Role of macrophage sialoadhesin in host defense against the sialylated pathogen group B <em>Streptococcus</em>

ABSTRACT: Several bacterial pathogens decorate their surfaces with sialic acid (Sia) residues within cell wall components or capsular exopolysaccharides. Sialic acid expression can promote bacterial virulence by blocking complement activation or by engagement of inhibitory sialic acid-binding immunoglobulin-like lectins (Siglecs) on host leukocytes. Expressed at high levels on splenic and lymph node macrophages, sialoadhesin (Sn) is a unique Siglec with an elongated structure that lacks intracellular signaling motifs. Sialoadhesin allows macrophage to engage certain sialylated pathogens and stimulate inflammatory responses, but the in vivo significance of sialoadhesin in infection has not been shown. We demonstrate that macrophages phagocytose the sialylated pathogen group B Streptococcus (GBS) and increase bactericidal activity via sialoadhesin-sialic-acid-mediated recognition. Sialoadhesin expression on marginal zone metallophillic macrophages in the spleen trapped circulating GBS and restricted the spread of the GBS to distant organs, reducing mortality. Specific IgM antibody responses to GBS challenge were also impaired in sialoadhesin-deficient mice. Thus, sialoadhesin represents a key bridge to orchestrate innate and adaptive immune defenses against invasive sialylated bacterial pathogens. KEY MESSAGE: Sialoadhesin is critical for macrophages to phagocytose and clear GBS. Increased GBS organ dissemination in the sialoadhesin-deficient mice. Reduced anti-GBS IgM production in the sialoadhesin-deficient mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00109-014-1157-y) contains supplementary material, which is available to authorized users

Composite structural motifs of binding sites for delineating biological functions of proteins

Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs which represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.Comment: 34 pages, 7 figure

Prediction Tools for Unfavourable Outcomes in Clostridium difficile Infection: A Systematic Review

CONTEXT: Identifying patients at risk for adverse outcomes of Clostridium difficile infection (CDI), including recurrence and death, will become increasingly important as novel therapies emerge, which are more effective than traditional approaches but very expensive. Clinical prediction rules (CPRs) can improve the accuracy of medical decision-making. Several CPRs have been developed for CDI, but none has gained a widespread acceptance. METHODS: We systematically reviewed studies describing the derivation or validation of CPRs for unfavourable outcomes of CDI, in medical databases (Medline, Embase, PubMed, Web of Science and Cochrane) and abstracts of conferences. RESULTS: Of 2945 titles and abstracts screened, 13 studies on the derivation of a CPR were identified: two on recurrences, five on complications (including mortality), five on mortality alone and one on response to treatment. Two studies on the validation of different severity indices were also retrieved. Most CPRs were developed as secondary analyses using cohorts assembled for other purposes. CPRs presented several methodological limitations that could explain their limited use in clinical practice. Except for leukocytosis, albumin and age, there was much heterogeneity in the variables used, and most studies were limited by small sample sizes. Eight models used a retrospective design. Only four studies reported the incidence of the outcome of interest, even if this is essential to evaluate the potential usefulness of a model in other populations. Only five studies performed multivariate analyses to adjust for confounders. CONCLUSIONS: The lack of weighing variables, of validation, calibration and measures of reproducibility, the weak validities and performances when assessed, and the absence of sensitivity analyses, all led to suboptimal quality and debatable utility of those CPRs. Evidence-based tools developed through appropriate prospective cohorts would be more valuable for clinicians than empirically-developed CPRs

Estimating Sensitivity of Laboratory Testing for Influenza in Canada through Modelling

Background: The weekly proportion of laboratory tests that are positive for influenza is used in public health surveillance systems to identify periods of influenza activity. We aimed to estimate the sensitivity of influenza testing in Canada based on results of a national respiratory virus surveillance system. Methods and Findings: The weekly number of influenza-negative tests from 1999 to 2006 was modelled as a function of laboratory-confirmed positive tests for influenza, respiratory syncytial virus (RSV), adenovirus and parainfluenza viruses, seasonality, and trend using Poisson regression. Sensitivity was calculated as the number of influenza positive tests divided by the number of influenza positive tests plus the model-estimated number of false negative tests. The sensitivity of influenza testing was estimated to be 33 % (95%CI 32–34%), varying from 30–40 % depending on the season and region. Conclusions: The estimated sensitivity of influenza tests reported to this national laboratory surveillance system is considerably less than reported test characteristics for most laboratory tests. A number of factors may explain this difference, including sample quality and specimen procurement issues as well as test characteristics. Improved diagnosis would permit better estimation of the burden of influenza

