Stage-Specific Inhibition of MHC Class I Presentation by the Epstein-Barr Virus BNLF2a Protein during Virus Lytic Cycle

gamma-herpesvirus Epstein-Barr virus (EBV) persists for life in infected individuals despite the presence of a strong immune response. During the lytic cycle of EBV many viral proteins are expressed, potentially allowing virally infected cells to be recognized and eliminated by CD8+ T cells. We have recently identified an immune evasion protein encoded by EBV, BNLF2a, which is expressed in early phase lytic replication and inhibits peptide- and ATP-binding functions of the transporter associated with antigen processing. Ectopic expression of BNLF2a causes decreased surface MHC class I expression and inhibits the presentation of indicator antigens to CD8+ T cells. Here we sought to examine the influence of BNLF2a when expressed naturally during EBV lytic replication. We generated a BNLF2a-deleted recombinant EBV (ΔBNLF2a) and compared the ability of ΔBNLF2a and wild-type EBV-transformed B cell lines to be recognized by CD8+ T cell clones specific for EBV-encoded immediate early, early and late lytic antigens. Epitopes derived from immediate early and early expressed proteins were better recognized when presented by ΔBNLF2a transformed cells compared to wild-type virus transformants. However, recognition of late antigens by CD8+ T cells remained equally poor when presented by both wild-type and ΔBNLF2a cell targets. Analysis of BNLF2a and target protein expression kinetics showed that although BNLF2a is expressed during early phase replication, it is expressed at a time when there is an upregulation of immediate early proteins and initiation of early protein synthesis. Interestingly, BNLF2a protein expression was found to be lost by late lytic cycle yet ΔBNLF2a-transformed cells in late stage replication downregulated surface MHC class I to a similar extent as wild-type EBV-transformed cells. These data show that BNLF2a-mediated expression is stage-specific, affecting presentation of immediate early and early proteins, and that other evasion mechanisms operate later in the lytic cycle

Signatures of Majorana fermions in hybrid superconductor-semiconductor nanowire devices

Majorana fermions are particles identical to their own antiparticles. They have been theoretically predicted to exist in topological superconductors. We report electrical measurements on InSb nanowires contacted with one normal (Au) and one superconducting electrode (NbTiN). Gate voltages vary electron density and define a tunnel barrier between normal and superconducting contacts. In the presence of magnetic fields of order 100 mT we observe bound, mid-gap states at zero bias voltage. These bound states remain fixed to zero bias even when magnetic fields and gate voltages are changed over considerable ranges. Our observations support the hypothesis of Majorana fermions in nanowires coupled to superconductors.Comment: Raw data available at http://dx.doi.org/10.4121/uuid:8bf81177-2f2b-49c2-aaf5-d36739873dd

UDP-glycosyltransferases act as key determinants of host plant range in generalist and specialist Spodoptera species.

This is the final version. Available from National Academy of Sciences via the DOI in this record. Data, Materials, and Software Availability: The raw sequencing data for S. picta has been deposited at National Center for Biotechnology Information under the BioProject PRJNA1073306 (55). The genome assembly and annotation of S. picta and the transcriptomic raw data for different tissues of S. frugiperda have been deposited at DRYAD (56). All study data are included in the article and/or supporting information.Phytophagous insects have evolved sophisticated detoxification systems to overcome the antiherbivore chemical defenses produced by many plants. However, how these biotransformation systems differ in generalist and specialist insect species and their role in determining insect host plant range remains an open question. Here, we show that UDP-glucosyltransferases (UGTs) play a key role in determining the host range of insect species within the Spodoptera genus. Comparative genomic analyses of Spodoptera species that differ in host plant breadth identified a relatively conserved number of UGT genes in generalist species but high levels of UGT gene pseudogenization in the specialist Spodoptera picta. CRISPR-Cas9 knockouts of the three main UGT gene clusters of Spodoptera frugiperda revealed that UGT33 genes play an important role in allowing this species to utilize the poaceous plants maize, wheat, and rice, while UGT40 genes facilitate utilization of cotton. Further functional analyses in vivo and in vitro identified the UGT SfUGT33F32 as the key mechanism that allows generalist S. frugiperda to detoxify the benzoxazinoid DIMBOA (2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one), a potent insecticidal phytotoxin produced by poaceous plants. However, while this detoxification capacity is conserved in several generalist Spodoptera species, Spodoptera picta, which specializes on Crinum plants, is unable to detoxify DIMBOA due to a nonfunctionalizing mutation in SpUGT33F34. Collectively, these findings provide insight into the role of insect UGTs in host plant adaptation, the mechanistic basis of evolutionary transitions between generalism and specialism and offer molecular targets for controlling a group of notorious insect pests.National Natural Science Foundation of ChinaKey Research and Development Project of Henan ProvinceNatural Science Foundation of Henan ProvinceYoung Elite Scientists Sponsorship Program by Henan Association for Science and TechnologyNational Natural Science Foundation of ChinaInternationalization training of high-level talents in Henan Province

