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

Chemistry and biology of topoisomerase I inhibitors: Indenoisoquinolines and camptothecins

Topoisomerase I (top1) inhibitors have been shown to possess promising anticancer responses in clinical trials. This dissertation is dealing with two classes of top1 inhibitors. The first class of top1 inhibitors studied is indenoisoquinolines. In order to design better indenoisoquinoline analogs as anticancer drugs, a hypothetical binding model of indenoisoquinoline in the DNA-top1 cleavage complex was proposed based on the structural similarity between indenoisoquinoline and camptothecin (CPT). This model was further confirmed by quantum mechanics calculation, X-ray crystallography, and biological results of a pair of indenoisoquinoline enantiomers. Using this model as the design scaffold, a series of 11-aminoalkenyl- and 11-diaminoalkenylindenoisoquinolines were designed and they showed potent top1 inhibition as well as cytotoxicity. The 11-substituents are proposed to project into the DNA minor groove in the DNA-top1 cleavage complexes. A potential DNA threading indenoisoquinoline with amino alkyl substituents at both C-11 and N-6 positions was also designed and synthesized. Although the threading agent demonstrated no top1 inhibition, a novel autoxidative cleavage reaction of 9-fluoredenes was discovered during the synthesis of this threading agent. Some indenoisoquinolines with modified 8,9-methylenedioxy moieties were also designed and synthesized based on the conformational differences in the nonscissile DNA strand between the DNA-top1 binary complex and DNA-top1-indenoisoquinoline ternary complex. Some of the indenoisoquinolines with aminoalkyl side chains displayed potent top1 inhibition, but generally they are not cytotoxic. The second class of top1 inhibitors investigated is CPTs, a classical type of top1 inhibitors. In order to understand the molecular forces dictating the binding orientation of CPT in the DNA-top1 cleavage complex, a quantum mechanics calculation was done by hypothesizing the π-π stacking interactions between CPT and its flanking base pairs are the predominant contribution to the binding interaction. The calculation results considering only the it-at stacking interactions can not only reproduce the experimental binding orientation of CPT, but also correlates very well with the experimentally observed DNA sequence selectivity in SV40 viral genome. Furthermore, the loss of biological activity of (R)-CPT and CPT-lactam is also due to the differences in π-π stacking. Based on the π-stacking hypothesis , some aromathecins were designed and synthesized

Validation of metabolisable energy prediction equation for de-oiled corn distillers dried grains with solubles fed to finishing pigs

This experiment was conducted to determine the accuracy of a prediction equation for metabolisable energy (ME) content generated from the chemical composition of de-oiled corn distillers dried grains with solubles (DDGS) in finishing pigs. A total of 72 pigs (average initial body weight 85.7 kg), with four pigs per pen and six pens per treatment, were fed one of the three experimental diets. The experimental diets were a corn-soybean meal basal diet or two diets containing 30% de-oiled DDGS diets. The experimental diets were formulated using ME values obtained from a prediction equation or NRC. ME prediction equation for the de-oiled DDGS was ME = 4066 – (46.3×%neutral detergent fibre (NDF)) + (45.8×%CP) – (106.2×%ash). Overall, the pigs fed the diet calculated with an ME from NRC had significantly lower ADG, feed efficiency, hot carcass weight, Longissimus muscle area and leptin concentration in serum compared with pigs fed the diet with an ME calculated by the prediction equation (p < 0.05). Glucose and low-density lipoprotein concentrations in pigs fed the diet calculated by NRC and were significantly reduced compared with pigs fed the control diet (p < 0.05). Lipase concentration in pigs fed the diet calculated by prediction equation was higher compared with pigs fed the diet calculated by NRC (p < 0.05). In conclusion, the prediction equation of ME content in de-oiled DDGS was more accurate than the value and its use resulted in improved pig performance

