A latent class probit model for analyzing pick any/N data

A latent class probit model is developed in which it is assumed that the binary data of a particular subject follow a finite mixture of multivariate Bermoulli distributions. An EM algorithm for fitting the model is described and a Monte Carlo procedure for testing the number of latent classes that is required for adequately describing the data is discussed. In the final section, an application of the latent class probit model to some intended purchase data for residential telecommunication devices is reported. Geert De Soete is supported as “Bevoegdverklaard Navorser” of the Belgian “Nationaal Fonds voor Wetenschappelijk Onderzoek.”     

FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation

Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.     

A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis

A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-κB signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20-deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-κB activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies.     

Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.     

Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis

Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are disorders characterized by increased bone density. The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic. We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis. In this study, LEMD3 interacted with BMP and activin-TGFbeta receptor-activated Smads and antagonized both signaling pathways in human cells.     

The Young J. H. van 't Hoff: The Background to the Publication of his 1874 Pamphlet on the Tetrahedral Carbon Atom,Together with a New English Translation

J. H. van 't Hoff's 1874 Dutch pamphlet, in which he proposed the spatial arrangement of atoms in a molecule, is one of the most significant documents in the history of chemistry. This essay presents a new narrative of Van 't Hoff's early life and places the appearance of the pamphlet within the context of the 'second golden age' of Dutch science. We argue that the combination of the reformed educational system in The Netherlands, the emergence of graphical molecular modelling within the theoretical and practical culture of chemistry during the 1860s and 1870s, as well as Van 't Hoff's own personal research trajectory, formed the background to his unprecedented attribution of spatial meaning to the traditional concept of atomic 'arrangement'. We also present a new English translation of the pamphlet, for we have found that the existing translation, published by G. M. Richardson in 1901, contains many errors, changes and omissions. The new version offers a more accurate rendition in English of Van 't Hoff's style and argument.     

高性能混凝土高温微观结构演化研究

通过热重分析、电镜扫描和汞压力测孔等方法,对高温过程中高性能混凝土材料的物理化学变化以及由此造成的微观结果变化进行了分析.相关试验和分析表明:造成升温过程中材料质量损失的主要原因是脱水和各种分解反应.在400℃之前,材料孔隙结构的变化主要来自材料内部水分的散失;400~500℃之间,由于材料发生分解反应,氢氧化钙的分解将提供大量的孔隙.这些结论将为进一步解释爆裂现象提供更为本质的试验支持,同时也为进一步建立高温情况下材料微观结构演化模型提供了试验基础.     

Least squares algorithms for constructing constrained ultrametric and additive tree representations of symmetric proximity data

A mathematical programming algorithm is developed for fitting ultrametric or additive trees to proximity data where external constraints are imposed on the topology of the tree. The two procedures minimize a least squares loss function. The method is illustrated on both synthetic and real data. A constrained ultrametric tree analysis was performed on similarities between 32 subjects based on preferences for ten odors, while a constrained additive tree analysis was carried out on some proximity data between kinship terms. Finally, some extensions of the methodology to other tree fitting procedures are mentioned.The first author is supported as Bevoegdverklaard Navorser of the Belgian Nationaal Fonds voor Wetenschappelijk Onderzoek.