Graph Theoretical Analysis of Functional Brain Networks: Test-Retest Evaluation on Short- and Long-Term Resting-State Functional MRI Data

Graph-based computational network analysis has proven a powerful tool to quantitatively characterize functional architectures of the brain. However, the test-retest (TRT) reliability of graph metrics of functional networks has not been systematically examined. Here, we investigated TRT reliability of topological metrics of functional brain networks derived from resting-state functional magnetic resonance imaging data. Specifically, we evaluated both short-term (<1 hour apart) and long-term (>5 months apart) TRT reliability for 12 global and 6 local nodal network metrics. We found that reliability of global network metrics was overall low, threshold-sensitive and dependent on several factors of scanning time interval (TI, long-term>short-term), network membership (NM, networks excluding negative correlations>networks including negative correlations) and network type (NT, binarized networks>weighted networks). The dependence was modulated by another factor of node definition (ND) strategy. The local nodal reliability exhibited large variability across nodal metrics and a spatially heterogeneous distribution. Nodal degree was the most reliable metric and varied the least across the factors above. Hub regions in association and limbic/paralimbic cortices showed moderate TRT reliability. Importantly, nodal reliability was robust to above-mentioned four factors. Simulation analysis revealed that global network metrics were extremely sensitive (but varying degrees) to noise in functional connectivity and weighted networks generated numerically more reliable results in compared with binarized networks. For nodal network metrics, they showed high resistance to noise in functional connectivity and no NT related differences were found in the resistance. These findings provide important implications on how to choose reliable analytical schemes and network metrics of interest

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

Use of an Electrochemical Split Cell Technique to Evaluate the Influence of Shewanella oneidensis Activities on Corrosion of Carbon Steel

Microbially induced corrosion (MIC) is a complex problem that affects various industries. Several techniques have been developed to monitor corrosion and elucidate corrosion mechanisms, including microbiological processes that induce metal deterioration. We used zero resistance ammetry (ZRA) in a split chamber configuration to evaluate the effects of the facultatively anaerobic Fe(III) reducing bacterium Shewanella oneidensis MR-1 on the corrosion of UNS G10180 carbon steel. We show that activities of S. oneidensis inhibit corrosion of steel with which that organism has direct contact. However, when a carbon steel coupon in contact with S. oneidensis was electrically connected to a second coupon that was free of biofilm (in separate chambers of the split chamber assembly), ZRA-based measurements indicated that current moved from the S. oneidensis-containing chamber to the cell-free chamber. This electron transfer enhanced the O2 reduction reaction on the coupon deployed in the cell free chamber, and consequently, enhanced oxidation and corrosion of that electrode. Our results illustrate a novel mechanism for MIC in cases where metal surfaces are heterogeneously covered by biofilms

Task-Related Effects on the Temporal and Spatial Dynamics of Resting-State Functional Connectivity in the Default Network

