Early SIV and HIV infection promotes the LILRB2/MHC-I inhibitory axis in cDCs

Classical dendritic cells (cDCs) play a pivotal role in the early events that tip the immune response toward persistence or viral control. In vitro studies indicate that HIV infection induces the dysregulation of cDCs through binding of the LILRB2 inhibitory receptor to its MHC-I ligands and the strength of this interaction was proposed to drive disease progression. However, the dynamics of the LILRB2/MHC-I inhibitory axis in cDCs during early immune responses against HIV are yet unknown. Here, we show that early HIV-1 infection induces a strong and simultaneous increase of LILRB2 and MHC-I expression on the surface of blood cDCs. We further characterized the early dynamics of LILRB2 and MHC-I expression by showing that SIVmac251 infection of macaques promotes coordinated up-regulation of LILRB2 and MHC-I on cDCs and monocytes/macrophages, from blood and lymph nodes. Orientation towards the LILRB2/MHC-I inhibitory axis starts from the first days of infection and is transiently induced in the entire cDC population in acute phase. Analysis of the factors involved indicates that HIV-1 replication, TLR7/8 triggering, and treatment by IL-10 or type I IFNs increase LILRB2 expression. Finally, enhancement of the LILRB2/MHC-I inhibitory axis is specific to HIV-1 and SIVmac251 infections, as expression of LILRB2 on cDCs decreased in naturally controlled chikungunya virus infection of macaques. Altogether, our data reveal a unique up-regulation of LILRB2 and its MHC-I ligands on cDCs in the early phase of SIV/HIV infection, which may account for immune dysregulation at a critical stage of the anti-viral response.     

Informational Branching Universe

This paper suggests an epistemic interpretation of Belnap’s branching space-times theory based on Everett’s relative state formulation of the measurement operation in quantum mechanics. The informational branching models of the universe are evolving structures defined from a partial ordering relation on the set of memory states of the impersonal observer. The totally ordered set of their information contents defines a linear “time” scale to which the decoherent alternative histories of the informational universe can be referred—which is quite necessary for assigning them a probability distribution. The “historical” state of a physical system is represented in an appropriate extended Hilbert space and an algebra of multi-branch operators is developed. An age operator computes the informational depth of historical states and its standard deviation can be used to provide a universal information/energy uncertainty relation. An information operator computes the encoding complexity of historical states, the rate of change of its average value accounting for the process of correlation destruction inherent to the branching dynamics. In the informational branching models of the universe, the asymmetry of phenomena in nature appears as a mere consequence of the subject’s activity of measuring, which defines the flow of time-information.     

Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.     

Minimum Sum of Squares Clustering in a Low Dimensional Space

Clustering with a criterion which minimizes the sum of squared distances to cluster centroids is usually done in a heuristic way. An exact polynomial algorithm, with a complexity in O(N ^p+1 logN), is proposed for minimum sum of squares hierarchical divisive clustering of points in a p-dimensional space with small p. Empirical complexity is one order of magnitude lower. Data sets with N = 20000 for p = 2, N = 1000 for p = 3, and N = 200 for p = 4 are clustered in a reasonable computing time.     

Ramsey sentences, structural realism and trivial realization

Several recent authors identify structural realism about scientific theories with the claim that the content of a scientific theory is expressible using its Ramsey sentence. Many of these authors have also argued that so understood, the view collapses into empiricist anti-realism, since an argument originally proposed by Max Newman in a review of Bertrand Russell’s The analysis of matter demonstrates that Ramsey sentences are trivially satisfied, and cannot make any significant claims about unobservables. In this paper I argue against both of these claims. Structural realism and Ramsey sentence realism are, in their most defensible versions, importantly different doctrines, and neither is committed to the premises required to demonstrate that they collapse into anti-realism.     

Multimodel Approach for Intelligent Control and Applications

IntroductionThemultimodelapproachappearsasapowerfultechniquetodealwithcomplex,nonlinearand/orilldefinedsystemsrepresentedusingasetofsimplelinearorsmoothlynonlinearmodelseachofthemallowingthegenerationofapartialcontroller.Differentapproachesexistintheliterature[1,2]tocopewiththetwokeypointsofthemultimodel/multicontrolstrategy:themodelbasisdeterminationandtheuseofpartialcontrollersinordertoderiveaglobalone.Hence,itappearsobviousthatoneofthemainobjectstofocusoninthemultimodel/multicontrolapproach…