Comprehensive analysis of the base composition around the transcription start site in Metazoa

BACKGROUND: The transcription start site of a metazoan gene remains poorly understood, mostly because there is no clear signal present in all genes. Now that several sequenced metazoan genomes have been annotated, we have been able to compare the base composition around the transcription start site for all annotated genes across multiple genomes. RESULTS: The most prominent feature in the base compositions is a significant local variation in G+C content over a large region around the transcription start site. The change is present in all animal phyla but the extent of variation is different between distinct classes of vertebrates, and the shape of the variation is completely different between vertebrates and arthropods. Furthermore, the height of the variation correlates with CpG frequencies in vertebrates but not in invertebrates and it also correlates with gene expression, especially in mammals. We also detect GC and AT skews in all clades (where %G is not equal to %C or %A is not equal to %T respectively) but these occur in a more confined region around the transcription start site and in the coding region. CONCLUSIONS: The dramatic changes in nucleotide composition in humans are a consequence of CpG nucleotide frequencies and of gene expression, the changes in Fugu could point to primordial CpG islands, and the changes in the fly are of a totally different kind and unrelated to dinucleotide frequencies

Swabbing for respiratory viral infections in older patients: a comparison of rayon and nylon flocked swabs

The purpose of this study was to compare the sampling efficacy of rayon swabs and nylon flocked swabs, and of oropharyngeal and nasopharyngeal specimens for the detection of respiratory viruses in elderly patients. Samples were obtained from patients 60 years of age or above who were newly admitted to Sorlandet Hospital Arendal, Norway. The patients were interviewed for current symptoms of a respiratory tract infection. Using rayon swabs and nylon flocked swabs, comparable sets of mucosal samples were harvested from the nasopharynx and the oropharynx. The samples were analysed using real-time polymerase chain reaction (PCR) methods. A total of 223 patients (mean age 74.9 years, standard deviation [SD] 9.0 years) were swabbed and a virus was recovered from 11% of the symptomatic patients. Regardless of the sampling site, a calculated 4.8 times higher viral load (95% confidence interval [CI] 1.3–17, p = 0.017) was obtained using the nylon flocked swabs as compared to the rayon swabs. Also, regardless of the type of swab, a calculated 19 times higher viral load was found in the samples from the nasopharynx as compared to the oropharynx (95% CI 5.4–67.4, p < 0.001). When swabbing for respiratory viruses in elderly patients, nasopharyngeal rather than oropharyngeal samples should be obtained. Nylon flocked swabs appear to be more efficient than rayon swabs

A Tunable Phonon-Exciton Fano System in Bilayer Graphene

Interference between different possible paths lies at the heart of quantum physics. Such interference between coupled discrete and continuum states of a system can profoundly change its interaction with light as seen in Fano resonance. Here we present a unique many-body Fano system composed of a discrete phonon vibration and continuous electron-hole pair transitions in bilayer graphene. Mediated by the electron-phonon interactions, the excited state is described by new quanta of elementary excitations of hybrid phonon-exciton nature. Infrared absorption of the hybrid states exhibit characteristic Fano lineshapes with parameters renormalized by many-body interactions. Remarkably, the Fano resonance in bilayer graphene is continuously tunable through electrical gating. Further control of the phonon-exciton coupling may be achieved with an optical field exploiting the excited state infrared activity. This tunable phonon-exciton system also offers the intriguing possibility of a 'phonon laser' with stimulated phonon amplification generated by population inversion of band-edge electrons.Comment: 21 pages, 3 figure

The impact of malignant nipple discharge cytology (NDc) in surgical management of breast cancer patients

