EFICAz²: enzyme function inference by a combined approach enhanced by machine learning

©2009 Arakaki et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2105/10/107doi:10.1186/1471-2105-10-107Background: We previously developed EFICAz, an enzyme function inference approach that combines predictions from non-completely overlapping component methods. Two of the four components in the original EFICAz are based on the detection of functionally discriminating residues (FDRs). FDRs distinguish between member of an enzyme family that are homofunctional (classified under the EC number of interest) or heterofunctional (annotated with another EC number or lacking enzymatic activity). Each of the two FDR-based components is associated to one of two specific kinds of enzyme families. EFICAz exhibits high precision performance, except when the maximal test to training sequence identity (MTTSI) is lower than 30%. To improve EFICAz's performance in this regime, we: i) increased the number of predictive components and ii) took advantage of consensual information from the different components to make the final EC number assignment. Results: We have developed two new EFICAz components, analogs to the two FDR-based components, where the discrimination between homo and heterofunctional members is based on the evaluation, via Support Vector Machine models, of all the aligned positions between the query sequence and the multiple sequence alignments associated to the enzyme families. Benchmark results indicate that: i) the new SVM-based components outperform their FDR-based counterparts, and ii) both SVM-based and FDR-based components generate unique predictions. We developed classification tree models to optimally combine the results from the six EFICAz components into a final EC number prediction. The new implementation of our approach, EFICAz², exhibits a highly improved prediction precision at MTTSI < 30% compared to the original EFICAz, with only a slight decrease in prediction recall. A comparative analysis of enzyme function annotation of the human proteome by EFICAz² and KEGG shows that: i) when both sources make EC number assignments for the same protein sequence, the assignments tend to be consistent and ii) EFICAz² generates considerably more unique assignments than KEGG. Conclusion: Performance benchmarks and the comparison with KEGG demonstrate that EFICAz² is a powerful and precise tool for enzyme function annotation, with multiple applications in genome analysis and metabolic pathway reconstruction. The EFICAz² web service is available at: http://cssb.biology.gatech.edu/skolnick/webservice/EFICAz2/index.htm

EFICAz2: enzyme function inference by a combined approach enhanced by machine learning

<p>Abstract</p> <p>Background</p> <p>We previously developed EFICAz, an enzyme function inference approach that combines predictions from non-completely overlapping component methods. Two of the four components in the original EFICAz are based on the detection of functionally discriminating residues (FDRs). FDRs distinguish between member of an enzyme family that are homofunctional (classified under the EC number of interest) or heterofunctional (annotated with another EC number or lacking enzymatic activity). Each of the two FDR-based components is associated to one of two specific kinds of enzyme families. EFICAz exhibits high precision performance, except when the maximal test to training sequence identity (MTTSI) is lower than 30%. To improve EFICAz's performance in this regime, we: i) increased the number of predictive components and ii) took advantage of consensual information from the different components to make the final EC number assignment.</p> <p>Results</p> <p>We have developed two new EFICAz components, analogs to the two FDR-based components, where the discrimination between homo and heterofunctional members is based on the evaluation, via Support Vector Machine models, of all the aligned positions between the query sequence and the multiple sequence alignments associated to the enzyme families. Benchmark results indicate that: i) the new SVM-based components outperform their FDR-based counterparts, and ii) both SVM-based and FDR-based components generate unique predictions. We developed classification tree models to optimally combine the results from the six EFICAz components into a final EC number prediction. The new implementation of our approach, EFICAz², exhibits a highly improved prediction precision at MTTSI < 30% compared to the original EFICAz, with only a slight decrease in prediction recall. A comparative analysis of enzyme function annotation of the human proteome by EFICAz²and KEGG shows that: i) when both sources make EC number assignments for the same protein sequence, the assignments tend to be consistent and ii) EFICAz²generates considerably more unique assignments than KEGG.</p> <p>Conclusion</p> <p>Performance benchmarks and the comparison with KEGG demonstrate that EFICAz²is a powerful and precise tool for enzyme function annotation, with multiple applications in genome analysis and metabolic pathway reconstruction. The EFICAz²web service is available at: <url>http://cssb.biology.gatech.edu/skolnick/webservice/EFICAz2/index.html</url></p

