Biosynthesis of cryptic lipopolysaccharide glycoforms in Haemophilus influenzae involves a mechanism similar to that required for O-antigen synthesis

It is generally thought that mucosal bacterial pathogens of the genera Haemophilus, Neisseria, and Moraxella elaborate lipopolysaccharide (LPS) that is fundamentally different from that of enteric organisms that express O-specific polysaccharide side chains. Haemophilus influenzae elaborates short-chain LPS that has a role in the pathogenesis of H. influenzae infections. We show that the synthesis of LPS in this organism can no longer be as clearly distinguished from that in other gram-negative bacteria that express an O antigen. We provide evidence that a region of the H. influenzae genome, the hmg locus, is involved in the synthesis of glycoforms in which tetrasaccharide units are added en bloc, not stepwise, to the normal core glycoforms, similar to the biosynthesis of an O-antigen.     

Genetic mapping at 3-kilobase resolution reveals inositol 1,4,5-triphosphate receptor 3 as a risk factor for type 1 diabetes in Sweden

We mapped the genetic influences for type 1 diabetes (T1D), using 2,360 single-nucleotide polymorphism (SNP) markers in the 4.4-Mb human major histocompatibility complex (MHC) locus and the adjacent 493 kb centromeric to the MHC, initially in a survey of 363 Swedish T1D cases and controls. We confirmed prior studies showing association with T1D in the MHC, most significantly near HLA-DR/DQ. In the region centromeric to the MHC, we identified a peak of association within the inositol 1,4,5-triphosphate receptor 3 gene (ITPR3; formerly IP3R3). The most significant single SNP in this region was at the center of the ITPR3 peak of association (P=1.7 x 10(-4) for the survey study). For validation, we typed an additional 761 Swedish individuals. The P value for association computed from all 1,124 individuals was 1.30 x 10(-6) (recessive odds ratio 2.5; 95% confidence interval [CI] 1.7-3.9). The estimated population-attributable risk of 21.6% (95% CI 10.0%-31.0%) suggests that variation within ITPR3 reflects an important contribution to T1D in Sweden. Two-locus regression analysis supports an influence of ITPR3 variation on T1D that is distinct from that of any MHC class II gene.     

Foreword: from the TRANSCRIPTOME conferences to the SYSTEMOSCOPE international consortium

This thematic issue issue of the Comptes rendus Biologies contains review articles, original papers and conference reports presented at the first two TRANSCRIPTOME conferences From Functional Genomics to Systems Biology and IMAGE Consortium Invitational workshops (Paris, November 2000 and Seattle, March 2002), and discussed during the inaugural meetings of the SYSTEMOSCOPE International Consortium (Paris, June 2003). We describe the founding principles, missions, working plan and policy for partnership and industrial development of SYSTEMOSCOPE to promote the study of the complexity of biological systems by integrating scientific, medical, ethical and economic issues in implementation of interdisciplinary projects for human health.     

Sibling competition arena: selfing and a competition arena can combine to constitute a barrier to gene flow in sympatry

Closely related species coexisting in sympatry provide critical insight into the mechanisms underlying speciation and the maintenance of genetic divergence. Selfing may promote reproductive isolation by facilitating local adaptation, causing reduced hybrid fitness in parental environments. Here, we propose a novel mechanism by which selfing can further impair interspecific gene flow: selfing may act to ensure that nonhybrid progeny systematically co-occur whenever hybrid genotypes are produced. Under a competition arena, the fitness differentials between nonhybrid and hybrid progeny are then magnified, preventing development of interspecific hybrids. We investigate whether this "sibling competition arena" can explain the coexistence in sympatry of closely related species of the plant fungal pathogens (Microbotryum) causing anther-smut disease. The probabilities of intrapromycelial mating (automixis), outcrossing, and sibling competition were manipulated in artificial inoculations to evaluate their contribution to reproductive isolation. We report that both intrapromycelial selfing and sibling competition significantly reduced rates of hybrid infection beyond that expected based solely upon selfing rates and noncompetitive fitness differentials between hybrid and nonhybrid progeny. Our results thus suggest that selfing and a sibling competition arena can combine to constitute a barrier to gene flow and diminish selection for additional barriers to gene flow in sympatry.     

Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.     

Low 2-dimensional CD4 T cell receptor affinity for myelin sets in motion delayed response kinetics

T cells recognizing self-peptides that mediate autoimmune disease and those that are responsible for efficacious immunity against pathogens may differ in affinity for antigen due to central and peripheral tolerance mechanisms. Here we utilize prototypical self-reactive (myelin) and viral-specific (LCMV) T cells from T cell receptor (TCR) transgenic mice (2D2 and SMARTA, respectively) to explore affinity differences. The T cells responsive to virus possessed >10,000 fold higher 2D affinity as compared to the self-reactive T cells. Despite their dramatically lower affinity for their cognate ligand, 2D2 T cells respond with complete, albeit delayed, activation (proliferation and cytokine production). SMARTA activation occurs rapidly, achieving peak phosphorylation of p38 (1 minute), Erk (30 minutes), and Jun (3 hours) as well as CD69 and CD25 upregulation (3 and 6 hours, respectively), with a corresponding early initiation of proliferation. 2D2 stimulation with MOG results in altered signaling--no phospho-Erk or phospho-p38 accumulation, significantly delayed activation kinetics of Jun (12 hours), and delayed but sustained SHP-1 activity--as well as delayed CD69 and CD25 expression (12-24 hours), and slow initiation of proliferation. This delay was not intrinsic to the 2D2 T cells, as a more potent antigen with >100-fold increased 2D affinity restored rapid response kinetics in line with those identified for the viral antigen. Taken together, these data demonstrate that time can offset low TCR affinity to attain full activation and suggest a mechanism by which low affinity T cells participate in autoimmune disease.     

Revolutionizing medicine in the 21(st) century through systems approaches

Personalized medicine is a term for a revolution in medicine that envisions the individual patient as the central focus of healthcare in the future. The term "personalized medicine", however, fails to reflect the enormous dimensionality of this new medicine that will be predictive, preventive, personalized, and participatory-a vision of medicine we have termed P4 medicine. This reflects a paradigm change in how medicine will be practiced that is revolutionary rather than evolutionary. P4 medicine arises from the confluence of a systems approach to medicine and from the digitalization of medicine that creates the large data sets necessary to deal with the complexities of disease. We predict that systems approaches will empower the transition from conventional reactive medical practice to a more proactive P4 medicine focused on wellness, and will reverse the escalating costs of drug development an will have enormous social and economic benefits. Our vision for P4 medicine in 10 years is that each patient will be associated with a virtual data cloud of billions of data points and that we will have the information technology for healthcare to reduce this enormous data dimensionality to simple hypotheses about health and/or disease for each individual. These data will be multi-scale across all levels of biological organization and extremely heterogeneous in type - this enormous amount of data represents a striking signal-to-noise (S/N) challenge. The key to dealing with this S/N challenge is to take a "holistic systems approach" to disease as we will discuss in this article.