ALBERT

Description: Mutations in the NF1 tumor suppressor gene cause Neurofibromatosis type 1 (NF1). Neurofibromin, the protein product of NF1 , functions as a negative regulator of Ras activity. Some NF1 patients develop cardiovascular disease, which represents an underrecognized disease complication and contributes to excess morbidity and mortality. Specifically, NF1 patients develop arterial occlusion resulting in tissue ischemia and sudden death. Murine studies demonstrate that heterozygous inactivation of Nf1 ( Nf1 +/– ) in bone marrow cells enhances neointima formation following arterial injury. Macrophages infiltrate Nf1 +/– neointimas, and NF1 patients have increased circulating inflammatory monocytes in their peripheral blood. Therefore, we tested the hypothesis that heterozygous inactivation of Nf1 in myeloid cells is sufficient for neointima formation. Specific ablation of a single copy of the Nf1 gene in myeloid cells alone mobilizes a discrete pro-inflammatory murine monocyte population via a cell autonomous and gene-dosage dependent mechanism. Furthermore, lineage-restricted heterozygous inactivation of Nf1 in myeloid cells is sufficient to reproduce the enhanced neointima formation observed in Nf1 +/– mice when compared with wild-type controls, and homozygous inactivation of Nf1 in myeloid cells amplified the degree of arterial stenosis after arterial injury. Treatment of Nf1 +/– mice with rosuvastatin, a stain with anti-inflammatory properties, significantly reduced neointima formation when compared with control. These studies identify neurofibromin-deficient myeloid cells as critical cellular effectors of Nf1 +/– neointima formation and propose a potential therapeutic for NF1 cardiovascular disease.

Description: Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants ( n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold ( P -value cutoff range: 3.9 x 10 –4 –5.6 x 10 –3 ) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals ( P 〈 5.0 x 10 –6 ) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P -values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis -eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

Description: Signcryption schemes play a vital role to accomplish confidentiality, integrity, authentication and non-repudiation of messages simultaneously. In the literature, many certificateless signcryption (CLSC) schemes have been designed; however, most of them are vulnerable to ephemeral secret leakage (ESL) attack. In these schemes, sender uses an ephemeral secret to compute a ciphertext on a message. However, there is a possibility to compromise the ephemeral secret, since it is generally pre-computed and stored in an insecure device. Furthermore, it is generated by an external source, which can be controlled by an adversary. Thus, from the knowledge of compromised ephemeral secret, an adversary may calculate the private key of the sender and the message from the eavesdropped ciphertext, and this problem is called ESL attack. In this paper, we proposed a leakage-free CLSC, which is secure against ESL attack in the random oracle model. The proposed scheme provides confidentiality under the Co-Bilinear Diffie–Hellman (Co-BDH) assumption and unforgeability based on Co-Computational Diffie–Hellman assumption.

Description: The telomerase is responsible for adding telomeric repeats to chromosomal ends and consists of the reverse transcriptase TERT and the RNA subunit TERC. The expression and activity of the telomerase are tightly regulated, and aberrant activation of the telomerase has been observed in 〉85% of human cancers. To better understand telomerase regulation, we performed immunoprecipitations coupled with mass spectrometry (IP-MS) and identified cold inducible RNA-binding protein (CIRP or hnRNP A18) as a telomerase-interacting factor. We have found that CIRP is necessary to maintain telomerase activities at both 32°C and 37°C. Furthermore, inhibition of CIRP by CRISPR-Cas9 or siRNA knockdown led to reduced telomerase activities and shortened telomere length, suggesting an important role of CIRP in telomere maintenance. We also provide evidence here that CIRP associates with the active telomerase complex through direct binding of TERC and regulates Cajal body localization of the telomerase. In addition, CIRP regulates the level of TERT mRNAs. At the lower temperature, TERT mRNA is upregulated in a CIRP-dependent manner to compensate for reduced telomerase activities. Taken together, these findings highlight the dual roles that CIRP plays in regulating TERT and TERC, and reveal a new class of telomerase modulators in response to hypothermia conditions.

