Recent Research Progress of Porous Graphene and Applications in Molecular Sieve, Sensor, and Supercapacitor.

Porous graphene, including 2D and 3D porous graphene, is widely researched recently. One of the most attractive features is the proper utilization of graphene defects, which combine the advantages of both graphene and porous materials, greatly enriching the applications of porous graphene in biology, chemistry, electronics, and other fields. In this review, the defects of graphene are first discussed to provide a comprehensive understanding of porous graphene. Then, the latest advancements in the preparation of 2D and 3D porous graphene are presented. The pros and cons of these preparation methods are discussed in detail, providing a direction for the fabrication of porous graphene. Moreover, various superior properties of porous graphene are described, laying the foundation for their promising applications. Owing to its abundant morphology, wide distribution of pore size, and remarkable properties benefited from porous structure, porous graphene can not only promote molecular diffusion and electron transfer but also expose more active sites. Consequently, a serious of applications containing gas sieving, liquid separation, sensors, and supercapacitors, are presented. Finally, the challenges confronted during preparation and characterization of porous graphene are discussed, offering guidance for the future development of porous graphene in fabrication, characterization, properties, and applications.

MGF6mARice: prediction of DNA N6-methyladenine sites in rice by exploiting molecular graph feature and residual block.

DNA N6-methyladenine (6mA) is produced by the N6 position of the adenine being methylated, which occurs at the molecular level, and is involved in numerous vital biological processes in the rice genome. Given the shortcomings of biological experiments, researchers have developed many computational methods to predict 6mA sites and achieved good performance. However, the existing methods do not consider the occurrence mechanism of 6mA to extract features from the molecular structure. In this paper, a novel deep learning method is proposed by devising DNA molecular graph feature and residual block structure for 6mA sites prediction in rice, named MGF6mARice. Firstly, the DNA sequence is changed into a simplified molecular input line entry system (SMILES) format, which reflects chemical molecular structure. Secondly, for the molecular structure data, we construct the DNA molecular graph feature based on the principle of graph convolutional network. Then, the residual block is designed to extract higher level, distinguishable features from molecular graph features. Finally, the prediction module is used to obtain the result of whether it is a 6mA site. By means of 10-fold cross-validation, MGF6mARice outperforms the state-of-the-art approaches. Multiple experiments have shown that the molecular graph feature and residual block can promote the performance of MGF6mARice in 6mA prediction. To the best of our knowledge, it is the first time to derive a feature of DNA sequence by considering the chemical molecular structure. We hope that MGF6mARice will be helpful for researchers to analyze 6mA sites in rice.

Persistence of Immunogenicity of a Purified Inactivated Zika Virus Vaccine Candidate in Healthy Adults: 2 Years of Follow-up Compared With Natural Infection.

BACKGROUND: We report 2-year persistence of immune response to Takeda's prophylactic purified formalin-inactivated whole Zika virus vaccine candidate (TAK-426) compared with that observed after natural infection. METHODS: A randomized, observer-blind, placebo-controlled, dose-selection, phase 1 trial was conducted in 18-49-year-old adults at 9 centers (7 in the United States, 2 in Puerto Rico) from 13 November 2017 to 24 November 2020. Primary objectives were safety, tolerability, and immunogenicity of 3 increasing doses of TAK-426 administered as 2 doses 28 days apart to flavivirus (FV)-naive and FV-primed adults. Here, we report on safety and persistence of immunity up to 2 years after primary vaccination with 10-µg TAK-426, the highest dose, and compare neutralizing antibody responses with those observed after natural infection. RESULTS: TAK-426 at 10-µg had an acceptable safety profile in FV-naive and FV-primed adults up to 24 months after dose 2. Seropositivity for neutralizing antibodies was 100% at 1 year, and 93.8% and 76.2% at 2 years in FV-naive and FV-primed groups, respectively. TAK-426 responses were comparable in magnitude and kinetics with those elicited by natural Zika virus infection. CONCLUSIONS: These results support the further clinical development of TAK-426 for both FV-naive and FV-primed populations. CLINICAL TRIALS REGISTRATION: NCT03343626.

