Distinct Molecular Mechanisms of Host Immune Response Modulation by Arenavirus NP and Z Proteins

Endemic to West Africa and South America, mammalian arenaviruses can cross the species barrier from their natural rodent hosts to humans, resulting in illnesses ranging from mild flu-like syndromes to severe and fatal haemorrhagic zoonoses. The increased frequency of outbreaks and associated high fatality rates of the most prevalent arenavirus, Lassa, in West African countries, highlights the significant risk to public health and to the socio-economic development of affected countries. The devastating impact of these viruses is further exacerbated by the lack of approved vaccines and effective treatments. Differential immune responses to arenavirus infections that can lead to either clearance or rapid, widespread and uncontrolled viral dissemination are modulated by the arenavirus multifunctional proteins, NP and Z. These two proteins control the antiviral response to infection by targeting multiple cellular pathways; and thus, represent attractive targets for antiviral development to counteract infection. The interplay between the host immune responses and viral replication is a key determinant of virus pathogenicity and disease outcome. In this review, we examine the current understanding of host immune defenses against arenavirus infections and summarise the host protein interactions of NP and Z and the mechanisms that govern immune evasion strategies

The role of single N-glycans in proteolytic processing and cell surface transport of the Lassa virus glycoprotein GP-C

Lassa virus glycoprotein is synthesised as a precursor (preGP-C) into the lumen of the endoplasmic reticulum. After cotranslational cleavage of the signal peptide, the immature GP-C is posttranslationally processed into the N-terminal subunit GP-1 and the C-terminal subunit GP-2 by the host cell subtilase SKI-1/S1P. The glycoprotein precursor contains eleven potential N-glycosylation sites. In this report, we investigated the effect of each N-glycan on proteolytic cleavage and cell surface transport by disrupting the consensus sequences of eleven potential N-glycan attachment sites individually. Five glycoprotein mutants with disrupted N-glycosylation sites were still proteolytically processed, whereas the remaining N-glycosylation sites are necessary for GP-C cleavage. Despite the lack of proteolytic processing, all cleavage-defective mutants were transported to the cell surface and remained completely endo H-sensitive. The findings indicate that N-glycans are needed for correct conformation of GP-C in order to be cleaved by SKI-1/S1P

A huge left atrial mass “not a myxoma”

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Superfluid phases of the three-species fermion gas

We discuss the zero temperature phase diagram of a dilute gas with three fermionic species. We make use of solvable limits to conjecture the behavior of the system in the "unitary" regions. The physics of the Thomas-Efimov effect plays a role in these considerations. We find a rich phase diagram with superfluid, gapless superfluid and inhomogeneous phases with different symmetry breaking patterns. We then discuss one particular possible experimental implementation in a system of ^6Li atoms and the possible phases arising in this system as an external magnetic field is varied across three overlaping Feshbach resonances. We also suggest how to experimentally distinguish the different phases.Comment: 4 pages, 1 figure, typos corrected and references adde

The role of myristoylation in the membrane association of the Lassa virus matrix protein Z

The Z protein is the matrix protein of arenaviruses and has been identified as the main driving force for budding. Both LCMV and Lassa virus Z proteins bud from cells in the absence of other viral proteins as enveloped virus-like particles. Z accumulates near the inner surface of the plasma membrane where budding takes place. Furthermore, biochemical data have shown that Z is strongly membrane associated. The primary sequence of Z lacks a typical transmembrane domain and until now it is not understood by which mechanism Z is able to interact with cellular membranes. In this report, we analyzed the role of N-terminal myristoylation for the membrane binding of Lassa virus Z. We show that disruption of the N-terminal myristoylation signal by substituting the N-terminal glycine with alanine (Z-G2A mutant) resulted in a significant reduction of Z protein association with cellular membranes. Furthermore, removal of the myristoylation site resulted in a relocalization of Z from a punctuate distribution to a more diffuse cellular distribution pattern. Finally, treatment of Lassa virus-infected cells with various myristoylation inhibitors drastically reduced efficient Lassa virus replication. Our data indicate that myristoylation of Z is critical for its binding ability to lipid membranes and thus, for effective virus budding

Lipomatous Hypertrophy of the Atrial Septum in a Patient Undergoing Coronary Artery Bypass Surgery

