Structural basis of complement membrane attack complex formation

In response to complement activation, the membrane attack complex (MAC) assembles from fluid-phase proteins to form pores in lipid bilayers. MAC directly lyses pathogens by a ‘multi-hit’ mechanism; however, sublytic MAC pores on host cells activate signalling pathways. Previous studies have described the structures of individual MAC components and subcomplexes; however, the molecular details of its assembly and mechanism of action remain unresolved. Here we report the electron cryo-microscopy structure of human MAC at subnanometre resolution. Structural analyses define the stoichiometry of the complete pore and identify a network of interaction interfaces that determine its assembly mechanism. MAC adopts a ‘split-washer’ configuration, in contrast to the predicted closed ring observed for perforin and cholesterol-dependent cytolysins. Assembly precursors partially penetrate the lipid bilayer, resulting in an irregular β-barrel pore. Our results demonstrate how differences in symmetric and asymmetric components of the MAC underpin a molecular basis for pore formation and suggest a mechanism of action that extends beyond membrane penetration

Ectogenesis and the case against the right to the death of the foetus

Ectogenesis, or the use of artificial wombs to allow a foetus to develop, will likely become a reality within a few decades, and could significantly affect the abortion debate. We first examine the implications for Judith Jarvis Thomson’s violinist analogy, which argues for a woman’s right to withdraw life support from the foetus and so terminate her pregnancy, even if the foetus is granted full moral status. We show that on Thomson’s reasoning, there is no right to the death of the foetus, and abortion is not permissible if ectogenesis is available, provided it is safe and inexpensive. This raises the question of whether there are persuasive reasons for the right to the death of the foetus that could be exercised in the context of ectogenesis. Eric Mathison and Jeremy Davis have examined several arguments for this right, doubting that it exists, while Joona Räsänen has recently criticized their reasoning. We respond to Räsänen’s analysis, concluding that his arguments are unsuccessful, and that there is no right to the death of the foetus in these circumstances

Acoustic Emission Linear Pulse Holography

This paper describes Acoustic Emission Linear Pulse Holography which combines the advantages of linear imaging and acoustic emission into a single NDE inspection system. This unique system produces a chronological linear holographic image of a flaw by utilizing the acoustic energy emitted during crack growth. Conventional linear holographic imaging uses an ultrasonic transducer to transmit energy into the volume being imaged. When the crack or defect reflects that energy, the crack acts as a new source of acoustic waves. To formulate an image of that source, a receiving transducer is scanned over the volume of interest and the phase of the received signals is measured at successive points on the scan. The innovation proposed in this paper is the utilization of the crack generated acoustic emission as the acoustic source and generation of a line image of the crack as it grows. A thirty-two point sampling array is used to construct phase-only linear holograms of simulated acoustic emission sources on large metal plates. The phases are calculated using the pulse time-of-flight (TOF) times from the reference transducer to the array of receivers. Computer reconstruction of the image is accomplished using a one-dimensional FFT algorithm (i.e., backward wave). Experimental results are shown which graphically illustrate the unique acoustic emission images of a single point and a linear crack in a 100 mm × 1220 mm × 1220 mm aluminum plate

A projective Dirac operator on CP^2 within fuzzy geometry

We propose an ansatz for the commutative canonical spin_c Dirac operator on CP^2 in a global geometric approach using the right invariant (left action-) induced vector fields from SU(3). This ansatz is suitable for noncommutative generalisation within the framework of fuzzy geometry. Along the way we identify the physical spinors and construct the canonical spin_c bundle in this formulation. The chirality operator is also given in two equivalent forms. Finally, using representation theory we obtain the eigenspinors and calculate the full spectrum. We use an argument from the fuzzy complex projective space CP^2_F based on the fuzzy analogue of the unprojected spin_c bundle to show that our commutative projected spin_c bundle has the correct SU(3)-representation content.Comment: reduced to 27 pages, minor corrections, minor improvements, typos correcte

Immunopathogenesis of canine chronic ulcerative stomatitis.

Canine Chronic Ulcerative Stomatitis is a spontaneously occurring inflammatory disease of the oral mucosa. An immune-mediated pathogenesis is suspected though not yet proven. We have recently reported on the clinical and histologic features, and identification of select leukocyte cell populations within the lesion. A clinical and histologic similarity to oral lichen planus of people was proposed. In the present study, these initial observations are extended by examining lesions from 24 dogs with clinical evidence of chronic ulcerative stomatitis. Because dogs with chronic ulcerative stomatitis often have concurrent periodontal disease, we wondered if dental plaque/biofilm may be a common instigator of inflammation in both lesions. We hypothesized that dogs with chronic ulcerative stomatitis would exhibit a spectrum of pathologic changes and phenotype of infiltrating leukocytes that would inform lesion pathogenesis and that these changes would differ from inflammatory phenotypes in periodontitis. Previously we identified chronic ulcerative stomatitis lesions to be rich in FoxP3+ and IL17+ cells. As such, we suspect that these leukocytes play an important role in lesion pathogenesis. The current study confirms the presence of moderate to large numbers of FoxP3+ T cells and IL17+ cells in all ulcerative stomatitis lesions using confocal immunofluorescence. Interestingly, the majority of IL17+ cells were determined to be non-T cells and IL17+ cell frequencies were negatively correlated with severity on the clinical scoring system. Three histologic subtypes of ulcerative stomatitis were determined; lichenoid, deep stomatitis and granulomatous. Periodontitis lesions, like stomatitis lesions, were B cell and plasma cell rich, but otherwise differed from the stomatitis lesions. Direct immunofluorescence results did not support an autoantibody-mediated autoimmune disease process. This investigation contributes to the body of literature regarding leukocyte involvement in canine idiopathic inflammatory disease pathogenesis

