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

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd

The glutamate receptor genes and schizophrenia: Gene expression studies of antipsychotic drug action and linkage analysis of the genetic susceptibility

Schizophrenia is a severe disabling neuropsychiatric syndrome affecting 0.85% of most human populations. Family, twin, and adoption studies in several ethnic populations have consistently implicated genetic factors as having an important pathogenic role in the disease. However, researchers have only recently begun to detect consistent evidence of linkage between schizophrenia and genetic markers, but no candidate genes have yet been implicated. It has been hypothesized that glutamate receptor function is important in either the aetiology or treatment of schizophrenia and therefore the glutamate receptor family of genes are potential susceptibility loci for schizophrenia. To test this hypothesis, twenty-three English and Icelandic schizophrenia families containing multiple cases of schizophrenia were genotyped with currently available microsatellite polymorphisms localized at the GluR5, GluR6 glutamate receptors and SLC1A5 glutamate/aspartate transporter loci. Lod scores, model-free linkage analysis, and extended relative pair analysis methods were used to test for linkage. No evidence of close linkage between schizophrenia and any of these loci was found. In addition, in order to understand how specific glutamate receptor genes are involved in the treatment of schizophrenia, a multiprobe oligonucleotide solution hybridization (MOSH) technique was used to examine the regulation of gene expression of the ionotropic glutamate receptor subunit genes. Four regions of the left rat brain following treatment with the optical isomers of flupenthixol at a dose of 0.2 mg/kg/day over a period of 1, 2, 4, 8, 12, 24 weeks were studied. A previous controlled trial showed that cis-flupenthixol had a significantly superior ability to ameliorate the positive symptoms of schizophrenia compared to its transisomer. Protein levels of the NMD A receptor subunit NR1, GluR2/3 and GluR6/7 glutamate receptors in the right brain were also examined by Western blotting technique with specific antibodies for these receptor subunits. In summary, the gene expression of specific NMD A receptor subunits in several regions of the left rat brain was altered by treatment with either the cis- or transisomer of the antipsychotic drug flupenthixol. NRl mRNA was significantly decreased throughout the 24 weeks treatment with trans-flupenthixol and after long-term (12 or 24 week) treatment with cis-flupenthixol in the frontal and subcortical areas. NR2B and NR2C mRNA expression demonstrated a dynamic pattern of change in different brain regions following treatment with flupenthixol whilst NR2A and NR2D gene expression was relatively unaffected except in the subcortical region. The gene expression of AMPA (GluRl-4) and kainate (GluR5-7, KA1, KA2) types of glutamate receptor subunits was unaffected following 4 and 24 weeks of treatment with either trans- or cis-flupenthixol. It would be difficult to make inferences about the pathophysiology of schizophrenia or any other psychiatric disorders solely based on drug mechanisms. However, these results indicate that adaptations in glutamate receptors may represent an important and novel mechanism through which neuroleptics exert some of their effects on brain function

Facile Synthesis of Radial-Like Macroporous Superparamagnetic Chitosan Spheres with In-Situ Co-Precipitation and Gelation of Ferro-Gels

<div><p>Macroporous chitosan spheres encapsulating superparamagnetic iron oxide nanoparticles were synthesized by a facile and effective one-step fabrication process. Ferro-gels containing ferrous cations, ferric cations and chitosan were dropped into a sodium hydroxide solution through a syringe pump. In addition, a sodium hydroxide solution was employed for both gelation (chitosan) and co-precipitation (ferrous cations and ferric cations) of the ferro-gels. The results showed that the in-situ co-precipitation of ferro-ions gave rise to a radial morphology with non-spheroid macro pores (large cavities) inside the chitosan spheres. The particle size of iron oxide can be adjusted from 2.5 nm to 5.4 nm by tuning the concentration of the sodium hydroxide solution. Using Fourier Transform Infrared Spectroscopy and X-ray diffraction spectra, the synthesized nanoparticles were illustrated as Fe₃O₄ nanoparticles. In addition, the prepared macroporous chitosan spheres presented a super-paramagnetic behaviour at room temperature with a saturation magnetization value as high as ca. 18 emu/g. The cytotoxicity was estimated using cell viability by incubating doses (0∼1000 µg/mL) of the macroporous chitosan spheres. The result showed good viability (above 80%) with alginate chitosan particles below 1000 µg/mL, indicating that macroporous chitosan spheres were potentially useful for biomedical applications in the future.</p> </div

Characterization of the iron oxide-chitosan composite spheres.

