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

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.

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

Cardiac Output Measurements in Septic Patients: Comparing the Accuracy of USCOM to PiCCO

USCOM is an ultrasound-based method which has been accepted for noninvasive hemodynamic monitoring in various clinical conditions (USCOM, Ultrasonic cardiac output monitoring). The present study aimed at comparing the accuracy of the USCOM device with that of the thermodilution technique in patients with septicemia. We conducted a prospective observational study in a medical but noncardiological ICU of a university hospital. Septic adult patients (median age 55 years, median SAPS-II-Score 43 points) on mechanical ventilation and catecholamine support were monitored with USCOM and PiCCO (n = 70). Seventy paired left-sided CO measurements (transaortic access = COUS-A) were obtained. The mean COUS-A were 6.55 l/min (±2.19) versus COPiCCO 6.5 l/min (±2.18). The correlation coefficient was r = 0.89. Comparison by Bland-Altman analysis revealed a bias of −0.36 l/min (±0.99 l/min) leading to a mean percentage error of 29%. USCOM is a feasible and rapid method to evaluate CO in septic patients. USCOM does reliably represent CO values as compared to the reference technique based on thermodilution (PiCCO). It seems to be appropriate in situations where CO measurements are most pertinent to patient management

Reality Meets Belief: A Mixed Methods Study on Character Strengths and Well-Being of Hospital Physicians

Positive psychology deals with factors that make life most worth living and focuses on enhancing individual potentials. Particularly, character strengths can positively contribute to well-being and work-related health, bearing a promising potential for professions, such as physicians, who are at risk for burnout or mental illnesses. This study aims to identify beneficial character strengths by examining the quantitative and qualitative data. In a cross-sectional multi-method study, 218 hospital physicians completed an online survey assessing their character strengths and their general and work-related well-being, comprising thriving, work engagement, and burnout dimensions (outcome variables). Quantitative data were analyzed for the total sample and by tertiary split. Additionally, interview-gathered opinions of four resident physicians and four medical specialist educators were collected to expand the perspective on which character strengths might be beneficial for the well-being of the resident physicians. The highest significant correlations between character strengths and outcome variables were found for hope and thriving (r = 0.67), zest, and work engagement (r = 0.67) as well as emotional exhaustion (r = −0.47), perseverance/leadership and depersonalization (r = −0.27), bravery, and reduced personal accomplishment (r = −0.39). Tertiary splits revealed that some correlations were not consistent across the entire scale continuum, for example, creativity was only significantly correlated with comparatively high levels of thriving (r = 0.28) or forgiveness with comparatively high levels of depersonalization (r = −0.34). Humility, social intelligence, and teamwork showed predominantly low correlations with all outcome variables (r = −0.17 − 0.34), although humility was stated by all interviewed medical specialist educators to be the most relevant for the well-being at work, and the latter two by three resident physicians, respectively. Different perspectives resulting from quantitative and qualitative data in terms of beneficial character strengths for work-related well-being may be driven by different work experiences, professional understandings, generational beliefs, or social expectations. Some significant correlations between character strengths and well-being outcomes varied depending on low, medium, or high outcomes. This raises questions about suitable work-related well-being interventions, as simple single intervention approaches (one intervention fits all) may not work for the respective outcome levels. These new findings warrant further research on how to foster the well-being of resident physicians at work