Elevated plasma CL-K1 level is associated with a risk of developing disseminated intravascular coagulation (DIC).

Collectin kidney 1 (CL-K1) is a recently identified collectin that is synthesized in most organs and circulates in blood. CL-K1 is an innate immune molecule that may play a significant role in host defense. As some collectins also play a role in coagulation, we hypothesized that an effect of CL-K1 may be apparent in disseminated intravascular coagulation (DIC), a gross derangement of the coagulation system that occurs in the setting of profound activation of the innate immune system. DIC is a grave medical condition with a high incidence of multiple organ failure and high mortality and yet there are no reliable biomarkers or risk factors. In our present study, we measured plasma CL-K1 concentration in a total of 659 specimens, including 549 DIC patients, 82 non-DIC patients and 27 healthy volunteers. The median plasma CL-K1 levels in these cohorts were 424, 238 and 245 ng/ml, respectively, with no significant difference in the latter two groups. The incidence of elevated plasma CL-K1 was significantly higher in the DIC patients compared to the non-DIC patients, resulting in an odds ratio of 1.929 (confidence interval 1.041-3.866). Infection, renal diseases, respiratory diseases, and cardiac diseases were more frequently observed in the DIC group than in the non-DIC group. In the DIC group, vascular diseases were associated with elevated plasma CL-K1 levels while age and acute illness had little effect on plasma CL-K1 levels. Independent of DIC, elevated plasma CL-K1 levels were associated with respiratory disease and coagulation disorders. These results suggest that specific diseases may affect CL-K1 synthesis in an organ dependent manner and that elevated plasma CL-K1 levels are associated with the presence of DIC. Further investigations in cohorts of patients are warranted. We propose that elevated plasma CL-K1 may be a new useful risk factor and possibly biomarker for the prediction of developing DIC.

Histone variant H2A.Z and linker histone H1 influence chromosome condensation in Saccharomyces cerevisiae.

Chromosome condensation is essential for the fidelity of chromosome segregation during mitosis and meiosis. Condensation is associated both with local changes in nucleosome structure and larger-scale alterations in chromosome topology mediated by the condensin complex. We examined the influence of linker histone H1 and variant histone H2A.Z on chromosome condensation in budding yeast cells. Linker histone H1 has been implicated in local and global compaction of chromatin in multiple eukaryotes, but we observe normal condensation of the rDNA locus in yeast strains lacking H1. However, deletion of the yeast HTZ1 gene, coding for variant histone H2A.Z, causes a significant defect in rDNA condensation. Loss of H2A.Z does not change condensin association with the rDNA locus or significantly affect condensin mRNA levels. Prior studies reported that several phenotypes caused by loss of H2A.Z are suppressed by eliminating Swr1, a key component of the SWR complex that deposits H2A.Z in chromatin. We observe that an htz1Δ swr1Δ strain has near-normal rDNA condensation. Unexpectedly, we find that elimination of the linker histone H1 can also suppress the rDNA condensation defect of htz1Δ strains. Our experiments demonstrate that histone H2A.Z promotes chromosome condensation, in part by counteracting activities of histone H1 and the SWR complex.

Mannose-binding lectin binds to amyloid ß protein and modulates inflammation.

Mannose-binding lectin (MBL), a soluble factor of the innate immune system, is a pattern recognition molecule with a number of known ligands, including viruses, bacteria, and molecules from abnormal self tissues. In addition to its role in immunity, MBL also functions in the maintenance of tissue homeostasis. We present evidence here that MBL binds to amyloid ß peptides. MBL binding to other known carbohydrate ligands is calcium-dependent and has been attributed to the carbohydrate-recognition domain, a common feature of other C-type lectins. In contrast, we find that the features of MBL binding to Aß are more similar to the reported binding characteristics of the cysteine-rich domain of the unrelated mannose receptor and therefore may involve the MBL cysteine-rich domain. Differences in MBL ligand binding may contribute to modulation of inflammatory response and may correlate with the function of MBL in processes such as coagulation and tissue homeostasis.

Histone variant H2A.Z promotes meiotic chromosome axis organization in Saccharomyces cerevisiae.

Progression through meiosis is associated with significant reorganization of chromosome structure, regulated in part by changes in histones and chromatin. Prior studies observed defects in meiotic progression in yeast strains lacking the linker histone H1 or variant histone H2A.Z. To further define the contributions of these chromatin factors, we have conducted genetic and cytological analysis of cells undergoing meiosis in the absence of H1 and H2A.Z. We find that a spore viability defect observed in strains lacking H2A.Z can be partially suppressed if cells also lack histone H1, while the combined loss of both H1 and H2A.Z is associated with elevated gene conversion events. Cytological analysis of Red1 and Rec8 staining patterns indicates that a subset of cells lacking H2A.Z fail to assemble a proper chromosome axis, and the staining pattern of the synaptonemal complex protein Zip1 in htz1Δ/htz1Δ cells mimics that of cells deficient for Rec8-dependent meiotic cohesion. Our results suggest a role for H2A.Z in the establishment or maintenance of the meiotic chromosome axis, possibly by promoting the efficient chromosome cohesion.

The effect of dopant at the Zr site on the proton conduction pathways of SrZrO3: an orthorhombic perovskite.

Doping orthorhombic SrZrO(3) at 12.5% of the Zr sites with Al(3+) leads to a local squaring of the lattice, while doping with larger Y(3+) increases local octahedral distortions. Proton activation energy barriers and transition state theory prefactors are calculated. The wide range of intra-, inter-, and rotational barriers suggest that a comprehensive pathway analysis is needed to find the limiting conduction barriers. Simple seven to ten step periodic pathways leading to system wide conduction are enumerated using vertex coding. At 900-1300 K, the average limiting barriers to long range conduction are 0.6 and 0.4 eV in Al/SrZrO(3) and Y/SrZrO(3), respectively, in reasonable agreement with the experiment. Path analysis gives the added insight that conduction pathways in Al/SrZrO(3) avoid doped regions, while conduction pathways in Y/SrZrO(3) traverse them.

