Beyond the frog: the evolution of homology models of human IKK?.
Ontology highlight
ABSTRACT:
SUBMITTER: Palermo NY
PROVIDER: S-EPMC3177977 | biostudies-literature | 2011 Oct
REPOSITORIES: biostudies-literature
Publications
Beyond the frog: the evolution of homology models of human IKKβ.
Palermo Nicholas Y NY Natarajan Amarnath A
Bioorganic & medicinal chemistry letters 20110819 20
Nuclear Factor κ B is implicated in tumor progression and chronic inflammatory diseases and is regulated by IκB kinase β (IKKβ). The crystal structure of IKKβ has been recently solved for Xenopus laevis. Homology models of human IKKβ have been developed prior to and after the crystal structure was solved. Here, we compare four models of human IKKβ and evaluate their performance in both broad and focused library docking studies. ...[more]
Similar Datasets
Project description:Structured cis-regulatory RNAs have evolved across all domains of life, highlighting the utility and plasticity of RNA as a regulatory molecule. Homologous RNA sequences and structures often have similar functions, but homology may also be deceiving. The challenges that derive from trying to assign function to structure and vice versa are not trivial. Bacterial riboswitches, viral and eukaryotic IRESes, CITEs, and 3' UTR elements employ an array of mechanisms to exert their effects. Bioinformatic searches coupled with biochemical and functional validation have elucidated some shared and many unique ways cis-regulators are employed in mRNA transcripts. As cis-regulatory RNAs are resolved in greater detail, it is increasingly apparent that shared homology can mask the full spectrum of mRNA cis-regulator functional diversity. Furthermore, similar functions may be obscured by lack of obvious sequence similarity. Thus looking beyond homology is crucial for furthering our understanding of RNA-based regulation.
| S-EPMC7609027 | biostudies-literature
Project description:Advances in bioacoustic technology, such as the use of automatic recording devices, allow wildlife monitoring at large spatial scales. However, such technology can produce enormous amounts of audio data that must be processed and analyzed. One potential solution to this problem is the use of automated sound recognition tools, but we lack a general framework for developing and validating these tools. Recognizers are computer models of an animal sound assembled from "training data" (i.e., actual samples of vocalizations). The settings of variables used to create recognizers can impact performance, and the use of different settings can result in large differences in error rates that can be exploited for different monitoring objectives. We used Song Scope (Wildlife Acoustics Inc.) to build recognizers and vocalizations of the wood frog (Lithobates sylvaticus) to test how different settings and amounts of training data influence recognizer performance. Performance was evaluated using precision (the probability of a recognizer match being a true match) and sensitivity (the proportion of vocalizations detected) based on a receiver operating characteristic (ROC) curve-determined score threshold. Evaluations were conducted using recordings not used to build the recognizer. Wood frog recognizer performance was sensitive to setting changes in four out of nine variables, and small improvements were achieved by using additional training data from different sites and from the same recording, but not from different recordings from the same site. Overall, the effect of changes to variable settings was much greater than the effect of increasing training data. Additionally, by testing the performance of the recognizer on vocalizations not used to build the recognizer, we discovered that Type I error rates appear idiosyncratic and do not recommend extrapolation from training to new data, whereas Type II errors showed more consistency and extrapolation can be justified. Optimizing variable settings on independent recordings led to a better match between recognizer performance and monitoring objectives. We provide general recommendations for application of this methodology with other species and make some suggestions for improvements.
| S-EPMC5415519 | biostudies-literature
Project description:Bcl-2 family proteins regulate apoptosis in animals. This protein family includes several homologous proteins and a collection of other proteins lacking sequence similarity except for a Bcl-2 homology (BH)3 motif. Thus, membership in the Bcl-2 family requires only one of the four BH motifs. On this basis, a growing number of diverse BH3-only proteins are being reported. Although compelling cell biological and biophysical evidence validates many BH3-only proteins, claims of significant BH3 sequence similarity are often unfounded. Computational and phylogenetic analyses suggest that only some BH3 motifs arose by divergent evolution from a common ancestor (homology), whereas others arose by convergent evolution or random coincidence (homoplasy), challenging current assumptions about which proteins constitute the extended Bcl-2 family.
| S-EPMC3582728 | biostudies-literature
Project description:Claudins are transmembrane proteins constituting one of three tight junction protein families. In patients with inflammatory bowel disease (IBD), disease activity-dependent changes in expression of certain claudins have been noted, thus making certain claudin family members potential therapy targets. A study was undertaken with the aim of exploring expression of claudins in human disease and two different animal models of IBD: dextrane sulfate sodium-induced colitis and adoptive transfer model of colitis. The expression of sealing claudin-1, claudin-3, claudin-4, and claudin-8, and pore-forming claudin-2 in humans and rodents has been evaluated by immunohistochemistry and quantitative polymerase chain reaction. Claudins were expressed by epithelial and cells of mesodermal origin and were found to be situated at the membrane, within the cytoplasm, or within the nuclei. Claudin expression by human mononuclear cells isolated from lamina propria has been confirmed by Western blot and flow cytometry. The claudin expression pattern in uninflamed and inflamed colon varied between species and murine strains. In IBD and both animal models, diverse alterations in claudin expression by epithelial and inflammatory cells were recorded. Tissue mRNA levels for each studied claudin reflected changes within cell lineage and, at the same time, mirrored the ratio between various cell types. Based on the results of the study, it can be concluded that 1) claudins are not expressed exclusively by epithelial cells, but by certain types of cells of mesodermal origin as well; 2) changes in the claudin mRNA level should be interpreted in the context of overall tissue alterations; and 3) both IBD animal models that were analyzed can be used for investigating claudins as a therapy target, respecting their similarities and differences highlighted in this study.
