End-to-End Neural Ad-hoc Ranking with Kernel Pooling

This paper proposes K-NRM, a kernel based neural model for document ranking. Given a query and a set of documents, K-NRM uses a translation matrix that models word-level similarities via word embeddings, a new kernel-pooling technique that uses kernels to extract multi-level soft match features, and a learning-to-rank layer that combines those features into the final ranking score. The whole model is trained end-to-end. The ranking layer learns desired feature patterns from the pairwise ranking loss. The kernels transfer the feature patterns into soft-match targets at each similarity level and enforce them on the translation matrix. The word embeddings are tuned accordingly so that they can produce the desired soft matches. Experiments on a commercial search engine's query log demonstrate the improvements of K-NRM over prior feature-based and neural-based states-of-the-art, and explain the source of K-NRM's advantage: Its kernel-guided embedding encodes a similarity metric tailored for matching query words to document words, and provides effective multi-level soft matches

Structural study of polyglutamine and molecular mechanism of toll-like receptor signaling

Huntington’s disease (HD) is caused by the expansion of a CAG repeats encoding polyglutamine (polyQ) in the first exon of Huntingtin (Htt) gene. In HD patients, polyQ contains 36-183 glutamine residues, whereas normal individuals have a polyQ of only 8-35 residues. To elucidate this threshold phenomenon of polyQ aggregation, fluorescence proteins CFP and YFP were attached to both ends of polyQ of different lengths. FRET (fluorescence resonance energy transfer) was conducted to characterize the conformation of polyQ in the pre-aggregation state. Our FRET data show that both the normal and expanded polyQ tracts reveal the same extended structure in low concentration. Longer polyQ has multiple cooperative binding sites with higher avidity. PolyQ tracts form aggregates when proteins exceed a critical concentration. The antibody MW1 Fv fragment binds to polyQ, breaks apart polyQ oligomer and stabilizes it in a more extended conformation. The addition of polyproline to the C-terminus inhibits polyQ aggregation by inducing PPII-like Helix structure. To understand how the flanking sequence affects the polyQ structure, the structure of Q10P10 peptide in complex with MW1 Fv was determined by protein crystallography and compared with Q10/Fv crystal structure. Q10P10 peptide bound to Fv has a similar extended structure as Q10 peptide when a polyproline tract adopts PPII helical structure sticking out of the complex. Toll-like receptors are transmembrane receptors on different kinds of leukocytes. They can recognize the structural conserved molecular motifs derived from microbes. On the upstream of the TLR signal pathway, TLRs recruit the adaptor protein-MyD88 through TIR/TIR domain interaction, and MyD88 recruits the downstream kinases IRAK4 and IRAK1 through death domain/death domain interaction. Pellino1, a newly identified E3 ubiquitin ligase, is also involved in TLR signaling by adding polyubiquitin chain to IRAK1 in conjugation with Ubc13/Uev1a E2 complex. TIR/TIR and DD/DD binding motifs were studied with techniques including mutagenesis, analytical gel filtration, NMR spectroscopy and crystallography. We identified a MyD88DD (E52QR62S) double-mutant that attenuates protein aggregation without interrupting the binding with IRAK4. This double mutant is a good candidate for structure determination by NMR spectroscopy. Our ubiquitination assay showed Pellino1 catalyzes polyubiquitination in the presence of Ubc13/Uev1a in vitro. Needle cluster-shaped crystals of Pellino1/Ubc13/ Uev1a protein complex were obtained by “hanging drop” method of vapor diffusion. Once the crystallization conditions are optimized, we will be able to collect X-ray diffraction data for this E2/E3 complex

Consistency and Variation in Kernel Neural Ranking Model

This paper studies the consistency of the kernel-based neural ranking model K-NRM, a recent state-of-the-art neural IR model, which is important for reproducible research and deployment in the industry. We find that K-NRM has low variance on relevance-based metrics across experimental trials. In spite of this low variance in overall performance, different trials produce different document rankings for individual queries. The main source of variance in our experiments was found to be different latent matching patterns captured by K-NRM. In the IR-customized word embeddings learned by K-NRM, the query-document word pairs follow two different matching patterns that are equally effective, but align word pairs differently in the embedding space. The different latent matching patterns enable a simple yet effective approach to construct ensemble rankers, which improve K-NRM's effectiveness and generalization abilities.Comment: 4 pages, 4 figures, 2 table

A Genome-Wide Analysis of Small Regulatory RNAs in the Human Pathogen Group A Streptococcus

The coordinated regulation of gene expression is essential for pathogens to infect and cause disease. A recently appreciated mechanism of regulation is that afforded by small regulatory RNA (sRNA) molecules. Here, we set out to assess the prevalence of sRNAs in the human bacterial pathogen group A Streptococcus (GAS). Genome-wide identification of candidate GAS sRNAs was performed through a tiling Affymetrix microarray approach and identified 40 candidate sRNAs within the M1T1 GAS strain MGAS2221. Together with a previous bioinformatic approach this brings the number of novel candidate sRNAs in GAS to 75, a number that approximates the number of GAS transcription factors. Transcripts were confirmed by Northern blot analysis for 16 of 32 candidate sRNAs tested, and the abundance of several of these sRNAs were shown to be temporally regulated. Six sRNAs were selected for further study and the promoter, transcriptional start site, and Rho-independent terminator identified for each. Significant variation was observed between the six sRNAs with respect to their stability during growth, and with respect to their inter- and/or intra-serotype-specific levels of abundance. To start to assess the contribution of sRNAs to gene regulation in M1T1 GAS we deleted the previously described sRNA PEL from four clinical isolates. Data from genome-wide expression microarray, quantitative RT-PCR, and Western blot analyses are consistent with PEL having no regulatory function in M1T1 GAS. The finding that candidate sRNA molecules are prevalent throughout the GAS genome provides significant impetus to the study of this fundamental gene-regulatory mechanism in an important human pathogen

