Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Cyclohexyl ketone inhibitors of Pin1 dock in a trans-diaxial cyclohexane conformation.

Cyclohexyl ketone substrate analogue inhibitors (Ac-pSer-Ψ[C = OCH]-Pip-tryptamine) of Pin1, the cell cycle regulatory peptidyl-prolyl isomerase (PPIase), were designed and synthesized as potential electrophilic acceptors for the Pin1 active site Cys113 nucleophile to test a proposed nucleophilic addition-isomerization mechanism. Because they were weak inhibitors, models of all three stereoisomers were docked into the active site of Pin1. Each isomer consistently minimized to a trans-diaxial cyclohexane conformation. From this, we hypothesize that Pin1 stretches substrates into a trans-pyrrolidine conformation to lower the barrier to isomerization. Our reduced amide inhibitor of Pin1 adopted a similar trans-pyrrolidine conformation in the crystal structure. The molecular model of 1, which mimics the l-Ser-l-Pro stereochemistry, in the Pin1 active site showed a distance of 4.4 Å, and an angle of 31° between Cys113-S and the ketone carbon. The computational models suggest that the mechanism of Pin1 PPIase is not likely to proceed through nucleophilic addition

X-ray crystal structures of intermediates (1<i>S</i>,3<i>R</i>,4<i>R</i>)-11 and <i>rac</i>-11 are shown above as displacement ellipsoid drawings (50%).

<p>The positional disorder of the benzyl group in <b><i>rac</i></b><b>-11</b> is shown as lighter lines. Hydrogen atoms are omitted for clarity. Structural depiction of the stereochemistries of <b>(1</b><b><i>S</i></b><b>,3</b><b><i>R</i></b><b>,4</b><b><i>R</i></b><b>)-11</b> and <b><i>rac</i></b><b>-11</b> are shown below each crystal structure.</p

Ketone inhibitors were designed to mimic the tetrahedral intermediate of proposed mechanism B.

<p>(A) Proposed Pin1 hydrogen-bond assisted twisted amide mechanism <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044226#pone.0044226-Schroeder1" target="_blank">[25]</a>, (B) Pin1 Cys113 nucleophilic-addition mechanism tetrahedral intermediate proposed by Ranganathan et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044226#pone.0044226-Ranganathan1" target="_blank">[26]</a>. (C) Electrophilic ketone inhibitor designed to mimic the proposed tetrahedral intermediate upon Cys113-S nucleophilic addition.</p

Models of cyclohexyl ketone inhibitors were docked with dynamic minimization.

<p>(A) <b>(1</b><b><i>S,</i></b><b>3</b><b><i>R,</i></b><b>4</b><b><i>R</i></b><b>)-1</b> in orange, (B) <b>(1</b><b><i>R,</i></b><b>3</b><b><i>R,</i></b><b>4</b><b><i>R</i></b><b>)-2</b> in blue, (C) <b>(1</b><b><i>S,</i></b><b>3</b><b><i>S,</i></b><b>4</b><b><i>S</i></b><b>)-2</b> in green, and (D) superposition of all atoms of <b>1</b> and <b><i>rac</i></b><b>-2</b>. Models were based on PDB 2Q5A <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044226#pone.0044226-Zhang2" target="_blank">[32]</a>, and minimized using Sybyl 8.1.1 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044226#pone.0044226-1" target="_blank">[42]</a>. Images were prepared using MacPyMol <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044226#pone.0044226-DeLano1" target="_blank">[44]</a>.</p

Pin1 is proposed to stretch the prolyl ring by binding phosphate and C-terminal residues tightly, creating a <i>trans</i>-pyrrolidine conformation of the substrate and forcing pyramidalization of the prolyl nitrogen in the twisted-amide mechanism.

<p>Distance measurements are from calculated structures of Ac–Pro–OH in the ground state and the <i>trans</i>-pyrrolidine transition state.</p

Pin1 inhibitors discussed are cyclohexyl ketones 1 and <i>rac</i>-2 (this work); reduced amides 3 and 4 [<b>27</b>]; (<i>Z</i>)-alkene 5 [<b>13</b>]; and α-ketoamides 6a and 6b [<b>14</b>].

<p>Pin1 inhibitors discussed are cyclohexyl ketones 1 and <i>rac</i>-2 (this work); reduced amides 3 and 4 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044226#pone.0044226-Xu3" target="_blank">[<b>27</b>]</a>; (<i>Z</i>)-alkene 5 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044226#pone.0044226-Zhao1" target="_blank">[<b>13</b>]</a>; and α-ketoamides 6a and 6b <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044226#pone.0044226-Xu2" target="_blank">[<b>14</b>]</a>.</p

Nanoconjugated NAP as a Potent and Periphery Selective Mu Opioid Receptor Modulator to Treat Opioid-Induced Constipation

Opioids are the mainstay for cancer and noncancer pain management. However, their use is often associated with multiple adverse effects. Among them, the most common and persistent one is probably opioid-induced constipation (OIC). Periphery selective opioid antagonists may alleviate the symptoms of OIC without compromising the analgesic effects of opioids. Recently our laboratories have identified one novel lead compound, 17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6ß-[(4′-pyridyl)acetamido]-morphinan (NAP), as a peripherally selective mu opioid receptor ligand carrying subnanomolar affinity to the mu opioid receptor and over 100-folds of selectivity over both the delta and kappa opioid receptors, with reasonable oral availability and half-life, and potential to treat OIC. Nanoparticle-based drug delivery systems are now widely considered due to their technological advantages such as good stability, high carrier capacity, low therapeutic side effects, etc. Herein we report nanoparticle supported NAP as a potential candidate for OIC treatment with improved peripheral selectivity over the original lead compound NAP

Phyllosphere Microorganisms: Sources, Drivers, and Their Interactions with Plant Hosts.

The leaves of plants are colonized by various microorganisms. In comparison to the rhizosphere, less is known about the characteristics and ecological functions of phyllosphere microorganisms. Phyllosphere microorganisms mainly originate from soil, air, and seeds. The composition of phyllosphere microorganisms is mainly affected by ecological and abiotic factors. Phyllosphere microorganisms execute multiple ecological functions by influencing leaf functions and longevity, seed mass, fruit development, and homeostasis of host growth. A plant can respond to phyllosphere microorganisms by secondary metabolite secretion and its immune system. Meanwhile, phyllosphere microorganisms play an important role in ecological stability and environmental safety assessment. However, as a result of the instability of the phyllosphere environment and the poor cultivability of phyllosphere microorganisms in the current research, there are still many limitations, such as the lack of insight into the mechanisms of plant–microorganism interactions, the roles of phyllosphere microorganisms in plant growth processes, the responses of phyllosphere microorganisms to plant metabolites, etc. This review summarizes the latest progress made in the research of the phyllosphere in recent years. This is beneficial for deepening our understanding of phyllosphere microorganisms and promoting the research of plant–atmosphere interactions, plant pathogens, and plant biological control.Environmental Biolog