Recent evidence points to two potentially fundamental aspects of the default network (DN), which have been relatively understudied. One is the temporal nature of the functional interactions among nodes of the network in the resting-state, usually assumed to be static. The second is possible influences of previous brain states on the spatial patterns (i.e., the brain regions involved) of functional connectivity (FC) in the DN at rest. The goal of the current study was to investigate modulations in both the spatial and temporal domains. We compared the resting-state FC of the DN in two runs that were separated by a 45 minute interval containing cognitive task execution. We used partial least squares (PLS), which allowed us to identify FC spatiotemporal patterns in the two runs and to determine differences between them. Our results revealed two primary modes of FC, assessed using a posterior cingulate seed – a robust correlation among DN regions that is stable both spatially and temporally, and a second pattern that is reduced in spatial extent and more variable temporally after cognitive tasks, showing switching between connectivity with certain DN regions and connectivity with other areas, including some task-related regions. Therefore, the DN seems to exhibit two simultaneous FC dynamics at rest. The first is spatially invariant and insensitive to previous brain states, suggesting that the DN maintains some temporally stable functional connections. The second dynamic is more variable and is seen more strongly when the resting-state follows a period of task execution, suggesting an after-effect of the cognitive activity engaged during task that carries over into resting-state periods

Observation of a ppb mass threshoud enhancement in \psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p}) decay

The decay channel $\psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p})$ is studied using a sample of $1.06\times 10^8$ $\psi^\prime$ events collected by the BESIII experiment at BEPCII. A strong enhancement at threshold is observed in the $p\bar{p}$ invariant mass spectrum. The enhancement can be fit with an $S$-wave Breit-Wigner resonance function with a resulting peak mass of $M=1861^{+6}_{-13} {\rm (stat)}^{+7}_{-26} {\rm (syst)} {\rm MeV/}c^2$ and a narrow width that is $\Gamma<38 {\rm MeV/}c^2$ at the 90% confidence level. These results are consistent with published BESII results. These mass and width values do not match with those of any known meson resonance.Comment: 5 pages, 3 figures, submitted to Chinese Physics

Free energy of binding of coiled-coil complexes with different electrostatic environments: the influence of force field polarisation and capping

Coiled-coils are well known protein–protein interaction motifs, with the leucine zipper region of activator protein-1 (AP-1) consisting of the c-Jun and c-Fos proteins being a typical example. Molecular dynamics (MD) simulations using the MM/GBSA method have been used to predict the free energy of interaction of these proteins. The influence of force field polarisation and capping on the predicted free energy of binding of complexes with different electrostatic environments (net charge) were investigated. Although both force field polarisation and peptide capping are important for the prediction of the absolute free energy of binding, peptide capping has the largest influence on the predicted free energy of binding. Polarisable simulations appear better suited to determine structural properties of the complexes of these proteins while non-polarisable simulations seem to give better predictions of the associated free energies of bindin

Increased Activity Imbalance in Fronto-Subcortical Circuits in Adolescents with Major Depression

BACKGROUND: A functional discrepancy exists in adolescents between frontal and subcortical regions due to differential regional maturational trajectories. It remains unknown how this functional discrepancy alters and whether the influence from the subcortical to the frontal system plays a primacy role in medication naïve adolescent with major depressive disorder (MDD). METHODOLOGY/PRINCIPAL FINDINGS: Eighteen MDD and 18 healthy adolescents were enrolled. Depression and anxiety severity was assessed by the Short Mood and Feeling Questionnaire (SMFQ) and Screen for Child Anxiety Related Emotional Disorders (SCARED) respectively. The functional discrepancy was measured by the amplitude of low-frequency fluctuations (ALFF) of resting-state functional MRI signal. Correlation analysis was carried out between ALFF values and SMFQ and SCARED scores. Resting brain activity levels measured by ALFF was higher in the frontal cortex than that in the subcortical system involving mainly (para) limbic-striatal regions in both HC and MDD adolescents. The difference of ALFF values between frontal and subcortical systems was increased in MDD adolescents as compared with the controls. CONCLUSIONS/SIGNIFICANCE: The present study identified an increased imbalance of resting-state brain activity between the frontal cognitive control system and the (para) limbic-striatal emotional processing system in MDD adolescents. The findings may provide insights into the neural correlates of adolescent MDD