Semiparametric pseudo-score and pseudo-likelihood for evaluating correlate of protection in vaccine trials.

In vaccine clinical trials, vaccine efficacy endpoint analysis is usually associated with in high cost or extended study duration, due to the generally low infection rate. Correlate of protection (CoP), which refers to surrogate endpoint, usually immunological response, that can reliably predict the treatment effect, provides a more efficient and less costly approach to evaluate the vaccine. To handle the challenge of the missingness in the unobserved surrogate immune biomarker, the pseudo-score (PS) method, semiparametric method and pseudo-likelihood (PL) method demonstrated their advantages on different aspects. In this article, we propose new methodologies to combine the advantages of PS and PL with semiparametric methods respectively, to achieve higher estimate efficiency, allow continuous baseline predictor variable, and handle multiple surrogate markers. The advantage of our methodologies are demonstrated by a simulation study in different settings and applied to a case study, which eventually can improve the chance of a successful trial.

A Systematic Review of INGARCH Models for Integer-Valued Time Series.

Count time series are widely available in fields such as epidemiology, finance, meteorology, and sports, and thus there is a growing demand for both methodological and application-oriented research on such data. This paper reviews recent developments in integer-valued generalized autoregressive conditional heteroscedasticity (INGARCH) models over the past five years, focusing on data types including unbounded non-negative counts, bounded non-negative counts, Z-valued time series and multivariate counts. For each type of data, our review follows the three main lines of model innovation, methodological development, and expansion of application areas. We attempt to summarize the recent methodological developments of INGARCH models for each data type for the integration of the whole INGARCH modeling field and suggest some potential research topics.

Efficacy of a Dengue Vaccine Candidate (TAK-003) in Healthy Children and Adolescents 2 Years after Vaccination.

BACKGROUND: Takeda's dengue vaccine is under evaluation in an ongoing phase 3 efficacy study; we present a 2-year update. METHODS: Children (20 099, 4-16 years old) were randomized to receive 2 doses of TAK-003 or placebo 3 months apart and are under surveillance to detect dengue by serotype-specific RT-PCR. RESULTS: Cumulative efficacy against dengue approximately 27 months since first dose was 72.7% (95% confidence interval [CI], 67.1%-77.3%), including 67.0% (95% CI, 53.6%-76.5%) in dengue-naive and 89.2% (95% CI, 82.4%-93.3%) against hospitalized dengue. In the second year, decline in efficacy was observed (56.2%; 95% CI, 42.3%-66.8%) with the largest decline in 4-5 year olds (24.5%; 95% CI, -34.2% to 57.5%); efficacy was 60.6% (95% CI, 43.8%-72.4%) in 6-11 year and 71.2% (95% CI, 41.0%-85.9%) in 12-16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to efficacy differences in year-by-year analysis. No related serious adverse events occurred during the second year. CONCLUSIONS: TAK-003 demonstrated continued benefit independent of baseline serostatus in reducing dengue with some decline in efficacy during the second year. Three-year data will be important to see if efficacy stabilizes or declines further.Clinical Trials Registration. NCT02747927.Takeda's tetravalent dengue vaccine (TAK-003) continued to demonstrate benefit in reducing dengue independent of baseline serostatus up to 2 years after completing vaccination with some decline in efficacy during the second year in 4-16 year olds in dengue-endemic countries.

Magnetoresistance in Organic Spin Valves Based on Acid-Exfoliated 2D Covalent Organic Frameworks Thin Films.

