The norovirus NS3 protein is a dynamic lipid- and microtubule-associated protein involved in viral RNA replication

Norovirus (NoV) infections are a significant health burden to society, yet the lack of reliable tissue culture systems has hampered the development of appropriate antiviral therapies. Here we show that the NoV NS3 protein, derived from murine NoV (MNV), is intimately associated with the MNV replication complex and the viral replication intermediate double-stranded RNA (dsRNA). We observed that when expressed individually, MNV NS3 and NS3 encoded by human Norwalk virus (NV) induced the formation of distinct vesicle-like structures that did not colocalize with any particular protein markers to cellular organelles but localized to cellular membranes, in particular those with a high cholesterol content. Both proteins also showed some degree of colocalization with the cytoskeleton marker β-tubulin. Although the distribution of MNV and NV NS3s were similar, NV NS3 displayed a higher level of colocalization with the Golgi apparatus and the endoplasmic reticulum (ER). However, we observed that although both proteins colocalized in membranes counterstained with filipin, an indicator of cholesterol content, MNV NS3 displayed a greater association with flotillin and stomatin, proteins known to associate with sphingolipid- and cholesterol-rich microdomains. Utilizing time-lapse epifluorescence microscopy, we observed that the membrane-derived vesicular structures induced by MNV NS3 were highly motile and dynamic in nature, and their movement was dependent on intact microtubules. These results begin to interrogate the functions of NoV proteins during virus replication and highlight the conserved properties of the NoV NS3 proteins among the seven Norovirus genogroups

Using impression data to improve models of online social influence

Influence, the ability to change the beliefs and behaviors of others, is the main currency on social media. Extant studies of influence on social media, however, are limited by publicly available data that record expressions (active engagement of users with content, such as likes and comments), but neglect impressions (exposure to content, such as views) and lack “ground truth” measures of influence. To overcome these limitations, we implemented a social media simulation using an original, web-based micro-blogging platform. We propose three influence models, leveraging expressions and impressions to create a more complete picture of social influence. We demonstrate that impressions are much more important drivers of influence than expressions, and our models accurately identify the most influential accounts in our simulation. Impressions data also allow us to better understand important social media dynamics, including the emergence of small numbers of influential accounts and the formation of opinion echo chambers

A New Method for Finding Vacua in String Phenomenology

One of the central problems of string-phenomenology is to find stable vacua in the four dimensional effective theories which result from compactification. We present an algorithmic method to find all of the vacua of any given string-phenomenological system in a huge class. In particular, this paper reviews and then extends hep-th/0606122 to include various non-perturbative effects. These include gaugino condensation and instantonic contributions to the superpotential.Comment: 27 pages, 5 .eps figures. V2: Minor corrections, reference adde

BRST Quantization of Noncommutative Gauge Theories

In this paper, the BRST symmetry transformation is presented for the noncommutative U(N) gauge theory. The nilpotency of the charge associated to this symmetry is then proved. As a consequence for the space-like non-commutativity parameter, the Hilbert space of physical states is determined by the cohomology space of the BRST operator as in the commutative case. Further, the unitarity of the S-matrix elements projected onto the subspace of physical states is deduced.Comment: 20 pages, LaTeX, no figures, one reference added, to appear in Phys. Rev.

What can we learn from GRBs?

We review our recent results on the classification of long and short gamma-ray bursts (GRBs) in different subclasses. We provide observational evidences for the binary nature of GRB progenitors. For long bursts the induced gravitational collapse (IGC) paradigm proposes as progenitor a tight binary system composed of a carbon-oxygen core (COcore) and a neutron star (NS) companion; the supernova (SN) explosion of the COcore triggers a hypercritical accretion process onto the companion NS. For short bursts a NS–NS merger is traditionally adopted as the progenitor. We also indicate additional sub-classes originating from different progenitors: (COcore)–black hole (BH), BH–NS, and white dwarf–NS binaries. We also show how the outcomes of the further evolution of some of these sub-classes may become the progenitor systems of other sub-classes

MRI/US fusion-guided prostate biopsy allows for equivalent cancer detection with significantly fewer needle cores in biopsy-naive men

PURPOSE:We aimed to investigate the efficiency and cancer detection of magnetic resonance imaging (MRI) / ultrasonography (US) fusion-guided prostate biopsy in a cohort of biopsy-naive men compared with standard-of-care systematic extended sextant transrectal ultrasonography (TRUS)-guided biopsy.METHODS:From 2014 to 2016, 72 biopsy-naive men referred for initial prostate cancer evaluation who underwent MRI of the prostate were prospectively evaluated. Retrospective review was performed on 69 patients with lesions suspicious for malignancy who underwent MRI/US fusion-guided biopsy in addition to systematic extended sextant biopsy. Biometric, imaging, and pathology data from both the MRI-targeted biopsies and systematic biopsies were analyzed and compared.RESULTS:There were no significant differences in overall prostate cancer detection when comparing MRI-targeted biopsies to standard systematic biopsies (P = 0.39). Furthermore, there were no significant differences in the distribution of severity of cancers based on grade groups in cases with cancer detection (P = 0.68). However, significantly fewer needle cores were taken during the MRI/US fusion-guided biopsy compared with systematic biopsy (63% less cores sampled, P < 0.001)CONCLUSION:In biopsy-naive men, MRI/US fusion-guided prostate biopsy offers equal prostate cancer detection compared with systematic TRUS-guided biopsy with significantly fewer tissue cores using the targeted technique. This approach can potentially reduce morbidity in the future if used instead of systematic biopsy without sacrificing the ability to detect prostate cancer, particularly in cases with higher grade disease

