The Energetics of Halogenated Ethylenes (Ethynes) and 1,3-Butadienes (Butadiynes): A Computational and Conceptual Study of Substituent Effects and “Dimerization”

The energetics of ethylenes and 1,3-butadienes may be interrelated by the reaction: RHC=CH2 + H2C=CHR\u27 → RHC=CH−CH=CHR\u27 + H2. Shown earlier to be nearly enthalpically thermoneutral for a variety of hydrocarbon cases, we are now interested in the related energetics of halogenated alkenes and alkynes. Using quantum chemical calculations, we have studied this as recast as the isodesmic reactions: 2(H2C=CHX) + H2C=CH−CH=CH2 → p,q-di-X-1,3-butadiene + 2H2C=CH2 2(HC≡CX) + HC≡C−C≡CH → di-X-butadiyne + 2HC≡CH. Here p,q- = 1,3-; 1,4- and 2,3- with X = F, Cl, Br, and I. The halogen and location-dependent deviations from near enthalpic thermoneutrality are discussed

Common genetic determinants of intraocular pressure and primary open-angle Glaucoma

10.1371/journal.pgen.1002611PLoS Genetics85

Using Structural Kinetic Modeling To Identify Key Determinants of Stability in Reaction Networks

Kinetic modeling is increasingly used to understand the reaction dynamics of metabolic systems. However, one major drawback of kinetic modeling is that appropriate rate parameters required to implement such models are often unavailable. To circumvent this limitation, an approach known as structural kinetic modeling was developed as a way to understand the dynamics of reaction networks without explicitly requiring rate parameters. This study describes a novel approach to use structural kinetic modeling to identify reaction components that contribute most significantly to mediating network stability. We applied this method to analyze the metabolic pathway of glycolysis in yeast. As a result, we identified specific metabolic components that contribute most significantly to defining the stability properties of the glycolysis reaction network and predict the responses of these components to perturbations. These results were validated via comparison to a conventional kinetic model of glycolysis. Thus, applying our approach allows more detailed information about the stability and dynamics of the metabolic network to now be accessible without requiring rate parameters. We anticipate that this method can focus efforts of experimental studies by identifying the susceptibility of reaction components to metabolic engineering. The approach may be applied to a variety of complex reaction networks

PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner.

Streptococcus pneumoniae is a major cause of pneumonia and a leading cause of death world-wide. Antibody-mediated immune responses can confer protection against repeated exposure to S. pneumoniae, yet vaccines offer only partial protection. Patients with Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated a conditional knock-in mouse model of this disease and identify a CD19+B220- B cell subset that is induced by PI3Kδ signaling, resides in the lungs, and is correlated with increased susceptibility to S. pneumoniae during early phases of infection via an antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves survival rates following S. pneumoniae infection in wild-type mice and in mice with activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the severity of S. pneumoniae infection, representing a potential therapeutic target.Wellcome, MRC, BBSR

Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4×10−8), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6×10−8). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4×10−2 for rs11656696 and p = 9.1×10−4 for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation

Association of rs11656696 and rs7555523 with glaucoma.

<p>Association of rs11656696 and rs7555523 with glaucoma.</p

Expression levels of GAS7 and TMCO1 in human ocular tissues.

<p>Quantitative determination of <i>GAS7</i> and <i>TMCO1</i> mRNA expression levels in human ocular tissues by using real-time PCR technology (n = 4). The expression levels were normalized against GAPDH and the results are expressed as copynumber/µg RNA. Co, cornea; Tr, trabecular meshwork; Ir, iris; Le, lens; Ci, ciliary body; Re, retina; Ch, choroid; La, lamina cribrosa; Op, optic nerve.</p

Results of the meta-analysis of the gene discovery cohorts: loci associated with IOP (p<10⁻⁵).

<p>SNP = single nucleotide polymorphism; Chrom = chromosome; MA(F) = minor allele (frequency); SE = standard error.</p>*<p>number of SNPs with p<10⁻⁵ in the region.</p><p>According NCBI build 37.1, rs11656696 is located at position 10033679 in the growth-arrest-specific gene <i>GAS7</i> while an earlier build allocated the SNP at 9974404 (<a href="http://www.ncbi.nlm.nih.gov" target="_blank">http://www.ncbi.nlm.nih.gov</a>).</p