Covalent organic frameworks (COFs), as a burgeoning class of crystalline porous materials, have made significant progress in their application to optoelectronic devices such as field-effect transistors, memristors, and photodetectors. However, the insoluble features of microcrystalline two-dimensional (2D) COF powders limit development of their thin film devices. Additionally, the exploration of spin transport properties in this category of π-conjugated skeleton materials remains vacant thus far. Herein, an imine-linked 2D Py-Np COF nanocrystalline powder was synthesized by Schiff base condensation of 4,4',4'',4'''-(pyrene-1,3,6,8-tetrayl)tetraaniline and naphthalene-2,6-dicarbaldehyde. Then, we prepared a large-scale free-standing Py-Np COF film via a top-down strategy of chemically assisted acid exfoliation. Moreover, high-quality COF films acted as active layers were transferred onto ferromagnetic La0.67 Sr0.33 MnO3 (LSMO) electrodes for the first attempt to fabricate organic spin valves (OSVs) based on 2D COF materials. This COF-based OSV device with a configuration of LSMO/Py-Np COF/Co/Au demonstrated a remarkable magnetoresistance (MR) value up to -26.5 % at 30 K. Meanwhile, the MR behavior of the COF-based OSVs exhibited a highly temperature dependence and operational stability. This work highlights the enormous application prospects of 2D COFs in organic spintronics and provides a promising approach for developing electronic and spintronic devices based on acid-exfoliated COF thin films.

Three-year Efficacy and Safety of Takeda's Dengue Vaccine Candidate (TAK-003).

BACKGROUND: Takeda's live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across 8 dengue-endemic countries. Previously, we have reported its efficacy and safety in both seronegative and seropositive participants and that its performance varies by serotype, with some decline in efficacy from first to second year postvaccination. This exploratory analysis provides an update with cumulative and third-year data. METHODS: Healthy 4-16 year olds (n = 20099) were randomized 2:1 to receive TAK-003 or placebo (0, 3 month schedule). The protocol included baseline serostatus testing of all participants and detection of all symptomatic dengue throughout the trial with a serotype specific reverse transcriptase-polymerase chain reaction. RESULTS: Cumulative efficacy after 3 years was 62.0% (95% confidence interval, 56.6-66.7) against virologically confirmed dengue (VCD) and 83.6% (76.8-88.4) against hospitalized VCD. Efficacy was 54.3% (41.9-64.1) against VCD and 77.1% (58.6-87.3) against hospitalized VCD in baseline seronegatives, and 65.0% (58.9-70.1) against VCD and 86.0% (78.4-91.0) against hospitalized VCD in baseline seropositives. Efficacy against VCD during the third year declined to 44.7% (32.5-54.7), whereas efficacy against hospitalized VCD was sustained at 70.8% (49.6-83.0). Rates of serious adverse events were 2.9% in TAK-003 group and 3.5% in placebo group during the ongoing long-term follow-up (ie, second half of the 3 years following vaccination), but none were related. No important safety risks were identified. CONCLUSIONS: TAK-003 was efficacious against symptomatic dengue over 3 years. Efficacy declined over time but remained robust against hospitalized dengue. A booster dose evaluation is planned.

An effective method to resolve ambiguous bisulfite-treated reads.

BACKGROUND: The combination of the bisulfite treatment and the next-generation sequencing is an important method for methylation analysis, and aligning the bisulfite-treated reads (BS-reads) is the critical step for the downstream applications. As bisulfite treatment reduces the complexity of the sequences, a large portion of BS-reads might be aligned to multiple locations of the reference genome ambiguously, called multireads. These multireads cannot be employed in the downstream applications since they are likely to introduce artifacts. To identify the best mapping location of each multiread, existing Bayesian-based methods calculate the probability of the read at each position by considering how does it overlap with unique mapped reads. However, [Formula: see text]% of multireads are not overlapped with any unique reads, which are unresolvable for existing method. RESULTS: Here we propose a novel method (EM-MUL) that not only rescues multireads overlapped with unique reads, but also uses the overall coverage and accurate base-level alignment to resolve multireads that cannot be handled by current methods. We benchmark our method on both simulated datasets and real datasets. Experimental results show that it is able to align more than 80% of multireads to the best mapping position with very high accuracy. CONCLUSIONS: EM-MUL is an effective method designed to accurately determine the best mapping position of multireads in BS-reads. For the downstream applications, it is useful to improve the methylation resolution on the repetitive regions of genome. EM-MUL is free available at https://github.com/lmylynn/EM-MUL.