Space-Time Hybrid Model for Short-Time Travel Speed Prediction

Short-time traffic speed forecasting is a significant issue for developing Intelligent Transportation Systems applications, and accurate speed forecasting results are necessary inputs for Intelligent Traffic Security Information System (ITSIS) and advanced traffic management systems (ATMS). This paper presents a hybrid model for travel speed based on temporal and spatial characteristics analysis and data fusion. This proposed methodology predicts speed by dividing the data into three parts: a periodic trend estimated by Fourier series, a residual part modeled by the ARIMA model, and the possible events affected by upstream or downstream traffic conditions. The aim of this study is to improve the accuracy of the prediction by modeling time and space variation of speed, and the forecast results could simultaneously reflect the periodic variation of traffic speed and emergencies. This information could provide decision-makers with a basis for developing traffic management measures. To achieve the research objective, one year of speed data was collected in Twin Cities Metro, Minnesota. The experimental results demonstrate that the proposed method can be used to explore the periodic characteristics of speed data and show abilities in increasing the accuracy of travel speed prediction

Vaccination of Gerbils with Bm-103 and Bm-RAL-2 Concurrently or as a Fusion Protein Confers Consistent and Improved Protection against Brugia malayi Infection.

BACKGROUND: The Brugia malayi Bm-103 and Bm-RAL-2 proteins are orthologous to Onchocerca volvulus Ov-103 and Ov-RAL-2, and which were selected as the best candidates for the development of an O. volvulus vaccine. The B. malayi gerbil model was used to confirm the efficacy of these Ov vaccine candidates on adult worms and to determine whether their combination is more efficacious. METHODOLOGY AND PRINCIPLE FINDINGS: Vaccine efficacy of recombinant Bm-103 and Bm-RAL-2 administered individually, concurrently or as a fusion protein were tested in gerbils using alum as adjuvant. Vaccination with Bm-103 resulted in worm reductions of 39%, 34% and 22% on 42, 120 and 150 days post infection (dpi), respectively, and vaccination with Bm-RAL-2 resulted in worm reductions of 42%, 22% and 46% on 42, 120 and 150 dpi, respectively. Vaccination with a fusion protein comprised of Bm-103 and Bm-RAL-2 resulted in improved efficacy with significant reduction of worm burden of 51% and 49% at 90 dpi, as did the concurrent vaccination with Bm-103 and Bm-RAL-2, with worm reduction of 61% and 56% at 90 dpi. Vaccination with Bm-103 and Bm-RAL-2 as a fusion protein or concurrently not only induced a significant worm reduction of 61% and 42%, respectively, at 150 dpi, but also significantly reduced the fecundity of female worms as determined by embryograms. Elevated levels of antigen-specific IgG were observed in all vaccinated gerbils. Serum from gerbils vaccinated with Bm-103 and Bm-RAL-2 individually, concurrently or as a fusion protein killed third stage larvae in vitro when combined with peritoneal exudate cells. CONCLUSION: Although vaccination with Bm-103 and Bm-RAL-2 individually conferred protection against B. malayi infection in gerbils, a more consistent and enhanced protection was induced by vaccination with Bm-103 and Bm-RAL-2 fusion protein and when they were used concurrently. Further characterization and optimization of these filarial vaccines are warranted

The hookworm Ancylostoma ceylanicum intestinal transcriptome provides a platform for selecting drug and vaccine candidates

BACKGROUND: The intestine of hookworms contains enzymes and proteins involved in the blood-feeding process of the parasite and is therefore a promising source of possible vaccine antigens. One such antigen, the hemoglobin-digesting intestinal aspartic protease known as Na-APR-1 from the human hookworm Necator americanus, is currently a lead candidate antigen in clinical trials, as is Na-GST-1 a heme-detoxifying glutathione S-transferase. METHODS: In order to discover additional hookworm vaccine antigens, messenger RNA was obtained from the intestine of male hookworms, Ancylostoma ceylanicum, maintained in hamsters. RNA-seq was performed using Illumina high-throughput sequencing technology. The genes expressed in the hookworm intestine were compared with those expressed in the whole worm and those genes overexpressed in the parasite intestine transcriptome were further analyzed. RESULTS: Among the lead transcripts identified were genes encoding for proteolytic enzymes including an A. ceylanicum APR-1, but the most common proteases were cysteine-, serine-, and metallo-proteases. Also in abundance were specific transporters of key breakdown metabolites, including amino acids, glucose, lipids, ions and water; detoxifying and heme-binding glutathione S-transferases; a family of cysteine-rich/antigen 5/pathogenesis-related 1 proteins (CAP) previously found in high abundance in parasitic nematodes; C-type lectins; and heat shock proteins. These candidates will be ranked for downstream antigen target selection based on key criteria including abundance, uniqueness in the parasite versus the vertebrate host, as well as solubility and yield of expression. CONCLUSION: The intestinal transcriptome of A. ceylanicum provides useful information for the identification of proteins involved in the blood-feeding process, representing a first step towards a reverse vaccinology approach to a human hookworm vaccine. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13071-016-1795-8) contains supplementary material, which is available to authorized users