Complement factor H binds malondialdehyde epitopes and protects from oxidative stress

Oxidative stress and enhanced lipid peroxidation are linked to many chronic inflammatory diseases, including age-related macular degeneration (AMD). AMD is the leading cause of blindness in Western societies, but its aetiology remains largely unknown. Malondialdehyde (MDA) is a common lipid peroxidation product that accumulates in many pathophysiological processes, including AMD. Here we identify complement factor H (CFH) as a major MDA-binding protein that can block both the uptake of MDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice. The CFH polymorphism H402, which is strongly associated with AMD, markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease aetiology. Our findings provide important mechanistic insights into innate immune responses to oxidative stress, which may be exploited in the prevention of and therapy for AMD and other chronic inflammatory diseases.     

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 epistemological virtues of assumptions: towards a coming of age of Boltzmann and Meinong’s objections to ‘the prejudice in favour of the actual’?

Two complementary debates of the turn of the nineteenth and twentieth century are examined here: the debate on the legitimacy of hypotheses in the natural sciences and the debate on intentionality and ‘representations without object’ in philosophy. Both are shown to rest on two core issues: the attitude of the subject and the mode of presentation chosen to display a domain of phenomena. An orientation other than the one which contributed to shape twentieth-century philosophy of science is explored through the analysis of the role given to assumptions in Boltzmann’s research strategy, where assumptions are contrasted to hypotheses, axioms, and principles, and in Meinong’s criticism of the privileged status attributed to representations in mental activities. Boltzmann’s computational style in mathematics and Meinong’s criticism of the confusion between representation and judgment give prominence to an indirect mode of presentation, adopted in a state of suspended belief which is characteristic of assumptions and which enables one to grasp objects that cannot be reached through direct representation or even analogies. The discussion shows how assumptions and the movement to fiction can be essential steps in the quest for objectivity. The conclusion restates the issues of the two debates in a contemporary perspective and shows how recent developments in philosophy of science and philosophy of language and mind can be brought together by arguing for a twofold conception of reference.     

COMPARISON OF TWO METHODS OF OPERATING THEATRE PLANNING： APPLICATION IN BELGIAN HOSPITAL

Operating Theatre is the centre of the hospital management＇s efforts. It constitutes the most expensive sector with more than 10% of the intended operating budget of the hospital. To reduce the costs while maintaining a good quality of care, one of the solutions is to improve the existent planning and scheduling methods by improving the services and surgical specialty coordination or finding the best estimation of surgical case durations. The other solution is to construct an effective surgical case plan and schedule. The operating theatre planning and scheduling is the two important steps, which aim to make a surgical case programming with an objective of obtaining a realizable and efficient surgical case schedule. This paper focuses on the first step, the operating theatre planning problem. Two planning methods are introduced and compared. Real data of a Belgian university hospital ＂Tivoli＂ are used for the experiments.     

Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation

Vertebrate eggs awaiting fertilization are arrested at metaphase of meiosis II by a biochemical activity termed cytostatic factor (CSF). This activity inhibits the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that triggers anaphase onset and mitotic/meiotic exit by targeting securin and M-phase cyclins for destruction. On fertilization a transient rise in free intracellular calcium causes release from CSF arrest and thus APC/C activation. Although it has previously been shown that calcium induces the release of APC/C from CSF inhibition through calmodulin-dependent protein kinase II (CaMKII), the relevant substrates of this kinase have not been identified. Recently, we characterized XErp1 (Emi2), an inhibitor of the APC/C and key component of CSF activity in Xenopus egg extract. Here we show that calcium-activated CaMKII triggers exit from meiosis II by sensitizing the APC/C inhibitor XErp1 for polo-like kinase 1 (Plx1)-dependent degradation. Phosphorylation of XErp1 by CaMKII leads to the recruitment of Plx1 that in turn triggers the destruction of XErp1 by phosphorylating a site known to serve as a phosphorylation-dependent degradation signal. These results provide a molecular explanation for how the fertilization-induced calcium increase triggers exit from meiosis II.     

Immune self-reactivity triggered by drug-modified HLA-peptide repertoire

Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T?cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs?6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.     

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.     

Highly effective SNP-based association mapping and management of recessive defects in livestock

The widespread use of elite sires by means of artificial insemination in livestock breeding leads to the frequent emergence of recessive genetic defects, which cause significant economic and animal welfare concerns. Here we show that the availability of genome-wide, high-density SNP panels, combined with the typical structure of livestock populations, markedly accelerates the positional identification of genes and mutations that cause inherited defects. We report the fine-scale mapping of five recessive disorders in cattle and the molecular basis for three of these: congenital muscular dystony (CMD) types 1 and 2 in Belgian Blue cattle and ichthyosis fetalis in Italian Chianina cattle. Identification of these causative mutations has an immediate translation into breeding practice, allowing marker assisted selection against the defects through avoidance of at-risk matings.     

Early planetesimal melting from an age of 4.5662 Gyr for differentiated meteorites

Long- and short-lived radioactive isotopes and their daughter products in meteorites are chronometers that can test models for Solar System formation. Differentiated meteorites come from parent bodies that were once molten and separated into metal cores and silicate mantles. Mineral ages for these meteorites, however, are typically younger than age constraints for planetesimal differentiation. Such young ages indicate that the energy required to melt their parent bodies could not have come from the most likely heat source-radioactive decay of short-lived nuclides ((26)Al and (60)Fe) injected from a nearby supernova-because these would have largely decayed by the time of melting. Here we report an age of 4.5662 +/- 0.0001 billion years (based on Pb-Pb dating) for basaltic angrites, which is only 1 Myr younger than the currently accepted minimum age of the Solar System and corresponds to a time when (26)Al and (60)Fe decay could have triggered planetesimal melting. Small (26)Mg excesses in bulk angrite samples confirm that (26)Al decay contributed to the melting of their parent body. These results indicate that the accretion of differentiated planetesimals pre-dated that of undifferentiated planetesimals, and reveals the minimum Solar System age to be 4.5695 +/- 0.0002 billion years.