An improved DNA-binding hot spot residues prediction method by exploring interfacial neighbor properties.

BACKGROUND: DNA-binding hot spots are dominant and fundamental residues that contribute most of the binding free energy yet accounting for a small portion of protein-DNA interfaces. As experimental methods for identifying hot spots are time-consuming and costly, high-efficiency computational approaches are emerging as alternative pathways to experimental methods. RESULTS: Herein, we present a new computational method, termed inpPDH, for hot spot prediction. To improve the prediction performance, we extract hybrid features which incorporate traditional features and new interfacial neighbor properties. To remove redundant and irrelevant features, feature selection is employed using a two-step feature selection strategy. Finally, a subset of 7 optimal features are chosen to construct the predictor using support vector machine. The results on the benchmark dataset show that this proposed method yields significantly better prediction accuracy than those previously published methods in the literature. Moreover, a user-friendly web server for inpPDH is well established and is freely available at http://bioinfo.ahu.edu.cn/inpPDH . CONCLUSIONS: We have developed an accurate improved prediction model, inpPDH, for hot spot residues in protein-DNA binding interfaces by given the structure of a protein-DNA complex. Moreover, we identify a comprehensive and useful feature subset including the proposed interfacial neighbor features that has an important strength for identifying hot spot residues. Our results indicate that these features are more effective than the conventional features considered previously, and that the combination of interfacial neighbor features and traditional features may support the creation of a discriminative feature set for efficient prediction of hot spot residues in protein-DNA complexes.

The transcription factors Egr2 and Egr3 are essential for the control of inflammation and antigen-induced proliferation of B and T cells.

Lymphocytes provide optimal responses against pathogens with minimal inflammatory pathology. However, the intrinsic mechanisms regulating these responses are unknown. Here, we report that deletion of both transcription factors Egr2 and Egr3 in lymphocytes resulted in a lethal autoimmune syndrome with excessive serum proinflammatory cytokines but also impaired antigen receptor-induced proliferation of B and T cells. Egr2- and Egr3-defective B and T cells had hyperactive signal transducer and activator of transcription-1 (STAT1) and STAT3 while antigen receptor-induced activation of transcription factor AP-1 was severely impaired. We discovered that Egr2 and/or Egr3 directly induced expression of suppressor of cytokine signaling-1 (SOCS1) and SOCS3, inhibitors of STAT1 and STAT3, and also blocked the function of Batf, an AP-1 inhibitor, in B and T cells. Thus, Egr2 and Egr3 regulate B and T cell function in adaptive immune responses and homeostasis by promoting antigen receptor signaling and controlling inflammation.

BCL6 mediates the effects of Gastrodin on promoting M2-like macrophage polarization and protecting against oxidative stress-induced apoptosis and cell death in macrophages.

Cerebral palsy (CP) is the most common childhood disability worldwide, yet biomarkers for predicting CP are lacking. By subjecting peripheral blood samples from 62 CP patients and 30 healthy controls to Affymetrix GeneChip® PrimeView™ HumanGene Expression Microarray analysis, we identified the novel biomarker B-cell lymphoma 6 (BCL6) as the most upregulated gene in the CP samples. Gastrodin is a traditional Chinese medicine and bioactive compound that promotes adductor angle release, as well as gross and fine motor performance by increasing Gross Motor Function Measure-66 and Fine Motor Function Measure-45 scores. Gastrodin upregulates the mRNA expression of Mgl2 and Mrc1, M2 macrophage markers, and arginase activity, an M2 polarization indicator, in murine RAW264.7 macrophages. Moreover, these effects were blocked by BCL6 siRNA, which also abrogated the protective effects of Gastrodin against hydrogen peroxide-induced apoptosis and death in RAW264.7 cells. Our work identified BCL6 as a novel biomarker for early prediction of CP. Moreover, we demonstrated that Gastrodin not only stimulated polarization toward M2-like macrophages, which promote tissue repair, but also rescued macrophages from oxidative stress, apoptosis and death by inducing BCL6 expression. BCL6-targeted therapeutic strategies have promise for improving motor performance in CP patients.