Toward Developing Chemical Modulators of Hsp60 as Potential Therapeutics

The 60 kDa heat shock protein (Hsp60) is classically known as a mitochondrial chaperonin protein working together with co-chaperonin 10 kDa heat shock protein (Hsp10). This chaperonin complex is essential for folding proteins newly imported into mitochondria. However, Hsp60, and/or Hsp10 have also been shown to reside in other subcellular compartments including extracellular space, cytosol, and nucleus. The proteins in these extra-mitochondrial compartments may possess a wide range of functions dependent or independent of its chaperoning activity. But the mechanistic details remain unknown. Mutations in Hsp60 gene have been shown to be associated with neurodegenerative disorders. Abnormality in expression level and/or subcellular localization have also been detected from different diseased tissues including inflammatory diseases and various cancers. Therefore, there is a strong interest in developing small molecule modulators of Hsp60. Most of the reported inhibitors were discovered through various chemoproteomics strategies. In this review, we will describe the recent progress in this area with reported inhibitors from both natural products and synthetic compounds. The former includes mizoribine, epolactaene, myrtucommulone, stephacidin B, and avrainvillamide while the latter includes o-carboranylphenoxyacetanilides and gold (III) porphyrins. The potencies of the known inhibitors range from low micromolar to millimolar concentrations. The potential applications of these inhibitors include anti-cancer, anti-inflammatory diseases, and anti-autoimmune diseases

Super High Dosing with a Novel Buttiauxella Phytase Continuously Improves Growth Performance, Nutrient Digestibility, and Mineral Status of Weaned Pigs

This study was conducted to evaluate the efficacy of a novel Buttiauxella phytase to pigs fed P-deficient, corn-soybean meal diets. One hundred and twenty crossbred piglets (9.53 +/- 0.84 kg) were allocated to one of five treatments which consisted of four low P diets (0.61 % Ca and 0.46 % total P) supplemented with 0, 500, 1,000, or 20,000 FTU/kg phytase as well as a positive control diet (0.77 % Ca and 0.62 % total P). Each treatment had six replicated pens with four pigs per pen. Pigs were fed the experimental diets for 28 days. Phytase supplementation linearly improved (P < 0.05) average daily gain (ADG), feed conversion ratio (FCR), and apparent total tract digestibility (ATTD) of dry matter, gross energy, crude protein, Ca, and P in weaned pigs. Super high dosing with phytase (20,000 FTU/kg) further increased (P < 0.05) ADG compared with 500 FTU/kg phytase inclusion group, as well as ATTD of Ca and P. Metacarpal bone characteristics and several trace mineral concentration in bone, plasma, or organ tissues were linearly (P < 0.05) improved at increasing dose of phytase. Super high dosing with phytase (20,000 FTU/kg) supplementation improved (P < 0.05) Mn and Zn concentration in bone compared to normal dose of phytase supplementation (500 or 1,000 FTU/kg). In conclusion, supplementation of 500 FTU of Buttiauxella phytase/kg and above effectively hydrolyzed phytate in a low-P corn-soybean diet for pigs. In addition, a super high dosing with phytase (20,000 FTU/kg) improved macro- or micro mineral availability and growth performance

Long Noncoding RNA EZR-AS1 Regulates the Proliferation, Migration, and Apoptosis of Human Venous Endothelial Cells via SMYD3

Numerous studies have shown that long noncoding RNAs (lncRNAs) play essential roles in the development and progression of human cardiovascular diseases. However, whether lncRNA ezrin antisense RNA 1 (EZR-AS1) is associated with the progression of coronary heart disease (CHD) remains unclear. Accordingly, the aim of the present study was to evaluate the role of lncRNA EZR-AS1 in patients with CHD and in human venous endothelial cells (HUVECs). The findings revealed that lncRNA EZR-AS1 was highly expressed in the peripheral blood of patients with CHD. In vitro experiments showed that the overexpression of EZR-AS1 could enhance proliferation, migration, and apoptosis by upregulating the expression of EZR in HUVECs; downregulation of lncRNA EZR-AS1 resulted in the opposite effect. lncRNA EZR-AS1 was also found to regulate SET and MYND domain-containing protein 3 (SMYD3), a histone H3 lysine 4-specific methyltransferase, which subsequently mediated EZR transcription. Collectively, these results demonstrate that lncRNA EZR-AS1 plays an important role in HUVECs function via SMYD3 signaling