Cell-Free DNA and CXCL10 Derived from Bronchoalveolar Lavage Predict Lung Transplant Survival.

Standard methods for detecting chronic lung allograft dysfunction (CLAD) and rejection have poor sensitivity and specificity and have conventionally required bronchoscopies and biopsies. Plasma cell-free DNA (cfDNA) has been shown to be increased in various types of allograft injury in transplant recipients and CXCL10 has been reported to be increased in the lung tissue of patients undergoing CLAD. This study used a novel cfDNA and CXCL10 assay to evaluate the noninvasive assessment of CLAD phenotype and prediction of survival from bronchoalveolar lavage (BAL) fluid. A total of 60 BAL samples (20 with bronchiolitis obliterans (BOS), 20 with restrictive allograft syndrome (RAS), and 20 with stable allografts (STA)) were collected from 60 unique lung transplant patients; cfDNA and CXCL10 were measured by the ELISA-based KIT assay. Median cfDNA was significantly higher in BOS patients (6739 genomic equivalents (GE)/mL) versus STA (2920 GE/mL) and RAS (4174 GE/mL) (p < 0.01 all comparisons). Likelihood ratio tests revealed a significant association of overall survival with cfDNA (p = 0.0083), CXCL10 (p = 0.0146), and the interaction of cfDNA and CXCL10 (p = 0.023) based on multivariate Cox proportional hazards regression. Dichotomizing patients based on the median cfDNA level controlled for the mean level of CXCL10 revealed an over two-fold longer median overall survival time in patients with low levels of cfDNA. The KIT assay could predict allograft survival with superior performance compared with traditional biomarkers. These data support the pursuit of larger prospective studies to evaluate the predictive performance of cfDNA and CXCL10 prior to lung allograft failure

A poke in the eye: Inhibiting HIV-1 protease through its flap-recognition pocket

A novel mechanism of inhibiting HIV-1 protease (HIVp) is presented. Using computational solvent mapping to identify complementary interactions and the Multiple Protein Structure method to incorporate protein flexibility, we generated a receptor-based pharmacophore model of the flexible flap region of the semiopen, apo state of HIVp. Complementary interactions were consistently observed at the base of the flap, only within a cleft with a specific structural role. In the closed, bound state of HIVp, each flap tip docks against the opposite monomer, occupying this cleft. This flap-recognition site is filled by the protein and cannot be identified using traditional approaches based on bound, closed structures. Virtual screening and dynamics simulations show how small molecules can be identified to complement this cleft. Subsequent experimental testing confirms inhibitory activity of this new class of inhibitor. This may be the first new inhibitor class for HIVp since dimerization inhibitors were introduced 17 years ago. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 643–652, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at [email protected] Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58588/1/20993_ftp.pd

Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human

The Hedgehog (Hh) and Wnt/β-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well

Scaling analysis of the magnetic monopole mass and condensate in the pure U(1) lattice gauge theory

We observe the power law scaling behavior of the monopole mass and condensate in the pure compact U(1) gauge theory with the Villain action. In the Coulomb phase the monopole mass scales with the exponent \nu_m=0.49(4). In the confinement phase the behavior of the monopole condensate is described with remarkable accuracy by the exponent \beta_{exp}=0.197(3). Possible implications of these phenomena for a construction of a strongly coupled continuum U(1) gauge theory are discussed.Comment: Added references [1

Investigating long-term human ecodynamics in the European Arctic:Towards an integrated multi-scalar analysis of early and mid Holocene cultural, environmental and palaeodemographic sequences in Finnmark County, Northern Norway

Most parts of the Circumpolar Arctic have only discontinuous evidence for long-term human settlement. In contrast, Northern Norway has an unbroken archaeological record that extends back to the early Holocene. Numerous high-resolution archaeological and palaeoenvironmental records have been generated by commercial excavations and surveys, offering archaeologists unique opportunities to investigate long-term human ecodynamics in an Arctic coastal setting. To date, however, deeper analysis of the new datasets has yet to be undertaken. This paper aims to present a new synthesis of early and mid Holocene archaeological and paleoenvironmental sequences for Western Finnmark (11500-2000 cal BP). This enables us to identify three major phases of culture change that broadly correlate with climatic and environmental shifts. We then present emerging results from our multi-scalar analysis of the processes driving these transformations. At supra-regional and regional scales, our palaeodemographic modelling indicates major population events centered around 6000 cal BP and 4000 cal BP. At intra-regional scales, we are identifying spatial clustering of prehistoric settlements into local socio-economic communities. At the scale of local settlements, our analysis of house-pit chronologies is clarifying the degree of simultaneous occupation and re-use. We also draw on recent research into rock art and ritual landscapes in an effort to reconstruct the relationship between settlement clusters and general interaction patterns. Integration of these diverse lines of evidence is generating a vivid picture of thriving Arctic coastal communities, with indications that the timing and pace of cultural responses to climatic and environmental changes were more complex than previously thought