Mapping cell populations in flow cytometry data for cross-sample comparison using the Friedman-Rafsky test statistic as a distance measure.

Flow cytometry (FCM) is a fluorescence-based single-cell experimental technology that is routinely applied in biomedical research for identifying cellular biomarkers of normal physiological responses and abnormal disease states. While many computational methods have been developed that focus on identifying cell populations in individual FCM samples, very few have addressed how the identified cell populations can be matched across samples for comparative analysis. This article presents FlowMap-FR, a novel method for cell population mapping across FCM samples. FlowMap-FR is based on the Friedman-Rafsky nonparametric test statistic (FR statistic), which quantifies the equivalence of multivariate distributions. As applied to FCM data by FlowMap-FR, the FR statistic objectively quantifies the similarity between cell populations based on the shapes, sizes, and positions of fluorescence data distributions in the multidimensional feature space. To test and evaluate the performance of FlowMap-FR, we simulated the kinds of biological and technical sample variations that are commonly observed in FCM data. The results show that FlowMap-FR is able to effectively identify equivalent cell populations between samples under scenarios of proportion differences and modest position shifts. As a statistical test, FlowMap-FR can be used to determine whether the expression of a cellular marker is statistically different between two cell populations, suggesting candidates for new cellular phenotypes by providing an objective statistical measure. In addition, FlowMap-FR can indicate situations in which inappropriate splitting or merging of cell populations has occurred during gating procedures. We compared the FR statistic with the symmetric version of Kullback-Leibler divergence measure used in a previous population matching method with both simulated and real data. The FR statistic outperforms the symmetric version of KL-distance in distinguishing equivalent from nonequivalent cell populations. FlowMap-FR was also employed as a distance metric to match cell populations delineated by manual gating across 30 FCM samples from a benchmark FlowCAP data set. An F-measure of 0.88 was obtained, indicating high precision and recall of the FR-based population matching results. FlowMap-FR has been implemented as a standalone R/Bioconductor package so that it can be easily incorporated into current FCM data analytical workflows.

Gene expression pattern analysis of a recombinant Escherichia coli strain possessing high growth and lycopene production capability when using fructose as carbon source.

OBJECTIVE: Escherichia coli K12f-pACLYC has a high capability for growth and lycopene production when using fructose as carbon source and the transcription of genes involved was compared in glucose-grown and fructose-grown cells. RESULTS: Escherichia coli K12f-pACLYC was grown on 10 g fructose l(-1) and reached 4.6 g DCW l(-1) with lycopene at 192 mg g DCW(-1), values that are 3-fold and 7-fold higher than when growing on glucose. Gene transcription profiles of fructose-grown and glucose-grown cells were compared. 384 differentially expressed genes (DEGs) with fold changes ≥4 were identified, and the transcription of genes involved in fructose uptake and metabolism, pyruvate catabolism, tricarboxylic acid cycle and oxidative phosphorylation varied significantly. These changes enhanced the metabolic flux into the Embden-Meyerhof-Parnas pathway and the tricarboxylic acid cylcle and coupled to oxidative phosphorylation. These enhanced activities provide more precursors, cofactors and energy needed for growth lycopene production. CONCLUSION: The high capability of E. coli K12f-pACLYC for growth and lycopene production when growing on fructose is due to transcriptional regulation, and the relevant genes were identified.

Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94.