The effect of yttrium dopant on the proton conduction pathways of BaZrO3, a cubic perovskite.

When BaZrO(3) is doped with Y in 12.5% of Zr sites, density functional theory with the PBE functional predicts octahedral distortions within a cubic phase yielding a greater variety of proton binding sites than undoped BaZrO(3). Proton binding sites, transition states, and normal modes are found and used to calculate transition state theory rate constants. The binding sites are used to represent vertices in a graph. The rate constants connecting binding sites are used to provide weights for graph edges. Vertex and color coding are used to find proton conduction pathways in BaZr(0.875)Y(0.125)O(3). Many similarly probable proton conduction pathways which can be periodically replicated to yield long range proton conduction are found. The average limiting barriers at 600 K for seven step and eight step periodic pathways are 0.29 and 0.30 eV, respectively. Inclusion of a lattice reorganization barrier raises these to 0.42 and 0.33 eV, respectively. The majority of the seven step pathways have an interoctahedral rate limiting step while the majority of the eight step pathways have an intraoctahedral rate limiting step. While the average limiting barrier of the seven step periodic pathway including a lattice reorganization barrier is closer to experiment, how to appropriately weight different length periodic pathways is not clear. Likely, conduction is influenced by combinations of different length pathways. Vertex and color coding provide useful ways of finding the wide variety of long range proton conduction pathways that contribute to long range proton conduction. They complement more traditional serial methods such as molecular dynamics and kinetic Monte Carlo.

Genomics Analysis of L-DOPA Exposure in Drosophila sechellia.

Drosophila sechellia is a dietary specialist fruit fly that evolved from a generalist ancestor to specialize on the toxic fruit of Morinda citrifolia This species pair has been the subject of numerous studies where the goal has largely been to determine the genetic basis of adaptations associated with host specialization. Because one of the most striking features of M. citrifolia fruit is the production of toxic volatile compounds that kill insects, most genomic studies in D. sechellia to date have focused on gene expression responses to the toxic compounds in its food. In this study, we aim to identify new genes important for host specialization by profiling gene expression response to 3,4-dihydroxyphenylalanine (L-DOPA). Recent work found it to be highly abundant in M. citrifolia, critical for reproductive success of D. sechellia, and supplementation of diet with the downstream pathway product dopamine can influence toxin resistance phenotypes in related species. Here we used a combination of functional genetics and genomics techniques to identify new genes that are important for D. sechellia ecological adaptation to this new niche. We show that L-DOPA exposure can affect toxin resistance phenotypes, identify genes with plastic responses to L-DOPA exposure, and functionally test an identified candidate gene. We found that knock-down of Esterase 6 (Est6) in a heterologous species alters toxin resistance suggesting Est6 may play an important role in D. sechellia host specialization.

Efficacy of recombinant chimeric lectins, consisting of mannose binding lectin and L-ficolin, against influenza A viral infection in mouse model study.

Influenza A virus infection could result in fatal complications. Although immunization is the most effective prevention it is not effective to pandemic infection and is less effective or not approved for certain age groups. Some influenza virus strains have developed resistance to antiviral agents. Thus, new therapeutic agents are urgently needed. We focused on innate immune molecules, including mannose-binding lectin (MBL). In order to optimize its antiviral activities, we have previously generated three recombinant chimeric lectins (RCL), by introducing portions of L-ficolin, another innate immune lectin. Our in vitro characterizations previously selected RCL2 and RCL3 for further investigations against viruses, including influenza viruses. Here, we examined efficacy of these lectins against infection with PR8 (H1N1) influenza A virus using mouse model studies and a human tracheal epithelial cell system. Our results provide in vivo evidence that RCL3 is effective agent against influenza virus infection. The therapeutic mechanisms are in part by providing host protective responses mediated by cytokines. We conclude that RCL3 is a potential new innate immune anti-influenza virus therapeutic agent.

Intradermal immunization with wall teichoic acid (WTA) elicits and augments an anti-WTA IgG response that protects mice from methicillin-resistant Staphylococcus aureus infection independent of mannose-binding lectin status.

The objectives of this study were to investigate the immune response to intradermal immunization with wall teichoic acid (WTA) and the effect of MBL deficiency in a murine model of infection with methicillin-resistant Staphylococcus aureus (MRSA). WTA is a bacterial cell wall component that is implicated in invasive infection. We tested susceptibility to MRSA infection in wild type (WT) and MBL deficient mice using two strains of MRSA: MW2, a community-associated MRSA (CA-MRSA); and COL, a healthcare-associated MRSA (HA-MRSA). We also performed in vitro assays to investigate the effects of anti-WTA IgG containing murine serum on complement activation and bacterial growth in whole blood. We found that MBL knockout (KO) mice are relatively resistant to a specific MRSA strain, MW2 CA-MRSA, compared to WT mice, while both strains of mice had similar susceptibility to a different strain, COL HA-MRSA. Intradermal immunization with WTA elicited and augmented an anti-WTA IgG response in both WT and MBL KO mice. WTA immunization significantly reduced susceptibility to both MW2 CA-MRSA and COL HA-MRSA, independent of the presence of MBL. The protective mechanisms of anti-WTA IgG are mediated at least in part by complement activation and clearance of bacteria from blood. The significance of these findings is that 1) Intradermal immunization with WTA induces production of anti-WTA IgG; and 2) This anti-WTA IgG response protects from infection with both MW2 CA-MRSA and COL HA-MRSA even in the absence of MBL, the deficiency of which is common in humans.