Simple and Effective Multi-Paragraph Reading Comprehension

We consider the problem of adapting neural paragraph-level question answering models to the case where entire documents are given as input. Our proposed solution trains models to produce well calibrated confidence scores for their results on individual paragraphs. We sample multiple paragraphs from the documents during training, and use a shared-normalization training objective that encourages the model to produce globally correct output. We combine this method with a state-of-the-art pipeline for training models on document QA data. Experiments demonstrate strong performance on several document QA datasets. Overall, we are able to achieve a score of 71.3 F1 on the web portion of TriviaQA, a large improvement from the 56.7 F1 of the previous best system.Comment: 11 pages, updated a referenc

Trends and patterns in antibiotic prescribing among out-of-hours primary care providers in England, 2010–14

Objectives: Antimicrobial resistance is a global threat, increasing morbidity and mortality. In England, publicly funded clinical commissioning groups (CCGs) commission out-of-hours (OOH) primary care services outside daytime hours. OOH consultations represent 1% of in-hours general practice (GP) consultations. Antibiotic prescriptions increased 32% in non-GP community services between 2010 and 2013. We describe OOH antibiotic prescribing patterns and trends between 2010 and 2014. Methods: We: estimated the proportion of CCGs with OOH data available; described and compared antibiotic prescribing by volume of prescribed items, seasonality and trends in GP and OOH, using linear regression; and compared the proportion of broad-spectrum to total antibiotic prescriptions in OOHs with their respective CCGs in terms of seasonality and trends, using binomial regression. Results: Data were available for 143 of 211 (68%) CCGs. OOH antibiotic prescription volume represented 4.5%-5.4% of GP prescription volume and was stable over time ( P  =   0.37). The proportion of broad-spectrum antibiotic prescriptions increased in OOH when it increased in the CCG they operated in (regression coefficient 0.98; 95% CI 0.96-0.99). Compared with GP, the proportion of broad-spectrum antibiotic prescriptions in OOH was higher but decreased both in GP and OOH (-0.57%, 95% CI - 0.54% to - 0.6% and -0.76%, 95% CI - 0.59% to - 0.93% per year, respectively). Conclusions: OOH proportionally prescribed more antibiotics than GPs although we could not comment on prescribing appropriateness. OOH prescribing volume was stable over time, and followed GP seasonal patterns. OOH antibiotic prescribing reflected the CCGs they operated in but with relatively more broad-spectrum antibiotics than in-hours GP. Understanding factors influencing prescribing in OOH will enable the development of tailored interventions promoting optimal prescribing in this setting

Wettability and Structural Evolution of Gold over a Single-Walled Carbon Nanotube: An Atomistic Investigation

Gold nanostructures with high surface area-to-volume ratio depict many applications for the design and development of advanced materials for the nanoelectronic, catalyst, optoelectronic, antibacterial properties, and so forth. For extensive applications, gold nanostructures can be synthesized by the deposition over various substrates, such as carbon nanotubes, graphite, silica, and so forth. In the present study, a thin molten gold film has been deposited over a single-walled carbon nanotube (SWCNT) to observe the wettability and phase transitions using molecular dynamics simulation. At high temperature (<i>T</i> = 2000 K), the gold film over a SWCNT depicts poor wettability and evolves into a globule. However, during cooling from 2000 to 10 K, the gold globule depicts phase transition from liquid to face-centered cubic crystalline structure. At the interface between gold and SWCNT, gold atoms organized both on- and off-positions over the hexagonal arrangement of carbon atoms of SWCNT. In the case of on-position, the gold atom was positioned in the middle of the hexagonal arrangement of carbon atoms. The off-position gold atom was situated just above the C–C bond of the SWCNT. Solvent-accessible surface areas (<i>S</i>), solid volume (<i>V</i>), dimensionless aspect ratio (κ = <i>S</i>³/<i>V</i>²), contact angle, adaptive common neighbor analysis, and radial density distribution function have been used for the analysis of wetting and structural evolution of gold over the SWCNT. The present theoretical investigation will enhance our understanding related to the solid-state physical phenomena for the development of various types of metallic nanostructures

Persistent expression of <i>Cotesia plutellae</i> bracovirus genes in parasitized host, <i>Plutella xylostella</i>

<div><p>Cotesia plutellae (= vestalis) bracovirus (CpBV) is symbiotic to an endoparasitoid wasp, <i>C</i>. <i>plutellae</i>, and plays crucial roles in parasitism against the diamondback moth, <i>Plutella xylostella</i>. CpBV virion genome consists of 35 circular DNAs encoding 157 putative open reading frames (ORFs). This study re-annotated 157 ORFs with update genome database and analyzed their gene expressions at early and late parasitic stages. Re-annotation has established 15 different viral gene families, to which 83 ORFs are assigned with remaining 74 hypothetical genes. Among 157 ORFs, 147 genes were expressed at early or late parasitic stages, among which 141 genes were expressed in both parasitic stages, indicating persistent nature of gene expression. Relative frequencies of different viral circles present in the ovarian lumen did not explain the expression variation of the viral ORFs. Furthermore, expression level of each viral gene was varied during parasitism along with host development. Highly up-regulated CpBV genes at early parasitic stage included BEN (<u>B</u>ANP, <u>E</u>₅R and <u>N</u>AC₁), ELP (EP1-like protein), IkB (inhibitor kB), P494 (protein 494 kDa) family genes, while those at late stage were mostly hypothetical genes. Along with the viral gene expression, 362 host genes exhibited more than two fold changes in expression levels at early parasitic stage compared to nonparasitized host. At late stage, more number (1,858) of host genes was regulated. These results suggest that persistent expression of most CpBV genes may be necessary to regulate host physiological processes during <i>C</i>. <i>plutellae</i> parasitism.</p></div

Top 10 highly regulated genes of <i>P</i>. <i>xylostella</i> parasitized by <i>C</i>. <i>plutellae</i> at early (P1) and late (P7) stages.