BDNF promotes target innervation of Xenopus mandibular trigeminal axons in vivo

<p>Abstract</p> <p>Background</p> <p>Trigeminal nerves consist of ophthalmic, maxillary, and mandibular branches that project to distinct regions of the facial epidermis. In <it>Xenopus </it>embryos, the mandibular branch of the trigeminal nerve extends toward and innervates the cement gland in the anterior facial epithelium. The cement gland has previously been proposed to provide a short-range chemoattractive signal to promote target innervation by mandibular trigeminal axons. Brain derived neurotrophic factor, BDNF is known to stimulate axon outgrowth and branching. The goal of this study is to determine whether BDNF functions as the proposed target recognition signal in the <it>Xenopus </it>cement gland.</p> <p>Results</p> <p>We found that the cement gland is enriched in BDNF mRNA transcripts compared to the other neurotrophins NT3 and NT4 during mandibular trigeminal nerve innervation. BDNF knockdown in <it>Xenopus </it>embryos or specifically in cement glands resulted in the failure of mandibular trigeminal axons to arborise or grow into the cement gland. BDNF expressed ectodermal grafts, when positioned in place of the cement gland, promoted local trigeminal axon arborisation <it>in vivo</it>.</p> <p>Conclusion</p> <p>BDNF is necessary locally to promote end stage target innervation of trigeminal axons <it>in vivo</it>, suggesting that BDNF functions as a short-range signal that stimulates mandibular trigeminal axon arborisation and growth into the cement gland.</p

High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer

Cell surface mannose 6-phosphate/insulin-like growth factor II receptors (M6P/IGF2R) bind and target exogenous insulin-like growth factor II (IGF2) to the prelysosomes where it is degraded. Loss of heterozygosity (LOH) for M6P/IGF2R is found in cancers, with mutational inactivation of the remaining allele. We exploited the normal allele-specific differential methylation of the M6P/IGF2R intron 2 CpG island to rapidly evaluate potential LOH in ovarian cancers, since every normal individual is informative. To this end, we developed a method for bisulfite modification of genomic DNA in 96-well format that allows for rapid methylation profiling. We identified ovarian cancers with M6P/IGF2R LOH, but unexpectedly also found frequent abnormal acquisition of methylation on the paternally inherited allele at intron 2. These results demonstrate the utility of our high-throughput method of bisulfite modification for analysis of large sample numbers. They further show that the methylation status of the intron 2 CpG island may be a useful indicator of LOH and biomarker of disease

Diagnostic accuracy of motor evoked potentials to detect neurological deficit during idiopathic scoliosis correction:a systematic review

OBJECTIVE The goal of this study was to evaluate the efficacy of intraoperative transcranial motor evoked potential (TcMEP) monitoring in predicting an impending neurological deficit during corrective spinal surgery for patients with idiopathic scoliosis (IS). METHODS The authors searched the PubMed and Web of Science database for relevant lists of retrieved reports and/or experiments published from January 1950 through October 2014 for studies on TcMEP monitoring use during IS surgery. The primary analysis of this review fit the operating characteristic into a hierarchical summary receiver operating characteristic curve model to determine the efficacy of intraoperative TcMEP-predicted change. RESULTS Twelve studies, with a total of 2102 patients with IS were included. Analysis found an observed incidence of neurological deficits of 1.38% (29/2102) in the sample population. Of the patients who sustained a neurological deficit, 82.8% (24/29) also had irreversible TcMEP change, whereas 17.2% (5/29) did not. The pooled analysis using the bivariate model showed TcMEP change with sensitivity (mean 91% [95% CI 34%-100%]) and specificity (mean 96% [95% CI 92-98%]). The diagnostic odds ratio indicated that it is 250 times more likely to observe significant TcMEP changes in patients who experience a new-onset motor deficit immediately after IS correction surgery (95% CI 11-5767). TcMEP monitoring showed high discriminant ability with an area under the curve of 0.98. CONCLUSIONS A patient with a new neurological deficit resulting from IS surgery was 250 times more likely to have changes in TcMEPs than a patient without new deficit. The authors' findings from 2102 operations in patients with IS show that TcMEP monitoring is a highly sensitive and specific test for detecting new spinal cord injuries in patients undergoing corrective spinal surgery for IS. They could not assess the value of TcMEP monitoring as a therapeutic adjunct owing to the limited data available and their study design