Country development and manuscript selection bias: a review of published studies

BACKGROUND: Manuscript selection bias is the selective publication of manuscripts based on study characteristics other than quality indicators. One reason may be a perceived editorial bias against the researches from less-developed world. We aimed to compare the methodological quality and statistical appeal of trials from countries with different development status and to determine their association with the journal impact factors and language of publication. METHODS: Selection criteria: Based on the World Bank income criteria countries were divided into four groups. All records of clinical trials conducted in each income group during 1993 and 2003 were included if they contained abstract and study sample size. Data sources: Cochrane Controlled Trials Register was searched and 50 articles selected from each income group using a systematic random sampling method in years 1993 and 2003 separately. Data extraction: Data were extracted by two reviewers on the language of publication, use of randomization, blinding, intention to treat analysis, study sample size and statistical significance. Disagreement was dealt with by consensus. Journal impact factors were obtained from the institute for scientific information. RESULTS: Four hundred records were explored. Country income had an inverse linear association with the presence of randomization (chi2 for trend = 5.6, p = 0.02) and a direct association with the use of blinding (chi2 for trend = 6.9, p = 0.008); although in low income countries the probability of blinding was increased from 36% in 1993 to 46% in 2003. In 1993 the results of 68% of high income trials and 64.7% of other groups were statistically significant; but in 2003 they were 66% and 82% respectively. Study sample size and income were the only significant predictors of journal impact factor. CONCLUSION: The impact of country development on manuscript selection bias is considerable and may be increasing over time. It seems that one reason may be more stringent implementation of the guidelines for improving the reporting quality of trials on developing world researchers. Another reason may be the presumptions of the researchers from developing world about the editorial bias against their nationality

Accidental Inflation in String Theory

We show that inflation in type IIB string theory driven by the volume modulus can be realized in the context of the racetrack-based Kallosh-Linde model (KL) of moduli stabilization. Inflation here arises through the volume modulus slow-rolling down from a flat hill-top or inflection point of the scalar potential. This situation can be quite generic in the landscape, where by uplifting one of the two adjacent minima one can turn the barrier either to a flat saddle point or to an inflection point supporting eternal inflation. The resulting spectral index is tunable in the range of 0.93 < n_s < 1, and there is only negligible production of primordial gravitational waves r < 10^{-6}. The flatness of the potential in this scenario requires fine-tuning, which may be justified taking into account the exponential reward by volume factors preferring the regions of the universe with the maximal amount of slow-roll inflation. This consideration leads to a tentative prediction of the spectral index $n_s\approx 0.95$ or $n_s \approx 0.93$ depending on whether the potential has a symmetry phi -> - phi or not.Comment: 15 pages, 6 figures, LaTeX, uses RevTex

Flat Connections in Open String Mirror Symmetry

We study a flat connection defined on the open-closed deformation space of open string mirror symmetry for type II compactifications on Calabi-Yau threefolds with D-branes. We use flatness and integrability conditions to define distinguished flat coordinates and the superpotential function at an arbitrary point in the open-closed deformation space. Integrability conditions are given for concrete deformation spaces with several closed and open string deformations. We study explicit examples for expansions around different limit points, including orbifold Gromov-Witten invariants, and brane configurations with several brane moduli. In particular, the latter case covers stacks of parallel branes with non-Abelian symmetry.Comment: 38 pages, 1 figure, v2: references adde

Integrated MicroRNA-mRNA-Analysis of Human Monocyte Derived Macrophages upon Mycobacterium avium subsp. hominissuis Infection

Many efforts have been made to understand basal mechanisms of mycobacterial infections. Macrophages are the first line of host immune defence to encounter and eradicate mycobacteria. Pathogenic species have evolved different mechanisms to evade host response, e.g. by influencing macrophage apoptotic pathways. However, the underlying molecular regulation is not fully understood. A new layer of eukaryotic regulation of gene expression is constituted by microRNAs. Therefore, we present a comprehensive study for identification of these key regulators and their targets in the context of host macrophage response to mycobacterial infections.We performed microRNA as well as mRNA expression analysis of human monocyte derived macrophages infected with several Mycobacterium avium hominissuis strains by means of microarrays as well as quantitative reverse transcription PCR (qRT-PCR). The data revealed the ability of all strains to inhibit apoptosis by transcriptional regulation of BCL2 family members. Accordingly, at 48 h after infection macrophages infected with all M. avium strains showed significantly decreased caspase 3 and 7 activities compared to the controls. Expression of let-7e, miR-29a and miR-886-5p were increased in response to mycobacterial infection at 48 h. The integrated analysis of microRNA and mRNA expression as well as target prediction pointed out regulative networks identifying caspase 3 and 7 as potential targets of let-7e and miR-29a, respectively. Consecutive reporter assays verified the regulation of caspase 3 and 7 by these microRNAs.We show for the first time that mycobacterial infection of human macrophages causes a specific microRNA response. We furthermore outlined a regulatory network of potential interactions between microRNAs and mRNAs. This study provides a theoretical concept for unveiling how distinct mycobacteria could manipulate host cell response. In addition, functional relevance was confirmed by uncovering the control of major caspases 3 and 7 by let-7e and miR-29a, respectively