<p>Top 10 highly regulated genes of <i>P</i>. <i>xylostella</i> parasitized by <i>C</i>. <i>plutellae</i> at early (P1) and late (P7) stages.</p

A revised annotation of 157 CpBV ORFs from 35 circles (C1-C35).

<p>Their sequences are obtained from GenBank with accession numbers of HQ009524-HQ009558.</p

Highly expressed CpBV genes in <i>P</i>. <i>xylostella</i> parasitized by <i>C</i>. <i>plutellae</i>.

<p>Expression levels were calculated by FPKM based on read numbers obtained from Illumina HiSeq. (A) Highly expressed CpBV genes at early (one day after parasitization: P1) and late (7 days after parasitization: P7) parasitic stages. (B) Classification of highly expressed genes more than 10,000 scores in FPKM values.</p

Persistent expression of <i>Cotesia plutellae</i> bracovirus genes in parasitized host, <i>Plutella xylostella</i> - Fig 1

<p><b>Phylogenetic analyses of 15 CpBV gene families:</b> (A) protein tyrosine phosphatase (PTP) (B) BANP, E5R and NAC1 (BEN) (C) Inhibitor kB (IkB) (D) EP1-like protein (ELP) (E) Serine-rich protein (SRP) (F) E94K (G) Cysteine-rich protein (CRP) (H) C type lectin (CTL) (I) P494 (J) CrV1 (K) Cystatin-like (CST) (L) Duffy-binding (DUFB) (M) viral histone H4 (vH4) (N) DNA helicase (dHEL), and (O) P325. Amino acid sequences of these genes were retrieved from GenBank with accession numbers listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200663#pone.0200663.s019" target="_blank">S3 Table</a>. Amino acid sequences were aligned with MEGA6 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200663#pone.0200663.ref024" target="_blank">24</a>]. Bootstrap values on branches were obtained with 500 repetitions.</p

Expression analysis of 157 ORFs of CpBV in <i>P</i>. <i>xylostella</i> parasitized by <i>C</i>. <i>plutellae</i> using RNA-Seq by Illumina HiSeq.

<p>Two parasitic stages were assessed at early (one day after parasitization: P1) and late (7 days after parasitization: P7) stages. (A) Venn diagram showing the number of CpBV genes expressed in both parasitic stages. 141 ORFs are commonly expressed in both stages whereas 6 genes are expressed at P1 or P7. (B) List of CpBV genes not expressed at either or both stages whose expression level was shown in FPKM. (C) RT-PCR analysis of 10 CpBV unexpressed genes at both parasitic stages. A ribosomal protein, <i>RL32</i>, gene with its gene-specific primers (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200663#pone.0200663.s017" target="_blank">S1 Table</a>) was used as a constitutively expressed reference gene.</p

α‑Helix Mimetics as Modulators of Aβ Self-Assembly

A key molecular species in Alzheimer’s disease (AD) is the Aβ₄₂ alloform of Aβ peptide, which is dominant in the amyloid plaques deposited in the brains of AD patients. Recent studies have decisively demonstrated that the prefibrillar soluble oligomers are the neurotoxic culprits and are associated with the pathology of AD. Nascent Aβ₄₂ is predominantly disordered but samples α-helical conformations covering residues 15–24 and 29–35 in the presence of micelles and structure-inducing solvents. In this report, a focused library of oligopyridylamide based α-helical mimetics was designed to target the central α-helix subdomain of Aβ (Aβ_13–26). A tripyridylamide, ADH-41, was identified as one of the most potent antagonists of Aβ fibrillation. Amyloid-assembly kinetics, transmission electron microscopy (TEM), and atomic force microscopy (AFM) show that ADH-41 wholly suppresses the aggregation of Aβ at a substoichiometric dose. Dot blot and ELISA assays demonstrate the inhibition of the putative neurotoxic Aβ oligomers. ADH-41 targets Aβ in a sequence and structure-specific manner, as it did not have any effect on the aggregation of islet amyloid polypeptide (IAPP), a peptide which shares sequence similarity with Aβ. Spectroscopic studies using NMR and CD confirm induction of α-helicity in Aβ mediated by ADH-41. Calorimetric and fluorescence titrations yielded binding affinity in the low micromolar range. ADH-41 was also effective at inhibiting the seed-catalyzed aggregation of Aβ probably by modulating the Aβ conformation into a fiber incompetent structure. Overall, we speculate that ADH-41 directs Aβ into off-pathway structures, and thereby alters various solution based functions of Aβ. Cell-based assays to assess the effect of ADH-41 on Aβ are underway and will be presented in due course