Peptide selectivity is a feature of inhibitory receptors for MHC class I expressed by natural killer (NK) cells. CD94-NKG2A operates in tandem with the polymorphic killer cell Ig-like receptors (KIR) and Ly49 systems to inhibit NK cells. However, the benefits of having two distinct inhibitory receptor-ligand systems are not clear. We show that noninhibitory peptides presented by HLA-E can augment the inhibition of NKG2A(+) NK cells mediated by MHC class I signal peptides through the engagement of CD94 without a signaling partner. Thus, CD94 is a peptide-selective NK cell receptor, and NK cells can be regulated by nonsignaling interactions. We also show that KIR(+) and NKG2A(+) NK cells respond with differing stoichiometries to MHC class I down-regulation. MHC-I-bound peptide functions as a molecular rheostat controlling NK cell function. Selected peptides which in isolation do not inhibit NK cells can have different effects on KIR and NKG2A receptors. Thus, these two inhibitory systems may complement each other by having distinct responses to bound peptide and surface levels of MHC class I.

Genetic complementation of hepatitis C virus nonstructural protein functions associated with replication exhibits requirements that differ from those for virion assembly.

UNLABELLED: Within the polyprotein encoded by hepatitis C virus (HCV), the minimum components required for viral RNA replication lie in the NS3-5B region, while virion assembly requires expression of all virus components. Here, we have employed complementation systems to examine the role that HCV polyprotein precursors play in RNA replication and virion assembly. In a trans-complementation assay, an HCV NS3-5A polyprotein precursor was required to facilitate efficient complementation of a replication-defective mutation in NS5A. However, this requirement for precursor expression was partially alleviated when a second functional copy of NS5A was expressed from an additional upstream cistron within the RNA to be rescued. In contrast, rescue of a virion assembly mutation in NS5A was more limited but exhibited little or no requirement for expression of functional NS5A as a precursor, even when produced in the context of a second replicating helper RNA. Furthermore, expression of NS5A alone from an additional cistron within a replicon construct gave greater rescue of virion assembly in cis than in trans. Combined with the findings of confocal microscope analysis examining the extent to which the two copies of NS5A from the various expression systems colocalize, the results point to NS3-5A playing a role in facilitating the integration of nonstructural (NS) proteins into viral membrane-associated foci, with this representing an early stage in the steps leading to replication complex formation. The data further imply that HCV employs a minor virion assembly pathway that is independent of replication. IMPORTANCE: In hepatitis C virus-infected cells, replication is generally considered an absolute prerequisite for virus particle formation. Here we investigated the role that the viral protein NS5A has in both replication and particle assembly using complementation assays and microscopy. We found that efficient rescue of replication required NS5A to be expressed as part of a larger polyprotein, and this correlated with detection of NS5A at sites where replication occurred. In contrast, rescue of particle assembly did not require expression of NS5A within the context of a polyprotein. Interestingly, although only partial restoration of particle assembly was possible by complementation, that proportion that could be rescued benefitted from expressing NS5A from the same RNA being packaged. Collectively, these findings provide new insight into aspects of polyprotein function. They also support the existence of a minor virion assembly pathway that bypasses replication.

A comparative study of aroma-active compounds between dark and milk chocolate: relationship to sensory perception.

BACKGROUND: The most important aroma-active compounds of two types of chocolate and cocoa liquor used for their production were analysed by gas chromatography-olfactometry-mass spectrometry (GC-O-MS) and aroma extract dilution analysis (AEDA). Furthermore, the relationship between odorants and sensory perception of chocolate was measured by quantitative analysis, sensory evaluation and correlation analysis. In addition, some chemicals were added to the original dark or milk chocolate to validate their roles in the aroma property of chocolate. RESULTS: A total of 32 major aroma-active compounds were identified in the chocolate with the flavour dilution factors of 27-729 by AEDA, including seven aldehydes, six pyrazines, three pyrroles, four carboxylic acids, four lactones, two alcohols, two ketones, one ester, one pyrone, one furan and one sulfur-containing compound. Further quantitative analysis showed that dark chocolate had higher contents of pyrazine, pyrrole, carboxylic acids, alcohols and Strecker aldehydes, whereas the concentration of lactones, esters, long chain aldehydes and ketones were higher in the milk type. CONCLUSION: Differences in volatile composition and descriptive flavour attributes between the dark and milk chocolate were observed. The relationship between aroma-active compounds and sensory perception in the chocolate was verified.

