Adverse outcome pathway (AOP)-based computational models provide state-of-the-art prediction for human skin sensitizers and are promising alternatives to animal testing. However, little is known ...about their applicability to pesticides due to scarce pesticide data for evaluation. Moreover, pesticides traditionally have been tested on animals without human data, making validation difficult. Direct application of AOP-based models to pesticides may be inappropriate since their original applicability domains were designed to maximize reliability for human response prediction on diverse chemicals but not pesticides. This study proposed to identify a consensus chemical space with concordant human responses predicted by the SkinSensPred online tool and animal testing data to reduce animal testing. The identified consensus chemical space for non-sensitizers achieved high concordance of 85% and 100% for the cross-validation and independent test, respectively. The reconfigured SkinSensPred can be applied as the first-tier tool for identifying non-sensitizers to reduce. animal testing for pesticides by 19.6%.
Pupylation is an important post-translational modification in prokaryotes. A prokaryotic ubiquitin-like protein (Pup) is attached to proteins as a signal for selective degradation by proteasome. ...Several proteomics methods have been developed for the identification of pupylated proteins and pupylation sites. However, pupylation sites of many experimentally identified pupylated proteins are still unknown. The development of sequence-based prediction methods can help to accelerate the identification of pupylation sites and gain insights into the substrate specificity and regulatory functions of pupylation. A novel tool iPUP is developed for the computational identification of pupylation sites. A composition of k-spaced amino acid pairs is utilized to represent a peptide sequence. Top ranked k-spaced amino acid pairs are subsequently selected by using a sequential backward feature elimination algorithm. The 10-fold cross-validation performance of iPUP trained by using the composition of 150 top ranked k-spaced amino acid pairs and support vector machines is 0.83 for the area under receiver operating characteristic curve. The importance analysis of k-spaced amino acid pairs shows that terminal space-containing pairs are useful for discriminating pupylation sites from non-pupylation sites. A sequence analysis confirms that lysines close to C-terminus tend to be pupylated. In contrast, lysines close to N-terminus are less likely to be pupylated. The iPUP tool can predict pupylation sites with probability scores for prioritizing promising pupylation sites. Both the online server and the standalone software of iPUP are freely available for academic use at http://cwtung.kmu.edu.tw/ipup.
•The composition of k-spaced amino acid pairs is utilized to predict and analyze pupylation sites.•The proposed method is more accurate than existing methods.•Top ranked k-spaced amino acid pairs are analyzed to provide insights into the substrate specificity of pupylation.•Both web server and standalone software are available for prediction.•Probability scores are available for prioritizing pupylation sites.
The placental barrier protects the fetus from exposure to some toxicants and is vital for drug development and risk assessment of environmental chemicals. However, in vivo experiments for assessing ...the placental barrier permeability of chemicals is not ethically acceptable. Although ex vivo placental perfusion methods provide good alternatives for the assessment of placental barrier permeability, the application to a large number of test chemicals could be time- and resource-consuming. Computational prediction models for ex vivo placental barrier permeability are therefore desirable. A total of 87 chemicals and corresponding 1444 physicochemical properties were divided into training and test datasets. Three types of algorithms including linear regression, random forest, and ensemble models were applied to develop prediction models for ex vivo placental barrier permeability. Among the tested models, the ensemble model integrating the previous two methods performed best for predicting ex vivo human placental barrier permeability with correlation coefficients of 0.887 and 0.825 when considering the applicability domain. An additional test on seven newly curated chemicals from the literature showed a good correlation coefficient of 0.879 which was further improved to 0.921 by considering the variation of experiments. In this study, the first valid predicting model for ex vivo human placental barrier permeability was developed following the OECD guideline. The model is expected to be useful for assessing the human placental barrier permeability and can be integrated with developmental toxicity prediction models for investigating the toxic effects of chemicals on the fetus.
Human papillomavirus (HPV) is the well‐established etiologic factor for cervical neoplasia. Cervical conization constitutes an effective treatment for high‐grade cervical intraepithelial neoplasia ...(HG‐CIN). We conducted an observational study for long‐term outcomes and HPV genotype changes after conization for HG‐CIN. Between 2008 and 2014, patients with newly diagnosed HG‐CIN before conization (surveillance new SN group) and those who had undergone conization without hysterectomy (surveillance previous SP group) were enrolled. HPV testing and Pap smear were performed periodically for the SN and SP (collectively S) groups. All other patients receiving conization for HG‐CIN during the study period were identified from our hospital database. Those eligible but not enrolled into our study were assigned to the non‐surveillance (non‐S) group. For the S group (n = 493), the median follow‐up period was 74.3 months. Eighty‐four cases had recurrent CIN Grade 2 or worse (CIN2+) (5‐year cumulative rate: 14.8%), of which six had invasive cancer. Among the 84 patients, 65 (77.4%) exhibited type‐specific persistence in the paired HPV results, whereas only 7 (8.3%) harbored new HPV types that belonged to the 9‐valent vaccine types. Among the 7397 non‐S patients, 789 demonstrated recurrent CIN2+, of which 57 had invasive cancer. The stages distribution of those progressed to invasive cancer in the non‐S group were more advanced than the S group (P = .033). Active surveillance might reduce the severity of those progressed to cancer. Because a majority of the patients with recurrent CIN2+ had persistent type‐specific HPV infections, effective therapeutic vaccines are an unmet medical need.
