Profile-profile comparisons by COMPASS predict intricate homologies between protein families.
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ABSTRACT:
SUBMITTER: Sadreyev RI
PROVIDER: S-EPMC2366929 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDetection of common evolutionary origin (homology) is a primary means of inferring protein structure and function. At present, comparison of protein families represented as sequence profiles is arguably the most effective homology detection strategy. However, finding the best way to represent evolutionary information of a protein sequence family in the profile, to compare profiles and to estimate the biological significance of such comparisons, remains an active area of research.ResultsHere, we present a new homology detection method based on sequence profile-profile comparison. The method has a number of new features including position-dependent gap penalties and a global score system. Position-dependent gap penalties provide a more biologically relevant way to represent and align protein families as sequence profiles. The global score system enables an analytical solution of the statistical parameters needed to estimate the statistical significance of profile-profile similarities. The new method, together with other state-of-the-art profile-based methods (HHsearch, COMPASS and PSI-BLAST), is benchmarked in all-against-all comparison of a challenging set of SCOP domains that share at most 20% sequence identity. For benchmarking, we use a reference ("gold standard") free model-based evaluation framework. Evaluation results show that at the level of protein domains our method compares favorably to all other tested methods. We also provide examples of the new method outperforming structure-based similarity detection and alignment. The implementation of the new method both as a standalone software package and as a web server is available at http://www.ibt.lt/bioinformatics/coma.ConclusionDue to a number of developments, the new profile-profile comparison method shows an improved ability to match distantly related protein domains. Therefore, the method should be useful for annotation and homology modeling of uncharacterized proteins.
| S-EPMC2837030 | biostudies-literature
Project description:BackgroundGuselkumab is an interleukin-23 inhibitor indicated for the treatment of moderate-to-severe plaque psoriasis in adults. Guselkumab has demonstrated additional benefit in patients with early inadequate response to ustekinumab. Long-term efficacy comparisons of guselkumab and ustekinumab are currently lacking among ustekinumab-naive patients.ObjectivesTo assess the relative efficacy of guselkumab and ustekinumab for maintenance therapy of moderate-to-severe plaque psoriasis, using individual patient data (IPD) from randomized controlled trials.MethodsIPD for guselkumab from the VOYAGE 1 and 2 trials were pooled and compared with IPD for ustekinumab from the NAVIGATE trial. Multivariable logistic regression analyses compared guselkumab 100 mg and ustekinumab 45 mg or 90 mg for the achievement and maintenance of Psoriasis Area and Severity Index (PASI) 90, 75 and 100 responses up to 40 weeks. The regression models accounted for a range of clinically relevant covariates (e.g. age, sex, psoriasis duration). Relative efficacy was expressed using odds ratios (ORs) and predicted probability of treatment response associated with each intervention.ResultsPatients receiving guselkumab had significantly higher probabilities of achieving a PASI 90 response than patients receiving ustekinumab, at both week 16 [70·4% vs. 46·0%, OR 2·79, 95% confidence interval (CI) 2·22-3·45] and week 40 (74·2% vs. 54·5%, OR 2·40, 95% CI 1·89-3·13]. Guselkumab was also associated with a significantly increased likelihood of achieving both PASI 75 and PASI 100 responses at weeks 16 and 40, compared with ustekinumab.ConclusionsAdjusted analyses leveraging IPD demonstrate that guselkumab has a significantly higher probability of achieving and maintaining PASI treatment responses through week 40 than ustekinumab does.
| S-EPMC7496582 | biostudies-literature
Project description:BACKGROUND:Obesity is a risk factor for colorectal cancer, yet metabolic distinctions between healthy right and left colon tissue, before cancer is diagnosed, remains largely unknown. This study compared right-ascending and left-descending colon tissue metabolomes to identify differences from the stool metabolome in normal weight, overweight, and obese adults. AIM:To examine right and left colon tissue metabolites according to body mass index that may serve as mechanistic targets for interventions and biomarkers for colon cancer risk. METHODS:Global, non-targeted metabolomics was applied to assess right-ascending and left-descending colon tissue collected from healthy adults undergoing screening colonoscopies to test the hypothesis that BMI differentially impacts colon tissue metabolite profiles. The colon tissue and stool metabolome of healthy adults (n = 24) was analyzed for metabolite signatures and metabolic pathway networks implicated in progression of colorectal cancer. RESULTS:Ascending and descending colon contained 504 host, food, and microbiota-derived metabolites from normal weight, overweight and obese adults grouped according to body mass index. Amino acids, lipids, and nucleotides were among the chemical types that further differentiated from the stool metabolite profiles. Normal weight adults had 46 significantly different metabolites between ascending and descending colon tissue locations, whereas there were 37 metabolite differences in overweight and 28 metabolite differences for obese adults (P < 0.05). Obese adults had trimethylamine N-oxide, endocannabinoids and monoacylglycerols with different relative abundances identified between ascending and descending colon. Primary and secondary bile acids, vitamins, and fatty acids also showed marked relative abundance differences in colon tissue from overweight/obese adults. CONCLUSION:There were metabolite profile differences between right-ascending and left-descending colon tissue in healthy adults. Colon lipids and other metabolites in obese and overweight adults were distinguished from normal weight participants and associated with gut inflammation, nutrient absorption, and products of microbiota metabolism.