Description: Protein kinase R (PKR) is a vital component of host innate immunity against viral infection. However, the mechanism underlying inactivation of PKR by influenza A virus (IAV) remains elusive. Here, we found that vault RNAs (vtRNAs) were greatly induced in A549 cells and mouse lungs after infection with IAV. The viral NS1 protein was shown to be the inducer triggering the upregulation of vtRNAs. Importantly, silencing vtRNA in A549 cells significantly inhibited IAV replication, whereas overexpression of vtRNAs markedly promoted the viral replication. Furthermore, in vivo studies showed that disrupting vtRNA expression in mice significantly decreased IAV replication in infected lungs. The vtRNA knockdown animals exhibited significantly enhanced resistance to IAV infection, as evidenced by attenuated acute lung injury and spleen atrophy and consequently increased survival rates. Interestingly, vtRNAs promoted viral replication through repressing the activation of PKR and the subsequent antiviral interferon response. In addition, increased expression of vtRNAs was required for efficient suppression of PKR by NS1 during IAV infection. Moreover, vtRNAs were also significantly upregulated by infections of several other viruses and involved in the inactivation of PKR signaling by these viruses. These results reveal a novel mechanism by which some viruses circumvent PKR-mediated innate immunity.

Description: The highly conserved Paf1 complex (PAF1C) plays critical roles in RNA polymerase II transcription elongation and in the regulation of histone modifications. It has also been implicated in other diverse cellular activities, including posttranscriptional events, embryonic development and cell survival and maintenance of embryonic stem cell identity. Here, we report the structure of the human Paf1/Leo1 subcomplex within PAF1C. The overall structure reveals that the Paf1 and Leo1 subunits form a tightly associated heterodimer through antiparallel beta-sheet interactions. Detailed biochemical experiments indicate that Leo1 binds to PAF1C through Paf1 and that the Ctr9 subunit is the key scaffold protein in assembling PAF1C. Furthermore, we show that the Paf1/Leo1 heterodimer is necessary for its binding to histone H3, the histone octamer, and nucleosome in vitro . Our results shed light on the PAF1C assembly process and substrate recognition during various PAF1C-coordinated histone modifications.

Description: Motivation: Numerous public microarray datasets are valuable resources for the scientific communities. Several online tools have made great steps to use these data by querying related datasets with users’ own gene signatures or expression profiles. However, dataset annotation and result exhibition still need to be improved. Results: ExpTreeDB is a database that allows for queries on human and mouse microarray experiments from Gene Expression Omnibus with gene signatures or profiles. Compared with similar applications, ExpTreeDB pays more attention to dataset annotations and result visualization. We introduced a multiple-level annotation system to depict and organize original experiments. For example, a tamoxifen-treated cell line experiment is hierarchically annotated as ‘agent-〉drug-〉estrogen receptor antagonist-〉tamoxifen’. Consequently, retrieved results are exhibited by an interactive tree-structured graphics, which provide an overview for related experiments and might enlighten users on key items of interest. Availability and implementation: The database is freely available at http://biotech.bmi.ac.cn/ExpTreeDB . Web site is implemented in Perl, PHP, R, MySQL and Apache. Contact: boxc@bmi.ac.cn Supplementary information: Supplementary data are available at Bioinformatics online.

Description: High-throughput screening and computational technology has greatly changed the face of microbiology in better understanding pathogen–host interactions. Genome-wide RNA interference (RNAi) screens have given rise to a new class of host genes designated as Essential Host Factors (EHFs), whose knockdown effects significantly influence pathogenic infections. Therefore, we present the first release of a manually-curated bioinformatics database and analysis resource EHFPI (Essential Host Factors for Pathogenic Infection, http://biotech.bmi.ac.cn/ehfpi ). EHFPI captures detailed article, screen, pathogen and phenotype annotation information for a total of 4634 EHF genes of 25 clinically important pathogenic species. Notably, EHFPI also provides six powerful and data-integrative analysis tools, i.e. EHF Overlap Analysis, EHF-pathogen Network Analysis, Gene Enrichment Analysis, Pathogen Interacting Proteins (PIPs) Analysis, Drug Target Analysis and GWAS Candidate Gene Analysis, which advance the comprehensive understanding of the biological roles of EHF genes, as in diverse perspectives of protein–protein interaction network, drug targets and diseases/traits. The EHFPI web interface provides appropriate tools that allow efficient query of EHF data and visualization of custom-made analysis results. EHFPI data and tools shall keep available without charge and serve the microbiology, biomedicine and pharmaceutics research communities, to finally facilitate the development of diagnostics, prophylactics and therapeutics for human pathogens.