Surface plasmon resonance enhanced light absorption and photothermal therapy in the second near-infrared window.

Enhanced near-field at noble metal nanoparticle surfaces due to localized surface plasmon resonance (LSPR) has been researched in fields ranging from biomedical to photoelectrical applications. However, it is rarely explored on nonmetallic nanomaterials discovered in recent years, which can also support LSPR by doping-induced free charge carriers, let alone the investigation of an intricate system involving both. Here we construct a dual plasmonic hybrid nanosystem Au-Cu9S5 with well controlled interfaces to study the coupling effect of LSPR originating from the collective electron and hole oscillations. Cu9S5 LSPR is enhanced by 50% in the presence of Au, and the simulation results confirm the coupling effect and the enhanced local field as well as the optical power absorption on Cu9S5 surface. This enhanced optical absorption cross section, high photothermal transduction efficiency (37%), large light penetration depth at 1064 nm, excellent X-ray attenuation ability, and low cytotoxicity enable Au-Cu9S5 hybrids for robust photothermal therapy in the second near-infrared (NIR) window with low nanomaterial dose and laser flux, making them potential theranostic nanomaterials with X-ray CT imaging capability. This study will benefit future design and optimization of photoabsorbers and photothermal nanoheaters utilizing surface plasmon resonance enhancement phenomena for a broad range of applications.

IL-2-engineered nano-APC effectively activates viral antigen-mediated T cell responses from chronic hepatitis B virus-infected patients.

Impaired function of virus-specific T cells resulting from virus persistence is one of the major mechanisms underlying the development of chronic hepatitis B viral infection. Previously, we found that IL-2 can restore the effector function of T cells rendered tolerant by Ag persistence. However, systemic administration of IL-2 induces organ pathology and expansion of T regulatory cells. In this study, we show that nano-APC with engineered HLA alleles and IL-2 deliver peptide-MHC complexes, costimulatory molecules, and IL-2 to Ag-responding T cells, resulting in enhanced expression of CD25 and activation of TCR signaling pathways, while suppressing PD-1 expression on viral-responding CD8 T cells from chronic hepatitis B virus patients. The enhanced activation of CD4 and CD8 T cells induced by IL-2-nano-APC was Ag dependent and IL-2-nano-APC did not affect T regulatory cells. At a size of 500 nm, the nano-APC effectively induce immune synapse formation on Ag-specific T cells and accumulate as free particles in the lymphoid organs. These attributes of IL-2-nano-APC or other bioadjuvant-engineered nano-APC have profound implications for their use as a therapeutic strategy in the treatment of chronic hepatitis B virus infection or other chronic viral diseases.

ViPR: an open bioinformatics database and analysis resource for virology research.

The Virus Pathogen Database and Analysis Resource (ViPR, www.ViPRbrc.org) is an integrated repository of data and analysis tools for multiple virus families, supported by the National Institute of Allergy and Infectious Diseases (NIAID) Bioinformatics Resource Centers (BRC) program. ViPR contains information for human pathogenic viruses belonging to the Arenaviridae, Bunyaviridae, Caliciviridae, Coronaviridae, Flaviviridae, Filoviridae, Hepeviridae, Herpesviridae, Paramyxoviridae, Picornaviridae, Poxviridae, Reoviridae, Rhabdoviridae and Togaviridae families, with plans to support additional virus families in the future. ViPR captures various types of information, including sequence records, gene and protein annotations, 3D protein structures, immune epitope locations, clinical and surveillance metadata and novel data derived from comparative genomics analysis. Analytical and visualization tools for metadata-driven statistical sequence analysis, multiple sequence alignment, phylogenetic tree construction, BLAST comparison and sequence variation determination are also provided. Data filtering and analysis workflows can be combined and the results saved in personal 'Workbenches' for future use. ViPR tools and data are available without charge as a service to the virology research community to help facilitate the development of diagnostics, prophylactics and therapeutics for priority pathogens and other viruses.