<p>(a) FTIR spectra of chitosan spheres (gray line) and iron oxide nanoparticle-loaded chitosan spheres (black line). (b) X-ray diffraction pattern from iron oxides nanoparticle-loaded chitosan spheres prepared from the NaOH solutions with various concentrations.</p

Morphologies of the synthesyzed chitosan spheres.

<p>(a) An optical image of the iron oxide nanoparticles loaded chitosan spheres. (b) SEM images of chitosan spheres without (left) and with (right) iron oxide nanoparticles. (c) and (d) show the cross-section images of chitosan spheres (without iron oxide nanoparticles). Inset in (c) shows the sliced hemispheres of chitosan sphere. Inset in (d) shows details of the internal structure. (e) and (f) show the cross-section images of iron oxide nanoparticles loaded chitosan spheres.</p

Schematic of the formation process of macroporous chitosan spheres.

<p>Schematic of the formation process of macroporous chitosan spheres.</p

The geographic distributions and complex genetic relationships among four Sorghum taxa identified in Taiwan

The genus Sorghum consists of 25 species, including Sorghum bicolor (L.) Moench, one of the top five cereal crops cultivated globally, and S. halepense, one of the most noxious weeds. Weedy Sorghum possesses outstanding adaptability and drought tolerance thrives in diverse environments and becomes an invasive plant worldwide. Taiwan is a unique place possessing suitable habitats for four Sorghum taxa, S. bicolor ssp. bicolor, var. technicum, ssp. verticilliflorum and S. halepense, which were identified by key morphological features. The four Sorghum taxa showed distinct geographic distributions, revealing that invasiveness was influenced by their own characteristics and human activities. The sporadic distributions of cultivated S. bicolor ssp. bicolor and var. technicum may be attributed to human disturbance and agricultural activities. The rhizomatous S. halepense was widely distributed and showed the highest genetic diversity (He &gt; 0.776) among the four taxa, with its strong adaptation to various environments threatening the agricultural practices and ecosystem in Taiwan. In contrast, the newly naturalised S. bicolor ssp. verticilliflorum was confined to and dominant in southern Taiwan, with the lowest genetic diversity (He &lt; 0.272). Significant genetic differentiation (F-ST = 0.5207) between the two ssp. verticilliflorum subpopulations was associated with natural geographic isolation. This study concretely elucidated the geographic distributions, genetic diversity and relatedness of invasive and escaped Sorghum taxa, indicating the potential aggressiveness and hazard of weedy Sorghum in Taiwan

Genetic variants in NECTIN4 encoding an adhesion molecule are associated with continued opioid use.

Methadone is a synthetic opioid used as maintenance treatment for patients addicted to heroin. Skin irritation is one of the adverse events caused by opioid use. 344 methadone maintenance treatment (MMT) patients were recruited with records and measurements on methadone dose, plasma methadone concentrations, and treatment emergent symptom scales (TESS). 15 patients reported with skin irritation. Five SNPs located within the NECTIN4 genetic region were genotyped. The NECTIN4 gene within the adherens junction interaction pathway was associated with methadone dose in pathway-based genome wide association analyses (P = 0.0008). Three highly-linked SNPs, rs11265549, rs3820097, and rs4656978, were significantly associated with methadone dose (P = 0.0003), plasma concentrations of R,S-methadone (P = 0.0004) and TNF-α (P = 0.010) in all 344 MMT patients, and with self-report skin irritation symptom scores (P = 0.010) in the 15 MMT patients who reported with skin irritation. To identify the possible roles of plasma level of Nectin-4 in the responses to MMT and opioid use, additional age- and gender-matched 51 controls and 83 methadone-free abstinent former heroin users were recruited. Plasma level of Nectin-4 was the highest in MMT patients among the three groups. The results suggest involvement of genetic variants on NECTIN4 in methadone dose. Plasma Nectin-4 level is likely an indicator for continued use of opioids