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High‐grade cervical intraepithelial neoplasia (HG‐CIN), a cervical carcinoma precursor, frequently is caused by high‐risk human papillomavirus (hr‐HPV) infection. HG‐CIN can be treated by cervical conization, though the procedure does not eradicate hr‐HPV, potentially enabling CIN recurrence. Here, in Taiwanese patients, investigation of HPV genotype changes in relation to HG‐CIN status after conization shows that 77.4 percent of patients with recurrent CIN 2 grade or worse (CIN2+) after conization had persistent type‐specific HPV infections. Vaccination against the remaining high‐risk HPVs prevented recurrent CIN2+ in only 8.3 percent of patients, revealing an unmet need for effective therapeutic vaccines.
Indole-3-acetic acid (IAA), a protein-bound uremic toxin resulting from gut microbiota-driven tryptophan metabolism, increases in hemodialysis (HD) patients. IAA may induce endothelial dysfunction, ...inflammation, and oxidative stress, elevating cardiovascular and cognitive risk in HD patients. However, research on the microbiome-IAA association is limited. This study aimed to explore the gut microbiome's relationship with plasma IAA levels in 72 chronic HD patients aged over 18 (August 2016-January 2017). IAA levels were measured using tandem mass spectrometry, and gut microbiome analysis utilized 16s rRNA next-generation sequencing. Linear discriminative analysis effect size and random forest analysis distinguished microbial species linked to IAA levels. Patients with higher IAA levels had reduced microbial diversity. Six microbial species significantly associated with IAA levels were identified;
,
,
, and
were enriched in low-IAA individuals, while
and
were enriched in high-IAA individuals. This study sheds light on specific gut microbiota species influencing IAA levels, enhancing our understanding of the intricate interactions between the gut microbiota and IAA metabolism.
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity during adolescence, leading to altered postural control with compromised stability. To identify the effects of AIS on ...whole-body balance control during obstacle-crossing, 14 adolescents with Lenke 1 thoracic AIS and 14 healthy controls were compared in terms of the inclination angle (IA) of the body's center of mass (COM) relative to the center of pressure (COP), the rate of change of IA (RCIA) and the jerk index of IA. Between-side comparisons were also performed for the AIS group. The patients showed less smooth COM-COP motion in the sagittal plane with significantly increased anterior RCIA and IA jerk index during crossing with either the concave side (p = 0.001) or the convex side (p = 0.001) leading when compared to healthy controls. In the frontal plane, the patients showed close-to-zero RCIA (p = 0.002) while crossing with the leading limb, with an increased IA magnitude (p = 0.039) only while crossing with the concave-side limb leading. The patients with Lenke 1 thoracic AIS were found to cross obstacles with altered, compromised COM-COP control in both sagittal and frontal planes when compared to healthy controls. The results suggest that the thoracic spinal deformity in Lenke 1 AIS affects the whole-body balance control during obstacle-crossing, which should be monitored for signs of increased risk of loss of balance in the management of such patient groups.
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•For early OSCC, MDR < 0.5 is an independent factor for disease-free survival.•Without adjuvant RT, clear or close margins (MDR ≥ 0.5) yield similar survival rates.•Without adjuvant ...RT, MDR < 0.5 correlates with increased local/regional recurrence risks.•MDR ≥ 0.5 can be used as the parameter to an oncologic safe margin.
In early-stage oral squamous cell carcinoma (OSCC) patients, whether the margin-to-depth-of-invasion ratio (MDR) can assist in stratifying the prognosis remains unclear.
Patients diagnosed with early stage OSCC at National Taiwan University Hospital between January 2007 and December 2021 were reviewed. Patients with margin > 1 mm were classified into two groups: MDR < 0.5 and MDR ≥ 0.5.