| S-EPMC6969882 | biostudies-literature
Project description:BackgroundMothers and children in families with one immigrant parent have been reported to be healthier than those in native families; however, the health of the fathers in these families has rarely been discussed in literature.ObjectiveWe aimed to comprehensively compare the health of all the family members between families with one immigrant parent (native fathers, immigrant mothers, and their children) and native families (native fathers, native mothers, and their children).MethodsWe conducted a cohort study by using the Taiwan Maternal and Child Health Database to recruit live-born children and their parents from 2004 to 2016. Overall, we identified 90,670 fathers, 91,270 mothers, and 132,457 children in families with one immigrant parent and 1,666,775 fathers, 1,734,104 mothers, and 2,637,191 children in native families and followed up with them from 2004 to 2017. The outcomes comprised common physical and mental disorders, catastrophic illnesses, mortality, and child adversities and accidents. The covariates comprised the child's year of birth, parental age, low-income status, and physical or mental disorder status. Logistic regression was performed to compare the risks of the outcomes between families with one immigrant parent and native families.ResultsThe parents in families with one immigrant parent were more likely to be of low-income status and were older than the parents in native families. After adjusting for the covariates, fathers in families with one immigrant parent were found to have higher risks of physical and mental disorders, catastrophic illness, and mortality than fathers in native families. Conversely, mothers in families with one immigrant parent had lower risks of physical and mental disorders, catastrophic illness, and mortality than mothers in native families. Finally, the children in families with one immigrant parent generally had better physical and mental health but higher risks for leukemia, liver diseases, autism spectrum disorder, and road traffic accidents than children in native families.ConclusionsThe health status of the members of families with one immigrant parent was nonhomogeneous, and the poorer general health of fathers in such families suggests health inequalities in families with one immigrant parent.
| S-EPMC9808584 | biostudies-literature
Project description:PurposeThe ChicagO Multiethnic Prevention and Surveillance Study or 'COMPASS' is a population-based cohort study with a goal to examine the risk and determinants of cancer and chronic disease. COMPASS aims to address factors causing and/or exacerbating health disparities using a precision health approach by recruiting diverse participants in Chicago, with an emphasis on those historically underrepresented in biomedical research.ParticipantsNearly 8000 participants have been recruited from 72 of the 77 Chicago community areas. Enrolment entails the completion of a 1-hour long survey, consenting for past and future medical records from all sources, the collection of clinical and physical measurement data and the on-site collection of biological samples including blood, urine and saliva. Indoor air monitoring data and stool samples are being collected from a subset of participants. On collection, all biological samples are processed and aliquoted within 24 hours before long-term storage and subsequent analysis.Findings to dateThe cohort reported an average age of 53.7 years, while 80.5% identified as African-American, 5.7% as Hispanic and 47.8% as men. Over 50% reported earning less than US$15 000 yearly, 35% were obese and 47.8% were current smokers. Moreover, 38% self-reported having had a diagnosis of hypertension, while 66.4% were measured as hypertensive at enrolment.Future plansWe plan to expand recruitment up to 100 000 participants from the Chicago metropolitan area in the next decade using a hybrid community and clinic-based recruitment framework that incorporates data collection through mobile medical units. Follow-up data collection from current cohort members will include serial samples, as well as longitudinal health, lifestyle and behavioural assessment. We will supplement self-reported data with electronic medical records, expand the collection of biometrics and biosamples to facilitate increasing digital epidemiological study designs and link to state and/or national level databases to ascertain outcomes. The results and findings will inform potential opportunities for precision disease prevention and mitigation in Chicago and other urban areas with a diverse population.RegistrationNA.
| S-EPMC7497521 | biostudies-literature
Project description:Three helicase structures have been determined recently: that of the DNA helicase PcrA, that of the hepatitis C virus RNA helicase, and that of the Escherichia coli DNA helicase Rep. PcrA and Rep belong to the same super-family of helicases (SF1) and are structurally very similar. In contrast, the HCV helicase belongs to a different super-family of helicases, SF2, and shows little sequence homology with the PcrA/Rep helicases. Yet, the HCV helicase is structurally similar to Rep/PcrA, suggesting preservation of structural scaffolds and relationships between helicase motifs across these two super-families. The comparison study presented here also reveals the existence of a new helicase motif in the SF1 family of helicases.
