Characterization of the Influences of Human Cytomegalovirus Glycoprotein O (gO) Expression on gH/gL Complexes Assembly and Its Polymorphisms on Cell-free and Cell-to-cell Spread, and Antibody Neutralization.

Human cytomegalovirus (HCMV) is widely spread throughout the world and immunocompromised individuals can suffer severe diseases from HCMV infection. Once the infection is established, HCMV can spread through the body and infect many major somatic cell types. The glycoproteins H and L (gH/gL) on HCMV envelope can be bound by either gO or the UL128-131 proteins to form complexes gH/gL/gO and gH/gL/UL128-131 that are critical for viral entry and spread, and these two complexes are important targets of neutralizing antibodies. Strains of HCMV vary considerably in the levels of gH/gL/gO and gH/gL/UL128-131. gO is one of the most diverse loci among strains with 10-30% of amino acid sequence differences. In this thesis I explored the mechanisms behind the complex assembly differences between strains and the impacts of interstrain gO diversity on the biology of HCMV. My results uncovered that the strain variations in the assembly of gH/gL complexes is due to the differences in the expression level of gO and UL128-131, while gO amino acid sequence differences have no influence on the complexes assembly. Interestingly, the diversity of gO has dramatic impacts on HCMV cell-free and cell-to-cell spread as well as on antibody neutralization and these effects of gO polymorphisms are epistatically dependent on other variable loci in the virus genome. My study could help to understand the complexity of genotypes observed in clinical samples and decode the challenge for intervention approaches against HCMV

Synthesis of new chiral organosulfur donors with hydrogen bonding functionality and their first charge transfer salts

The syntheses of a range of enantiopure organosulfur donors with hydrogen bonding groups are described including TTF related materials with two, four, six and eight hydroxyl groups and multiple stereogenic centres and a pair of chiral N-substituted BEDT-TTF acetamides. Three charge transfer salts of enantiopure poly-hydroxy-substituted donors are reported, including a 4:1 salt with the meso stereoisomer of the dinuclear [Fe2(oxalate)5 ]4- anion in which both cation and anion have chiral components linked together by hydrogen bonding, and a semiconducting salt with triiodide

The effect of fission-energy Xe ion irradiation on the structural integrity and dissolution of the CeO2_2 matrix

© 2016 The Authors.This work considers the effect of fission fragment damage on the structural integrity and dissolution of the CeO₂ matrix in water, as a simulant for the UO₂ matrix of spent nuclear fuel. For this purpose, thin films of CeO₂ on Si substrates were produced and irradiated by 92 MeV 129Xe23+ ions to a fluence of 4.8 × 1015 ions/cm2 to simulate fission damage that occurs within nuclear fuels along with bulk CeO₂ samples. The irradiated and unirradiated samples were characterised and a static batch dissolution experiment was conducted to study the effect of the induced irradiation damage on dissolution of the CeO₂ matrix. Complex restructuring took place in the irradiated films and the irradiated samples showed an increase in the amount of dissolved cerium, as compared to the corresponding unirradiated samples. Secondary phases were also observed on the surface of the irradiated CeO₂ films after the dissolution experiment.The irradiation experiment was performed at the Grand Accélérateur National d’Ions Lourds (GANIL) Caen, France, and supported by the French Network EMIR. The support in planning and execution of the experiment by the CIMAP-CIRIL and the GANIL staff, especially, I. Monnet, C. Grygiel, T. Madi and F. Durantel is much appreciated. Thanks are given to I. Buisman and M. Walker from the Department of Earth Sciences, University of Cambridge for help in conducting electron probe microanalysis and polishing the samples, respectively. A.J. Popel acknowledges funding from the UK EPSRC (grant EP/I036400/1 and EP/L018616/1) and Radioactive Waste Management Ltd (formerly the Radioactive Waste Management Directorate of the UK Nuclear Decommissioning Authority, contract NPO004411A-EPS02)

Prediction of Phenotypic Antimicrobial Resistance Profiles From Whole Genome Sequences of Non-typhoidal Salmonella enterica