We analyzed 911 pT1-2N0M0 OSCC patients, 723 (79.36 %) with MDR ≥ 0.5 and 188 (20.64 %) with MDR < 0.5. Patients in the MDR < 0.5 group displayed a significantly higher local recurrence rate (odds ratio 2.81, p = 0.002) compared with MDR ≥ 0.5 group. The 5-year disease-free survival were 80.8 % for clear margin, 76.3 % for close margin (MDR ≥ 0.5), and 65.2 % for close margin (MDR < 0.5). The overall survival displayed a similar pattern, with 5-year rates of 88.3 % for clear margin, 86.8 % for close margin (MDR ≥ 0.5), and 75.0 % for close margin (MDR < 0.5). There were no significant overall survival differences between the two MDR ≥ 0.5 groups, but both were significantly superior to patients with MDR < 0.5 (p = 0.001; p = 0.01). After multivariant cox analysis, MDR < 0.5 was a significant risk factor for disease-free survival (p < 0.001).
For early stage OSCC patients without positive margin (≦1mm), the survival outcome between MDR ≥ 0.5 group and MDR < 0.5 group was significantly different. The MDR < 0.5 group had significantly higher risk of local recurrence that may warrant adjuvant treatment.
Ubiquitylation plays an important role in regulating protein functions. Recently, experimental methods were developed toward effective identification of ubiquitylation sites. To efficiently explore ...more undiscovered ubiquitylation sites, this study aims to develop an accurate sequence-based prediction method to identify promising ubiquitylation sites.
We established an ubiquitylation dataset consisting of 157 ubiquitylation sites and 3676 putative non-ubiquitylation sites extracted from 105 proteins in the UbiProt database. This study first evaluates promising sequence-based features and classifiers for the prediction of ubiquitylation sites by assessing three kinds of features (amino acid identity, evolutionary information, and physicochemical property) and three classifiers (support vector machine, k-nearest neighbor, and NaïveBayes). Results show that the set of used 531 physicochemical properties and support vector machine (SVM) are the best kind of features and classifier respectively that their combination has a prediction accuracy of 72.19% using leave-one-out cross-validation.Consequently, an informative physicochemical property mining algorithm (IPMA) is proposed to select an informative subset of 531 physicochemical properties. A prediction system UbiPred was implemented by using an SVM with the feature set of 31 informative physicochemical properties selected by IPMA, which can improve the accuracy from 72.19% to 84.44%. To further analyze the informative physicochemical properties, a decision tree method C5.0 was used to acquire if-then rule-based knowledge of predicting ubiquitylation sites. UbiPred can screen promising ubiquitylation sites from putative non-ubiquitylation sites using prediction scores. By applying UbiPred, 23 promising ubiquitylation sites were identified from an independent dataset of 3424 putative non-ubiquitylation sites, which were also validated by using the obtained prediction rules.
We have proposed an algorithm IPMA for mining informative physicochemical properties from protein sequences to build an SVM-based prediction system UbiPred. UbiPred can predict ubiquitylation sites accompanied with a prediction score each to help biologists in identifying promising sites for experimental verification. UbiPred has been implemented as a web server and is available at http://iclab.life.nctu.edu.tw/ubipred.
Computational prioritization of chemicals for potential skin sensitization risks plays essential roles in the risk assessment of environmental chemicals and drug development. Given the huge number of ...chemicals for testing, computational methods enable the fast identification of high-risk chemicals for experimental validation and design of safer alternatives. However, the development of robust prediction model requires a large dataset of tested chemicals that is usually not available for most toxicological endpoints, especially for human data. A small training dataset makes the development of effective models difficult with insufficient coverage and accuracy. In this study, an ensemble tree-based multitask learning method was developed incorporating three relevant tasks in the well-defined adverse outcome pathway (AOP) of skin sensitization to transfer shared knowledge to the major task of human sensitizers. The results show both largely improved coverage and accuracy compared with three state-of-the-art methods. A user-friendly prediction server was available at
https://cwtung.kmu.edu.tw/skinsensdb/predict
. As AOPs for various toxicity endpoints are being actively developed, the proposed method can be applied to develop prediction models for other endpoints.
Prokaryotic ubiquitin-like protein (Pup), the firstly identified post-translational protein modifier in prokaryotes, is an important signal for the selective degradation of proteins. Recently, ...large-scale proteomics technology has been applied to identify a large number of pupylated proteins. The development of a database for managing pupylated proteins and pupylation sites is important for further analyses.
A database named PupDB is constructed by collecting experimentally identified pupylated proteins and pupylation sites from published studies and integrating the information of pupylated proteins with corresponding structures and functional annotations. PupDB is a web-based database with tools for browses and searches of pupylated proteins and interactive displays of protein structures and pupylation sites.
The structured and searchable database PupDB is expected to provide a useful resource for further analyzing the substrate specificity, identifying pupylated proteins in other organisms and developing computational tools for predicting pupylation sites. PupDB is freely available at http://cwtung.kmu.edu.tw/pupdb.
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