Discovery of a Distinct Superfamily of Kunitz-Type Toxin (KTT) from Tarantulas

BACKGROUND: Kuntiz-type toxins (KTTs) have been found in the venom of animals such as snake, cone snail and sea anemone. The main ancestral function of Kunitz-type proteins was the inhibition of a diverse array of serine proteases, while toxic activities (such as ion-channel blocking) were developed under a variety of Darwinian selection pressures. How new functions were grafted onto an old protein scaffold and what effect Darwinian selection pressures had on KTT evolution remains a puzzle. PRINCIPAL FINDINGS: Here we report the presence of a new superfamily of ktts in spiders (TARANTULAS: Ornithoctonus huwena and Ornithoctonus hainana), which share low sequence similarity to known KTTs and is clustered in a distinct clade in the phylogenetic tree of KTT evolution. The representative molecule of spider KTTs, HWTX-XI, purified from the venom of O. huwena, is a bi-functional protein which is a very potent trypsin inhibitor (about 30-fold more strong than BPTI) as well as a weak Kv1.1 potassium channel blocker. Structural analysis of HWTX-XI in 3-D by NMR together with comparative function analysis of 18 expressed mutants of this toxin revealed two separate sites, corresponding to these two activities, located on the two ends of the cone-shape molecule of HWTX-XI. Comparison of non-synonymous/synonymous mutation ratios (omega) for each site in spider and snake KTTs, as well as PBTI like body Kunitz proteins revealed high Darwinian selection pressure on the binding sites for Kv channels and serine proteases in snake, while only on the proteases in spider and none detected in body proteins, suggesting different rates and patterns of evolution among them. The results also revealed a series of key events in the history of spider KTT evolution, including the formation of a novel KTT family (named sub-Kuntiz-type toxins) derived from the ancestral native KTTs with the loss of the second disulfide bridge accompanied by several dramatic sequence modifications. CONCLUSIONS/SIGNIFICANCE: These finding illustrate that the two activity sites of Kunitz-type toxins are functionally and evolutionally independent and provide new insights into effects of Darwinian selection pressures on KTT evolution, and mechanisms by which new functions can be grafted onto old protein scaffolds

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

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Hysteretic Behavior of Eccentrically Loaded Reinforced Air-Entrained Concrete Columns under Combined Effects of Freeze-Thaw Cycles and Seawater Corrosion

Besides service loads, reinforced concrete structures in cold coastal seismic regions are subjected to multiple attacks of freeze-thaw cycles and seawater corrosion as well as the earthquake struck. An experimental study was conducted to investigate the seismic response of eccentrically loaded reinforced air-entrained concrete columns under alternative actions of freeze-thaw cycles and chloride corrosion. Results show that, after 300 times of freeze-thaw cycles alternated with 100 times of seawater immersion, the hysteretic behavior of the eccentrically loaded columns manifested an apparent asymmetric pattern. Under forward cyclic load, the existence of larger eccentric load rendered the reduction of the ultimate load and the ductility of a column by up to 20.3% and 46.05%, respectively, but it had a positive effect if reverse cyclic load was applied. The presence of eccentric load could have a considerable impact on the seismic behavior of reinforced air-entrained concrete columns served in an aggressive environment

Effect of Dietary Folic Acid Supplementation during Pregnancy on Blood Characteristics and Milk Composition of Ewes

The objective of the present study was to investigate the dynamic change of serum parameters and milk composition by dietary FA supplementation with ewes with different litter size from mating to lambing. The ewes were divided into six treatments (TW-CON, TW-F16, TW-F32, TR-CON, TR-F16, TR-F32) according to dietary FA levels (control, CON; 16 or 32 mg·kg−1 rumen-protect-FA supplementation, F16 and F32) and litter size (twin born, TW; and triplet born, TR). In serum, the concentration of folate increased linearly with dietary FA supplementation (P < 0.05), regardless of the litter size, they showed a quadratic response to gestation progression (P < 0.05). With dietary FA addition, IGFI-I levels significant increased from late gestation to after lambing (P < 0.05), and linearly increased immunoglobulin during the perinatal period (P < 0.05). In colostrum and milk at d 15, the content of folate, lactoferrin, and IgG were affected positively by FA supplementation (P < 0.05). IgG was higher in the TW group than TR in colostrum (P < 0.05), and lactoferrin in TW was lower than TR in milk of d 15 (P < 0.05). FA supplementation increased protein content in colostrum (P < 0.05), while it had no effect on the fat, lactose, and BUN of colostrum and milk of d 15 (P > 0.05). These results suggest that FA supplementation during gestation could regulate maternal blood metabolism and contribute to milk immune composition

Plasma Promotes Dry Reforming Reaction of CH₄ and CO₂ at Room Temperature with Highly Dispersed NiO/γ-Al₂O₃ Catalyst

Plasma is an efficient method that can activate inert molecules such as methane and carbon dioxide in a mild environment to make them reactive. In this work, we have prepared an AE-NiO/γ-Al2O3 catalyst using an ammonia-evaporation method for plasma promoted dry reforming reaction of CO2 and CH4 at room temperature. According to the characterization data of XRD, H2-TPR, TEM, XPS, etc., the AE-NiO/γ-Al2O3 catalyst has higher dispersion, smaller particle size and stronger metal-support interaction than the catalyst prepared by the traditional impregnation method. In addition, the AE-NiO/γ-Al2O3 catalyst also exhibits higher activity in dry reforming reaction. This work provides a feasible reference experience for the research of plasma promoted dry reforming reaction catalysts at room temperature

Plasma Promotes Dry Reforming Reaction of CH4 and CO2 at Room Temperature with Highly Dispersed NiO/γ-Al2O3 Catalyst

Plasma is an efficient method that can activate inert molecules such as methane and carbon dioxide in a mild environment to make them reactive. In this work, we have prepared an AE-NiO/γ-Al2O3 catalyst using an ammonia-evaporation method for plasma promoted dry reforming reaction of CO2 and CH4 at room temperature. According to the characterization data of XRD, H2-TPR, TEM, XPS, etc., the AE-NiO/γ-Al2O3 catalyst has higher dispersion, smaller particle size and stronger metal-support interaction than the catalyst prepared by the traditional impregnation method. In addition, the AE-NiO/γ-Al2O3 catalyst also exhibits higher activity in dry reforming reaction. This work provides a feasible reference experience for the research of plasma promoted dry reforming reaction catalysts at room temperature