Surveillance of antimicrobial resistance (AMR) in non-typhoidal Salmonella enterica (NTS), is essential for monitoring transmission of resistance from the food chain to humans, and for establishing effective treatment protocols. We evaluated the prediction of phenotypic resistance in NTS from genotypic profiles derived from whole genome sequencing (WGS). Genes and chromosomal mutations responsible for phenotypic resistance were sought in WGS data from 3,491 NTS isolates received by Public Health England’s Gastrointestinal Bacteria Reference Unit between April 2014 and March 2015. Inferred genotypic AMR profiles were compared with phenotypic susceptibilities determined for fifteen antimicrobials using EUCAST guidelines. Discrepancies between phenotypic and genotypic profiles for one or more antimicrobials were detected for 76 isolates (2.18%) although only 88/52,365 (0.17%) isolate/antimicrobial combinations were discordant. Of the discrepant results, the largest number were associated with streptomycin (67.05%, n = 59). Pan-susceptibility was observed in 2,190 isolates (62.73%). Overall, resistance to tetracyclines was most common (26.27% of isolates, n = 917) followed by sulphonamides (23.72%, n = 828) and ampicillin (21.43%, n = 748). Multidrug resistance (MDR), i.e., resistance to three or more antimicrobial classes, was detected in 848 isolates (24.29%) with resistance to ampicillin, streptomycin, sulphonamides and tetracyclines being the most common MDR profile (n = 231; 27.24%). For isolates with this profile, all but one were S. Typhimurium and 94.81% (n = 219) had the resistance determinants blaTEM-1, strA-strB, sul2 and tet(A). Extended-spectrum β-lactamase genes were identified in 41 isolates (1.17%) and multiple mutations in chromosomal genes associated with ciprofloxacin resistance in 82 isolates (2.35%). This study showed that WGS is suitable as a rapid means of determining AMR patterns of NTS for public health surveillance

Orbital ordering in the two-dimensional ferromagnetic semiconductor Rb_2CrCl_4

We present the results of electronic structure calculations for the two-dimensional ferromagnet Rb_2CrCl_4. They are obtained by the augmented spherical wave method as based on density functional theory and the local density approximation. In agreement with experimental data Rb_2CrCl_4 is found to be semiconducting and displays long-range ferromagnetic order of the localized Cr 3d moments. The magnetic properties are almost independent of the structural modifications arising from the Jahn-Teller instability, which leads from the parent body-centered tetragonal K_2NiF_4 structure to a side-centered orthorhombic lattice. In contrast, our calculations give evidence for a strong response of the optical band gap to the corresponding structural changes.Comment: 7 pages, 4 figures, for more information see http://www.physik.uni-augsburg.de/~eyert

Aquaporin expression in the human and canine intervertebral disc during maturation and degeneration

The intervertebral disc (IVD) is a highly hydrated tissue, the rich proteoglycan matrix imbibes water, enabling the disc to withstand compressive loads. During ageing and degeneration increased matrix degradation leads to dehydration and loss of function. Aquaporins (AQP) are a family of transmembrane channel proteins that selectively allow the passage of water in and out of cells and are responsible for maintaining water homeostasis in many tissues. Here, the expression of all 13 AQPs at gene and protein level was investigated in human and canine non‐degenerate and degenerate IVDs to develop an understanding of the role of AQPs during degeneration. Furthermore, in order to explore the transition of notochordal cells (NCs) towards nucleus pulposus (NP) cells, AQP expression was investigated in canine IVDs enriched in NCs to understand the role of AQPs in IVD maturation. AQP0, 1, 2, 3, 4, 5, 6, 7 and 9 were expressed at gene and protein level in both non‐degenerate and degenerate human NP tissue. AQP2 and 7 immunopositivity increased with degeneration in human NP tissue, whereas AQP4 expression decreased with degeneration in a similar way to AQP 1 and 5 shown previously. All AQP proteins that were identified in human NP tissue were also expressed in canine NP tissue. AQP2, 5, 6 and 9 were found to localise to vacuole‐like membranes and cell membranes in NC cells. In conclusion, AQPs were abundantly expressed in human and canine IVDs. The expression of many AQP isotypes potentially alludes to multi‐faceted functions related to adaption of NP cells to the conditions they encounter within their microenvironment in health and degeneration. The presence of AQPs within the IVD may suggest an adaptive role for these water channels during the development and maintenance of the healthy, mature IVD

New crystal packing arrangements in radical cation salts of BEDT-TTF with [Cr(NCS)6]3− and [Cr(NCS)5(NH3)]2−

BEDT-TTF forms three packing arrangement styles in its radical cation salts with [Cr(NCS)6]3− in two of which two trans-oriented isothiocyanate ligands penetrate the BEDT-TTF layers either at the point where a solvent (nitrobenzene) is incorporated in a stack of donors or by four donor molecules forming a “tube” motif to accept a ligand at each end along with a small solvent molecule in between (acetonitrile). The [Cr(NCS)5NH3]2− ion forms a related crystal packing arrangement with BEDT-TTF with a reduction in the number of “tube” motifs needed to accept an isothiocyanate ligand

Cleavage of a Neuroinvasive Human Respiratory Virus Spike Glycoprotein by Proprotein Convertases Modulates Neurovirulence and Virus Spread within the Central Nervous System.

