potential of this material has not been fully realized because of reliance on traditional, non-destructive methods that allow analysis of exposed surfaces only, and destructive methods that preserve only a single two-dimensional view of the interior of the specimen. Here, we have applied synchrotron-radiation X-ray tomographic microscopy (SRXTM), obtaining complete three-dimensional recordings at submicrometre resolution. The embryos are preserved by early diagenetic impregnation and encrustation with calcium phosphate, and differences in X-ray attenuation provide information about the distribution of these two diagenetic phases. Three-dimensional visualization of blastomere arrangement and diagenetic cement in cleavage embryos resolves outstanding questions about their nature, including the identity of the columnar blastomeres. The anterior and posterior anatomy of embryos of the bilaterian worm-like Markuelia confirms its position as a scalidophoran, providing new insights into body-plan assembly among constituent phyla. The structure of the developing germ band in another bilaterian, Pseudooides, indicates a unique mode of germ-band development. SRXTM provides a method of non-invasive analysis that rivals the resolution achieved even by destructive methods, probing the very limits of fossilization and providing insight into embryology during the emergence of metazoan phyla.