Evorus: A Crowd-powered Conversational Assistant Built to Automate Itself Over Time

Crowd-powered conversational assistants have been shown to be more robust than automated systems, but do so at the cost of higher response latency and monetary costs. A promising direction is to combine the two approaches for high quality, low latency, and low cost solutions. In this paper, we introduce Evorus, a crowd-powered conversational assistant built to automate itself over time by (i) allowing new chatbots to be easily integrated to automate more scenarios, (ii) reusing prior crowd answers, and (iii) learning to automatically approve response candidates. Our 5-month-long deployment with 80 participants and 281 conversations shows that Evorus can automate itself without compromising conversation quality. Crowd-AI architectures have long been proposed as a way to reduce cost and latency for crowd-powered systems; Evorus demonstrates how automation can be introduced successfully in a deployed system. Its architecture allows future researchers to make further innovation on the underlying automated components in the context of a deployed open domain dialog system.Comment: 10 pages. To appear in the Proceedings of the Conference on Human Factors in Computing Systems 2018 (CHI'18

High-resolution diffraction reveals magnetoelastic coupling and coherent phase separation in tetragonal CuMnAs

Tetragonal CuMnAs was the first antiferromagnet where reorientation of the N\'eel vector was reported to occur by an inverse spin galvanic effect. A complicating factor in the formation of phase-pure tetragonal CuMnAs is the formation of an orthorhombic phase with nearly the same stoichiometry. Pure-phase tetragonal CuMnAs has been reported to require an excess of Cu to maintain a single phase in traditional solid state synthesis reactions. Here we show that subtle differences in diffraction patterns signal pervasive inhomogeneity and phase separation, even in Cu-rich Cu$_{1.18}$Mn$_{0.82}$As. From calorimetry and magnetometry measurements, we identify two transitions corresponding to the N\'eel temperature (T$_N$) and an antiferromagnet to weak ferromagnet transition in Cu$_{1.18}$Mn$_{0.82}$As and CuMn$_{0.964}$As$_{1.036}$. These transitions have clear crystallographic signatures, directly observable in the lattice parameters upon in-situ heating and cooling. The immiscibility and phase separation could arise from a spinoidal decomposition that occurs at high temperatures, and the presence of a ferromagnetic transition near room temperature warrants further investigation of its effect on the electrical switching behavior.Comment: 10 pages, 9 figures, added author middle initia

Smoking susceptibility and its predictors among adolescents in China: Evidence from Ningbo City

Susceptibility to smoking is a risk factor of actual adolescent smoking behaviors. This study aimed to estimate the rate of smoking susceptibility and its predictors in China with a sample of 4,695 junior high school students in Ningbo, China. Core questions from the Global Youth Tobacco Survey (GYTS) were adapted to the China context and administered to these students. The rate of smoking susceptibility, measured by “Do you foresee yourself taking up smoking in the next 12 months”, is 6.1%. Results from logistic regression suggested that among boys, adolescents’ health knowledge that smoking can cause lung cancer (OR=2.73), the belief that smoking can help people relax (OR=2.32), and self-report of never having seen anti-smoking information on campus (OR=1.80) predicted increased susceptibility to smoking. Conversely, the belief that boys who smoke are less attractive (OR=0.64), that parents will have a problem with their child smoking (OR=0.50), having no friends or classmates who smoke (OR=0.22), and not seeing teachers smoke in the previous week (OR=0.61) predicted decreased susceptibility to smoking. Findings for girls were similar. This study suggested the need for comprehensive programs aiming to improve family, peer, and school environments to decrease smoking susceptibility among adolescents