International audienceHuman coronaviruses (HCoV) are respiratory pathogens that may be associated with the development of neurological diseases, in view of their neuroinvasive and neurotropic properties. The viral spike (S) glycoprotein is a major virulence factor for several coronavirus species, including the OC43 strain of HCoV (HCoV-OC43). In an attempt to study the role of this protein in virus spread within the central nervous system (CNS) and neurovirulence, as well as to identify amino acid residues important for such functions, we compared the sequence of the S gene found in the laboratory reference strain HCoV-OC43 ATCC VR-759 to S sequences of viruses detected in clinical isolates from the human respiratory tract. We identified one predominant mutation at amino acid 758 (from RRSR↓ G758 to RRSR↓R758), which introduces a putative furin-like cleavage (↓) site. Using a molecular cDNA infectious clone to generate a corresponding recombinant virus, we show for the first time that such point mutation in the HCoV-OC43 S glycoprotein creates a functional cleavage site between the S1 and S2 portions of the S protein. While the corresponding recombinant virus retained its neuroinvasive properties, this mutation led to decreased neurovirulence while potentially modifying the mode of virus spread, likely leading to a limited dissemination within the CNS. Taken together, these results are consistent with the adaptation of HCoV-OC43 to the CNS environment, resulting from the selection of quasi-species harboring mutations that lead to amino acid changes in viral genes, like the S gene in HCoV-OC43, which may contribute to a more efficient establishment of a less pathogenic but persistent CNS infection. This adaptative mechanism could potentially be associated with human encephalitis or other neurological degenerative pathologies

Gaps and inconsistencies in the current knowledge and implementation of biosafety and biosecurity practices for rickettsial pathogens

Introduction: Rickettsia spp. and Orientia spp. are the causes of neglected infections that can lead to severe febrile and systemic illnesses in humans. Implementing proper biosafety practices when handling these pathogens is crucial to ensure a safe and sustainable work environment. It is essential to assess the current knowledge and identify any potential gaps to develop effective measures that minimise the risk of exposure to these pathogens. By doing so, we can establish a comprehensive framework that promotes safety, mitigates hazards, and safeguards the well-being of personnel and the surrounding community. Methods and results: This review aimed to synthesise and determine the evidence base for biosafety precautions for Rickettsia spp. and Orientia spp. pathogens. Enhancing our understanding of the relative infectious risk associated with different strains of Rickettsia and Orientia spp. requires identifying the infectious dose of these pathogens that can cause human disease. The application of risk groups for Rickettsia and Orientia spp. is inconsistent across jurisdictions. There is also incomplete evidence regarding decontamination methods for these pathogens. With regards to Orientia spp. most of the available information is derived from experiments conducted with Rickettsia spp. Conclusions: Rickettsia and Orientia spp. are neglected diseases, as demonstrated by the lack of evidence-based and specific biosafety information about these pathogens. In the case of Orientia spp., most of the available information is derived from Rickettsia spp., which may not be appropriate and overstate the risks of working with this pathogen. The advent of effective antibiotic therapy and a better understanding of the true hazards and risks associated with pathogen manipulation should inform decisions, allowing a sustainable and safe work environment

Variation in resistance to multiple pathogen species:anther-smuts of Silene uniflora

The occurrence of multiple pathogen species on a shared host species is unexpected when they exploit the same micro-niche within the host individual. One explanation for such observations is the presence of pathogen-specific resistances segregating within the host population into sites that are differentially occupied by the competing pathogens. This study used experimental inoculations to test whether specific resistances may contribute to the maintenance of two species of anther-smut fungi, Microbotryum silenes-inflatae and Microbotryum lagerheimii, in natural populations of Silene uniflora in England and Wales. Overall, resistance to the two pathogens was strongly positively correlated among host populations and to a lesser degree among host families within populations. A few instances of specific resistance were also observed and confirmed by replicated inoculations. The results suggest that selection for resistance to one pathogen may protect the host from the emergence via host shifts of related pathogen species, and conversely that co-occurrence of two species of pathogens may be dependent on the presence of host genotypes susceptible to both