Effects of reconstituted collagen matrix on fates of mouse embryonic stem cells before and after induction for chondrogenic differentiation

Embryonic stem (ES) cells are pluripotent cells with great potential in regenerative medicine. However, controlling their differentiation toward homogeneous lineages is challenging. In this study, we aim to investigate the effects of reconstituted 3D collagen matrix on the fates of mouse ES (mES) cells before and after induction for chondrogenic differentiation. Specifically, mES cells were encapsulated and cultured in 3D collagen microspheres and exposed to induction signals at different time points. Growth characteristics and differentiation status of mES cells were then evaluated. Collagen microspheres provided a suitable microenvironment supporting mES cell growth and maintaining their undifferentiated status for certain period of time. At later time points, the proportion of undifferentiated mES cells gradually decreased, accompanied by increasing proportions of mesenchymal progenitor cells. This suggests the inductive role of collagen matrix in differentiating mES cells toward mesenchymal lineages. Moreover, a lower initial collagen monomer concentration facilitated the differentiation of mES cells into chondrogenic lineages, while induction at a later time point associated with a more advanced stage of chondrogenic differentiation. This indicates that both the initial collagen concentration and the time to induce differentiation significantly affected the fates of mES cells. This study contributes to future development of ES cell-based therapies. © Copyright 2009, Mary Ann Liebert, Inc.published_or_final_versionThe 7th Annual Meeting of the International Society for Stem Cell Research (ISSCR), Barcelona, Spain, 8-11 July 2009. In Tissue Engineering. Part A, 2009, v. 15 n. 10, p. 3071-308

Anophthalmia including next-generation sequencing-based approaches

Name of the disease (synonyms) See Table 1, Column 1-"Name of disease" and Column 2-"Alternative names". OMIM# of the disease See Table 1, Column 3-"OMIM# of the disease". Name of the analysed genes or DNA/chromosome segments and OMIM# of the gene(s) Core genes Name of the disease (synonyms) See Table 1, Column 1—“Name of disease” and Column 2—“Alternative names”. OMIM# of the disease See Table 1, Column 3—“OMIM# of the disease”. Name of the analysed genes or DNA/chromosome segments and OMIM# of the gene(s) Core genes (irrespective of being tested by Sanger sequencing or next-generation sequencing): See Table 1, Column 4—“Cytogenetic location”, Column 5—“Associated gene(s)” and Column 6—“OMIM# of associated gene(s)”. Additional genes (if tested by next-generation sequencing, including Whole exome/genome sequencing and panel sequencing): See Table 2, Column 1—“Gene”, Column 2—“Alternative names”, Column 3—“OMIM# of gene” and Column 4—“Cytogenetic location”. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the gene(s) in diagnostic, predictive and prenatal settings, and for risk assessment in relatives

Extended phase space thermodynamics for charged and rotating black holes and Born-Infeld vacuum polarization

We investigate the critical behaviour of charged and rotating AdS black holes in d spacetime dimensions, including effects from non-linear electrodynamics via the Born-Infeld action, in an extended phase space in which the cosmological constant is interpreted as thermodynamic pressure. For Reissner-Nordstrom black holes we find that the analogy with the Van der Walls liquid-gas system holds in any dimension greater than three, and that the critical exponents coincide with those of the Van der Waals system. We find that neutral slowly rotating black holes in four space-time dimensions also have the same qualitative behaviour. However charged and rotating black holes in three spacetime dimensions do not exhibit critical phenomena. For Born-Infeld black holes we define a new thermodynamic quantity B conjugate to the Born-Infeld parameter b that we call Born-Infeld vacuum polarization. We demonstrate that this quantity is required for consistency of both the first law of thermodynamics and the corresponding Smarr relation.Comment: 23 pages, 32 figures, v2: minor changes, upgraded reference

Uniform generation in trace monoids

We consider the problem of random uniform generation of traces (the elements of a free partially commutative monoid) in light of the uniform measure on the boundary at infinity of the associated monoid. We obtain a product decomposition of the uniform measure at infinity if the trace monoid has several irreducible components-a case where other notions such as Parry measures, are not defined. Random generation algorithms are then examined.Comment: Full version of the paper in MFCS 2015 with the same titl

Decay of Correlations in a Topological Glass

In this paper we continue the study of a topological glassy system. The state space of the model is given by all triangulations of a sphere with $N$ nodes, half of which are red and half are blue. Red nodes want to have 5 neighbors while blue ones want 7. Energies of nodes with other numbers of neighbors are supposed to be positive. The dynamics is that of flipping the diagonal between two adjacent triangles, with a temperature dependent probability. We consider the system at very low temperatures. We concentrate on several new aspects of this model: Starting from a detailed description of the stationary state, we conclude that pairs of defects (nodes with the "wrong" degree) move with very high mobility along 1-dimensional paths. As they wander around, they encounter single defects, which they then move "sideways" with a geometrically defined probability. This induces a diffusive motion of the single defects. If they meet, they annihilate, lowering the energy of the system. We both estimate the decay of energy to equilibrium, as well as the correlations. In particular, we find a decay like $t^{-0.4}$