Preventing Slips and Falls through Leisure-Time Physical Activity: Findings from a Study of Limited-Service Restaurants

Background/Objective Physical activity has been shown to be beneficial at improving health in some medical conditions and in preventing injury. Epidemiologic studies suggest that physical activity is one factor associated with a decreased risk for slips and falls in the older (≥65 years) adult population. While the risk of slips and falls is generally lower in younger than in older adults; little is known of the relative contribution of physical activity in preventing slips and falls in younger adults. We examined whether engagement in leisure-time physical activity (LTPA) was protective of slips and falls among a younger/middle-aged (≤50 years old) working population. Methods: 475 workers from 36 limited-service restaurants in six states in the U.S. were recruited to participate in a prospective cohort study of workplace slipping. Information on LTPA was collected at the time of enrollment. Participants reported their slip experience and work hours weekly for up to 12 weeks. We investigated the association between the rate of slipping and the rate of major slipping (i.e., slips that resulted in a fall and/or injury) and LTPA for workers 50 years of age and younger (n = 433, range 18–50 years old) using a multivariable negative binomial generalized estimating equation model. Results: The rate of major slips among workers who engaged in moderate (Adjusted Rate Ratio (RR) = 0.65; 95% Confidence Interval (CI) = [0.18–2.44]) and vigorous (RR = 0.64; 95%CI = [0.18–2.26]) LTPA, while non-significant, were approximately one-third lower than the rate of major slips among less active workers. Conclusion: While not statistically significant, the results suggest a potential association between engagement in moderate and vigorous LTPA and the rate of major slips in younger adults. Additional studies that examine the role of occupational and non-occupational physical activity on the risk of slips, trips and falls among younger and middle aged adults appear warranted

Accelerated Axonal Loss Following Acute CNS Demyelination in Mice Lacking Protein Tyrosine Phosphatase Receptor Type Z

Protein tyrosine phosphatase receptor type Z (Ptprz) is widely expressed in the mammalian central nervous system and has been suggested to regulate oligodendrocyte survival and differentiation. We investigated the role of Ptprz in oligodendrocyte remyelination after acute, toxin-induced demyelination in Ptprz null mice. We found neither obvious impairment in the recruitment of oligodendrocyte precursor cells, astrocytes, or reactive microglia/macrophage to lesions nor a failure for oligodendrocyte precursor cells to differentiate and remyelinate axons at the lesions. However, we observed an unexpected increase in the number of dystrophic axons by 3 days after demyelination, followed by prominent Wallerian degeneration by 21 days in the Ptprz-deficient mice. Moreover, quantitative gait analysis revealed a deficit of locomotor behavior in the mutant mice, suggesting increased vulnerability to axonal injury. We propose that Ptprz is necessary to maintain central nervous system axonal integrity in a demyelinating environment and may be an important target of axonal protection in inflammatory demyelinating diseases, such as multiple sclerosis and periventricular leukomalacia. (Am J Pathol 2012, 181:1518-1523; http://dx.doi.org/10.1016/j.ajpath.2012.07.011)UK Multiple Sclerosis SocietyMultiple Sclerosis International FederationUniv Cambridge, Dept Vet Med, Cambridge CB3 0ES, EnglandUniv Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB3 0ES, EnglandUniversidade Federal de São Paulo, Dept Biosci, Santos, BrazilMerck Serono Int, Geneva Res Ctr, Geneva, SwitzerlandUniversidade Federal de São Paulo, Dept Biosci, Santos, BrazilWeb of Scienc