New species of Colletotrichum from wild Poaceae and Cyperaceae plants in Iran

Twenty-two Colletotrichum strains were isolated from anthracnose symptoms or leaf spots on leaves of various wild Poaceae and Cyperaceae plants collected in three provinces of Iran and tentatively identified as belonging to the Graminicola species complex based on morphology. All strains were studied via a polyphasic approach combining colony characteristics, morphology and phylogeny inferred from multi-locus sequences, including the nuc rDNA ITS1-5.8S-ITS2 (ITS), partial sequences of the β-tubulin (tub2), actin (act), manganese superoxide dismutase 2 (sod2), DNA lyase 2 (apn2) genes, a 200-bp intron of the glyceraldehyde-3-phosphate dehydrogenase (gapdh), and the intergenic spacer between the apn2 gene and the mat1 idiomorph (apn2/mat1). Six species were distinguished, including three new species, namely C. caspicum, C. persicum, and C. sacchari, and three previously described species, C. cereale, C. nicholsonii and C. sublineola. Comprehensive morphological descriptions and illustrations are provided for all species. Furthermore, this study provided new insights into the distribution and host range of known species

Translational and rotational diffusion coefficients in nanofluids from polarized dynamic light scattering

Nanofluids representing nanometer-sized solid particles dispersed in liquids are of interest in many fields of process and energy engineering, e.g., heat transfer, catalysis, and the design of functionalized materials [1]. The physical, chemical, optical, and electronic properties of nanofluids are strongly driven by the size, shape, surface potential, and concentration of the nanoparticles. For the analysis of diffusive processes in nanofluids allowing access to, e.g., particle size and its distribution, dynamic light scattering (DLS) is the state-of-the-art technique. It is based on the analysis of microscopic fluctuations originating from the random thermal movement of particles in the continuous liquid phase at macroscopic thermodynamic equilibrium. For anisotropic particles or particle aggregates, besides translational diffusion also rotational diffusion occurs. To obtain the sum of the orientation-averaged translational (DT) and rotational (DR) diffusivities by depolarized DLS [2], a homodyne detection scheme is usually applied which can hardly be fulfilled in the experimental realization. Furthermore, the experiments are restricted to limited ranges for temperature, particle concentration, and viscosity

Giant crystal-electric-field effect and complex magnetic behavior in single-crystalline CeRh3Si2

Single-crystalline CeRh3Si2 was investigated by means of x-ray diffraction, magnetic susceptibility, magnetization, electrical resistivity, and specific heat measurements carried out in wide temperature and magnetic field ranges. Moreover, the electronic structure of the compound was studied at room temperature by cerium core-level x-ray photoemission spectroscopy (XPS). The physical properties were analyzed in terms of crystalline electric field and compared with results of ab-initio band structure calculations performed within the density functional theory approach. The compound was found to crystallize in the orthorhombic unit cell of the ErRh3Si2 type (space group Imma -- No.74, Pearson symbol: oI24) with the lattice parameters: a = 7.1330(14) A, b = 9.7340(19) A, and c = 5.6040(11) A. Analysis of the magnetic and XPS data revealed the presence of well localized magnetic moments of trivalent cerium ions. All physical properties were found to be highly anisotropic over the whole temperature range studied, and influenced by exceptionally strong crystalline electric field with the overall splitting of the 4f1 ground multiplet exceeding 5700 K. Antiferromagnetic order of the cerium magnetic moments at TN = 4.70(1)K and their subsequent spin rearrangement at Tt = 4.48(1) K manifest themselves as distinct anomalies in the temperature characteristics of all investigated physical properties and exhibit complex evolution in an external magnetic field. A tentative magnetic B-T phase diagram, constructed for B parallel to the b-axis being the easy magnetization direction, shows very complex magnetic behavior of CeRh3Si2, similar to that recently reported for an isostructural compound CeIr3Si2. The electronic band structure calculations corroborated the antiferromagnetic ordering of the cerium magnetic moments and well reproduced the experimental XPS valence band spectrum.Comment: 32 pages, 12 figures, to appear in Physical Review

Non-Zero Sum Games for Reactive Synthesis

In this invited contribution, we summarize new solution concepts useful for the synthesis of reactive systems that we have introduced in several recent publications. These solution concepts are developed in the context of non-zero sum games played on graphs. They are part of the contributions obtained in the inVEST project funded by the European Research Council.Comment: LATA'16 invited pape