Description: Predawn leaf water potential (LWP), the LWP between 09:00 and 10:30 h (termed minimum LWP), stem xylem hydraulic conductivity, foliar nitrogen, leaf gas exchange and leaf traits were measured on the same days in adults and 1-year-old to 7-year-old resprouts that had regrown after removing all the aboveground shoots. Height growth and accumulation of aboveground biomass quickly decreased with resprout age and there was no difference between 7-year-old resprouts and the uncut adults. Predawn LWP showed no significant difference between resprouts and adults, but the minimum LWP decreased gradually from –2.0 MPa in 1-year-old resprouts to –3.0 MPa in 7-year-old resprouts. The decrease in minimum LWP was associated with increased hydraulic resistance, as indicated by the gradual decrease in leaf area-specific hydraulic conductivity ( K L ) and sapwood area-specific hydraulic conductivity ( K S ) and the associated increase in stem native percentage loss of hydraulic conductivity in older than 2-year-old resprouts. The leaf nitrogen content per unit area ( N area ) also decreased steadily from 3.6 g m –2 in 1-year-old resprouts to 1.7 g m –2 in 7-year-old resprouts. With the decline in LWP and N area , the rate of leaf photosynthesis per unit area ( A area ) decreased from 20 μ mol m –2  s –1 in 1-year-old resprouts to 11 μ mol m –2  s –1 in 7-year-old resprouts. In adults, although K S decreased further compared with 7-year-old resprouts, the minimum LWP, K L , N area and the rate of photosynthesis increased by 0.3 MPa, 29, 34 and 23%, respectively. The results show that a progressive loss of stem hydraulic conductivity and a steady decrease in foliar nitrogen with age were associated with a decrease in the photosynthetic rate of Caragana korshinskii Kom. resprouts, possibly changing the allocation of photosynthetic assimilates and slowing resprout height growth.

Description: Motivation: Currently there are no curative anticancer drugs, and drug resistance is often acquired after drug treatment. One of the reasons is that cancers are complex diseases, regulated by multiple signaling pathways and cross talks among the pathways. It is expected that drug combinations can reduce drug resistance and improve patients’ outcomes. In clinical practice, the ideal and feasible drug combinations are combinations of existing Food and Drug Administration-approved drugs or bioactive compounds that are already used on patients or have entered clinical trials and passed safety tests. These drug combinations could directly be used on patients with less concern of toxic effects. However, there is so far no effective computational approach to search effective drug combinations from the enormous number of possibilities. Results: In this study, we propose a novel systematic computational tool DrugComboRanker to prioritize synergistic drug combinations and uncover their mechanisms of action. We first build a drug functional network based on their genomic profiles, and partition the network into numerous drug network communities by using a Bayesian non-negative matrix factorization approach. As drugs within overlapping community share common mechanisms of action, we next uncover potential targets of drugs by applying a recommendation system on drug communities. We meanwhile build disease-specific signaling networks based on patients’ genomic profiles and interactome data. We then identify drug combinations by searching drugs whose targets are enriched in the complementary signaling modules of the disease signaling network. The novel method was evaluated on lung adenocarcinoma and endocrine receptor positive breast cancer, and compared with other drug combination approaches. These case studies discovered a set of effective drug combinations top ranked in our prediction list, and mapped the drug targets on the disease signaling network to highlight the mechanisms of action of the drug combinations. Availability and implementation: The program is available on request. Contact: stwong@tmhs.org