BACKGROUND: The role of nipple discharge cytology (NDc) in the surgical management of breast cancer patients is unclear. We aimed: (i) to evaluate the effect of malignant NDc on the surgical approach to the nipple-areola complex, and (ii) to verify the association between malignant NDc and nipple malignancy. METHODS: We retrospectively analyzed a case series of 139 patients with NDc who underwent breast surgery. The clinical and histological findings, types of surgery with emphasis on nipple-areola complex amputation, immunohistochemical phenotypes of the carcinomas and measurements of the tumor-nipple distance were recorded. Additionally, in patients who showed HER2-positive lesions on definitive surgery, we evaluated the HER2 immunocytochemistry of the NDc smears. RESULTS: Thirty-two malignant and 107 benign/borderline NDc diagnoses were identified. All 32 malignant-NDc cases were histologically confirmed as malignant. Thirty borderline/benign-NDc cases were histologically diagnosed as malignant (sensitivity 58%). The majority of the patients with malignant NDc were treated with nipple-areola complex amputations in both the mastectomy and conservative surgery groups (P<0.001, chi251.77). Nipple involvement was strongly associated with HER2-positive ductal carcinoma in-situ (P<0.001, chi211.98). HER2 immunocytochemistry on the NDc revealed a 100% correlation with the immunocytochemistry performed on the surgical tissues. CONCLUSIONS: Malignant NDc influenced surgical management. The association of malignant NDc with nipple involvement is highly related to ductal carcinoma in-situ with HER2 overexpression. In case of HER2 positive NDc, nipple-areola complex involvement is more likely than in HER2 negative cases

New Variants and Age Shift to High Fatality Groups Contribute to Severe Successive Waves in the 2009 Influenza Pandemic in Taiwan

Past influenza pandemics have been characterized by the signature feature of multiple waves. However, the reasons for multiple waves in a pandemic are not understood. Successive waves in the 2009 influenza pandemic, with a sharp increase in hospitalized and fatal cases, occurred in Taiwan during the winter of 2010. In this study, we sought to discover possible contributors to the multiple waves in this influenza pandemic. We conducted a large-scale analysis of 4703 isolates in an unbiased manner to monitor the emergence, dominance and replacement of various variants. Based on the data from influenza surveillance and epidemic curves of each variant clade, we defined virologically and temporally distinct waves of the 2009 pandemic in Taiwan from May 2009 to April 2011 as waves 1 and 2, an interwave period and wave 3. Except for wave 3, each wave was dominated by one distinct variant. In wave 3, three variants emerged and co-circulated, and formed distinct phylogenetic clades, based on the hemagglutinin (HA) genes and other segments. The severity of influenza was represented as the case fatality ratio (CFR) in the hospitalized cases. The CFRs in waves 1 and 2, the interwave period and wave 3 were 6.4%, 5.1%, 15.2% and 9.8%, respectively. The results highlight the association of virus evolution and variable influenza severity. Further analysis revealed that the major affected groups were shifted in the waves to older individuals, who had higher age-specific CFRs. The successive pandemic waves create challenges for the strategic preparedness of health authorities and make the pandemic uncertain and variable. Our findings indicate that the emergence of new variants and age shift to high fatality groups might contribute potentially to the occurrence of successive severe pandemic waves and offer insights into the adjustment of national responses to mitigate influenza pandemics

Novel roles of the chemorepellent axon guidance molecule RGMa in cell migration and adhesion

The repulsive guidance molecule A (RGMa) is a contact-mediated axon guidance molecule that has significant roles in central nervous system (CNS) development. Here we have examined whether RGMa has novel roles in cell migration and cell adhesion outside the nervous system. RGMa was found to stimulate cell migration from Xenopus animal cap explants in a neogenin-dependent and BMP-independent manner. RGMa also stimulated the adhesion of Xenopus animal cap cells, and this adhesion was dependent on neogenin and independent of calcium. To begin to functionally characterize the role of specific domains in RGMa, we assessed the migratory and adhesive activities of deletion mutants. RGMa lacking the partial von Willebrand factor type D (vWF) domain preferentially perturbed cell adhesion, while mutants lacking the RGD motif affected cell migration. We also revealed that manipulating the levels of RGMa in vivo caused major migration defects during Xenopus gastrulation. We have revealed here novel roles of RGMa in cell migration and adhesion and demonstrated that perturbations to the homeostasis of RGMa expression can severely disrupt major morphogenetic events. These results have implications for understanding the role of RGMa in both health and disease