Background. Lipomatous hypertrophy of the atrial septum (LHAS) is a rare entity characterized by mass-forming deposition of fatty tissue within the atrial septum. To date, <300 cases have been reported; many of them were autopsy findings. The clinical presentation of LHAS varies from incidental asymptomatic mass (most frequent form) to severe life-threatening cardiovascular complications necessitating emergency cardiac surgery. Case Presentation. Here, we present the successful surgical resection of such a massive LHAS which was found incidentally on preoperative investigation of a 71-year-old patient with progressive coronary heart disease. Histology confirmed the diagnosis of lipomatous hypertrophy of the atrial septum. Conclusions. The described case report illustrates an unusual example of LHAS in a patient undergoing a planned coronary artery bypass surgery. In this case, surgical intervention was justified to avoid later outflow obstructions

Symbiotic modeling: Linguistic Anthropology and the promise of chiasmus

Reflexive observations and observations of reflexivity: such agendas are by now standard practice in anthropology. Dynamic feedback loops between self and other, cause and effect, represented and representamen may no longer seem surprising; but, in spite of our enhanced awareness, little deliberate attention is devoted to modeling or grounding such phenomena. Attending to both linguistic and extra-linguistic modalities of chiasmus (the X figure), a group of anthropologists has recently embraced this challenge. Applied to contemporary problems in linguistic anthropology, chiasmus functions to highlight and enhance relationships of interdependence or symbiosis between contraries, including anthropology’s four fields, the nature of human being and facets of being human

Automated Ground Truth Data Generation for Newspaper Document Images

In document image understanding, public ground-truthed datasets are an important part of scientific work. They do not only helpful for developing new methods, but they are also a point of intersection allowing to compare the methods performance without need to implement it. For document image understanding several datasets exists, each having its own pros and cons. Generating these datasets is time consuming and costly work and therefore each existing and new dataset is valuable. In this paper we propose a way to generate a ground-truthed dataset for newspapers. The ground truth in focus is layout analysis ground truth. The proposed two step approach consists of a layout generating module and an image matching module allowing to match the ground truth information from the synthetic data to the scanned version. Using the “MyNews ” system, newspaper layouts are generated using a news corpus. The output con-sists of a digital newspaper (PDF file) and an XML file con-taining geometric and logical layout information. In the second step, the PDF files are printed and scanned. Then the scanned document image is aligned with the synthetic image obtained by rendering the PDF. Finally the geometric and logical layout ground truth is mapped onto the scanned image.

Streptococcal toxic shock syndrome with associated necrotising fasciitis necessitating amputation of the lower extremity – A case report

Streptococcal toxic shock syndrome is a severe, invasive and life-threatening infection associated with a high risk of rapid multiorgan failure. It is associated with high morbidity and mortality. Streptococcal toxic shock syndrome is very commonly caused by group A- Streptococcus pyogenes, ß-haemolytic streptococcus, a typical human-specific gram-positive bacterial pathogen. We present here the case report of a 54-year-old man with a rapidly progressive streptococcal toxic shock syndrome due to necrotising fasciitis of the left lower limb and describe the successful treatment through close interdisciplinary care. </jats:p

Flow-Mediated Vasodilation Predicts Outcome in Patients With Chronic Heart Failure Comparison With B-Type Natriuretic Peptide

ObjectivesThe aim of this study was to assess the predictive potency of impaired endothelium-dependent flow-mediated vasodilation (FMD) in patients with chronic heart failure (CHF).BackgroundChronic heart failure is associated with reduced FMD; the prognostic impact of this observation is unknown.MethodsSeventy-five ambulatory CHF patients (United Network of Organ Sharing [UNOS] status 2) with a left ventricular ejection fraction (LVEF) ≤30%, despite optimized medical therapy (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, 100%; beta-blocker, 81%), were evaluated. Using high-resolution ultrasound, FMD of the brachial artery was assessed in addition to other neurohormonal, clinical, and hemodynamic variables. Age, gender, New York Heart Association (NYHA) functional class, LVEF, hemodynamic variables, B-type natriuretic peptide (BNP) levels, medical therapy, cardiovascular risk factors, and FMD were analyzed for prediction of the combined end point conversion to UNOS status 1 or death in a multivariate Cox model.ResultsUp to three years, 21 patients (28%) converted to UNOS status 1, and 6 patients (8%) died. Univariate risk factors for the combined end point were log BNP (p = 0.0032), FMD (p = 0.0033), NYHA functional class (p = 0.0132), beta-blocker therapy (p = 0.0367), and mean blood pressure (p = 0.0406). In the multivariate analysis, only FMD (p = 0.0007), log BNP (p = 0.0032), and mean blood pressure (p = 0.0475) were independently related to the combined end point. In the Kaplan-Meier plot, significantly more patients with FMD <6.8% (median) reached the combined end point, as compared with patients with FMD >6.8% (p = 0.004).ConclusionsIn CHF, impaired FMD is a strong, independent predictor of conversion to UNOS status 1 or death