| S-EPMC2143965 | biostudies-other
Project description:Using a recently developed approach for testing endocrine disruptive chemicals (EDCs) in amphibians, comprising synchronized tadpole exposure plus genetic and histological sexing of metamorphs in a flow-through-system, we tested the effects of 17?-Trenbolone (Tb), a widely used growth promoter in cattle farming, in three deeply diverged anuran families: the amphibian model species Xenopus laevis (Pipidae) and the non-models Bufo(tes) viridis (Bufonidae) and Hyla arborea (Hylidae). Trenbolone was applied in three environmentally and/or physiologically relevant concentrations (0.027?µg/L (10-10?M), 0.27?µg/L (10-9?M), 2.7?µg/L (10-8?M)). In none of the species, Tb caused sex reversals or masculinization of gonads but had negative species-specific impacts on gonad morphology and differentiation after the completion of metamorphosis, independently of genetic sex. In H. arborea and B. viridis, mounting Tb-concentration correlated positively with anatomical abnormalities at 27?µg/L (10-9?M) and 2.7?µg/L (10-8?M), occurring in X. laevis only at the highest Tb concentration. Despite anatomical aberrations, histologically all gonadal tissues differentiated seemingly normally when examined at the histological level but at various rates. Tb-concentration caused various species-specific mortalities (low in Xenopus, uncertain in Bufo). Our data suggest that deep phylogenetic divergence modifies EDC-vulnerability, as previously demonstrated for Bisphenol A (BPA) and Ethinylestradiol (EE2).
| S-EPMC6610071 | biostudies-literature
Project description:ALS results from the selective and progressive degeneration of motor neurons. Although the underlying disease mechanisms remain unknown, glial cells have been implicated in ALS disease progression. Here, we examine the effects of glial cell/motor neuron interactions on gene expression using the hSOD1(G93A) (the G93A allele of the human superoxide dismutase gene) mouse model of ALS. We detect striking cell autonomous and nonautonomous changes in gene expression in cocultured motor neurons and glia, revealing that the two cell types profoundly affect each other. In addition, we found a remarkable concordance between the cell culture data and expression profiles of whole spinal cords and acutely isolated spinal cord cells during disease progression in the G93A mouse model, providing validation of the cell culture approach. Bioinformatics analyses identified changes in the expression of specific genes and signaling pathways that may contribute to motor neuron degeneration in ALS, among which are TGF-β signaling pathways.
| S-EPMC3581928 | biostudies-literature
Project description:Polypharmacology is often a key contributor to the efficacy of a drug, but is also a potential risk. We investigated two hits discovered via a cell-based phenotypic screen, the CDK9 inhibitor CCT250006 (1) and the pirin ligand CCT245232 (2), to establish methodology to elucidate their secondary protein targets. Using computational pocket-based analysis, we discovered intrafamily polypharmacology for our kinase inhibitor, despite little overall sequence identity. The interfamily polypharmacology of 2 with B-Raf was used to discover a novel pirin ligand from a very small but privileged compound library despite no apparent ligand or binding site similarity. Our data demonstrates that in areas of drug discovery where intrafamily polypharmacology is often an issue, ligand dissimilarity cannot necessarily be used to assume different off-target profiles and that understanding interfamily polypharmacology will be important in the future to reduce the risk of idiopathic toxicity and in the design of screening libraries.
| S-EPMC6295861 | biostudies-literature
Project description:Group I chaperonins are large cylindrical-shaped nano-machines that function as a central hub in the protein quality control system in the bacterial cytosol, mitochondria and chloroplasts. In chloroplasts, proteins newly synthesized by chloroplast ribosomes, unfolded by diverse stresses, or translocated from the cytosol run the risk of aberrant folding and aggregation. The chloroplast chaperonin system assists these proteins in folding into their native states. A widely known protein folded by chloroplast chaperonin is the large subunit of ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco), an enzyme responsible for the fixation of inorganic CO2 into organic carbohydrates during photosynthesis. Chloroplast chaperonin was initially identified as a Rubisco-binding protein. All photosynthetic eucaryotes genomes encode multiple chaperonin genes which can be divided into ? and ? subtypes. Unlike the homo-oligomeric chaperonins from bacteria and mitochondria, chloroplast chaperonins are more complex and exists as intricate hetero-oligomers containing both subtypes. The Group I chaperonin requires proper interaction with a detachable lid-like co-chaperonin in the presence of ATP and Mg2+ for substrate encapsulation and conformational transition. Besides the typical Cpn10-like co-chaperonin, a unique co-chaperonin consisting of two tandem Cpn10-like domains joined head-to-tail exists in chloroplasts. Since chloroplasts were proposed as sensors to various environmental stresses, this diversified chloroplast chaperonin system has the potential to adapt to complex conditions by accommodating specific substrates or through regulation at both the transcriptional and post-translational levels. In this review, we discuss recent progress on the unique structure and function of the chloroplast chaperonin system based on model organisms Chlamydomonas reinhardtii and Arabidopsis thaliana. Knowledge of the chloroplast chaperonin system may ultimately lead to successful reconstitution of eukaryotic Rubisco in vitro.
| S-EPMC5780408 | biostudies-literature