| S-EPMC8635807 | biostudies-literature
Project description:Finite element human body models (HBMs) are becoming increasingly important numerical tools for traffic safety. Developing a validated and reliable HBM from the start requires integrated efforts and continues to be a challenging task. Mesh morphing is an efficient technique to generate personalized HBMs accounting for individual anatomy once a baseline model has been developed. This study presents a new image registration-based mesh morphing method to generate personalized HBMs. The method is demonstrated by morphing four baseline HBMs (SAFER, THUMS, and VIVA+ in both seated and standing postures) into ten subjects with varying heights, body mass indices (BMIs), and sex. The resulting personalized HBMs show comparable element quality to the baseline models. This method enables the comparison of HBMs by morphing them into the same subject, eliminating geometric differences. The method also shows superior geometry correction capabilities, which facilitates converting a seated HBM to a standing one, combined with additional positioning tools. Furthermore, this method can be extended to personalize other models, and the feasibility of morphing vehicle models has been illustrated. In conclusion, this new image registration-based mesh morphing method allows rapid and robust personalization of HBMs, facilitating personalized simulations.
| S-EPMC10236199 | biostudies-literature
Project description:Knowing protein function is crucial to advance molecular and medical biology, yet experimental function annotations through the Gene Ontology (GO) exist for fewer than 0.5% of all known proteins. Computational methods bridge this sequence-annotation gap typically through homology-based annotation transfer by identifying sequence-similar proteins with known function or through prediction methods using evolutionary information. Here, we propose predicting GO terms through annotation transfer based on proximity of proteins in the SeqVec embedding rather than in sequence space. These embeddings originate from deep learned language models (LMs) for protein sequences (SeqVec) transferring the knowledge gained from predicting the next amino acid in 33 million protein sequences. Replicating the conditions of CAFA3, our method reaches an Fmax of 37 ± 2%, 50 ± 3%, and 57 ± 2% for BPO, MFO, and CCO, respectively. Numerically, this appears close to the top ten CAFA3 methods. When restricting the annotation transfer to proteins with < 20% pairwise sequence identity to the query, performance drops (Fmax BPO 33 ± 2%, MFO 43 ± 3%, CCO 53 ± 2%); this still outperforms naïve sequence-based transfer. Preliminary results from CAFA4 appear to confirm these findings. Overall, this new concept is likely to change the annotation of proteins, in particular for proteins from smaller families or proteins with intrinsically disordered regions.
| S-EPMC7806674 | biostudies-literature
Project description:Mouse models, including patient-derived xenograft mice, are widely used to address questions in cancer research. However, there are documented flaws in these models that can result in the misrepresentation of human tumour biology and limit the suitability of the model for translational research. A coordinated effort to promote the more widespread development and use of 'non-animal human tissue' models could provide a clinically relevant platform for many cancer studies, maximising the opportunities presented by human tissue resources such as biobanks. A number of key factors limit the wide adoption of non-animal human tissue models in cancer research, including deficiencies in the infrastructure and the technical tools required to collect, transport, store and maintain human tissue for lab use. Another obstacle is the long-standing cultural reliance on animal models, which can make researchers resistant to change, often because of concerns about historical data compatibility and losing ground in a competitive environment while new approaches are embedded in lab practice. There are a wide range of initiatives that aim to address these issues by facilitating data sharing and promoting collaborations between organisations and researchers who work with human tissue. The importance of coordinating biobanks and introducing quality standards is gaining momentum. There is an exciting opportunity to transform cancer drug discovery by optimising the use of human tissue and reducing the reliance on potentially less predictive animal models.
| S-EPMC5560067 | biostudies-other
Project description:To explore the origins and consequences of tetraploidy in the African clawed frog, we sequenced the Xenopus laevis genome and compared it to the related diploid X. tropicalis genome. We characterize the allotetraploid origin of X. laevis by partitioning its genome into two homoeologous subgenomes, marked by distinct families of 'fossil' transposable elements. On the basis of the activity of these elements and the age of hundreds of unitary pseudogenes, we estimate that the two diploid progenitor species diverged around 34 million years ago (Ma) and combined to form an allotetraploid around 17-18 Ma. More than 56% of all genes were retained in two homoeologous copies. Protein function, gene expression, and the amount of conserved flanking sequence all correlate with retention rates. The subgenomes have evolved asymmetrically, with one chromosome set more often preserving the ancestral state and the other experiencing more gene loss, deletion, rearrangement, and reduced gene expression.
| S-EPMC5313049 | biostudies-literature
Project description:The genetic variation of our species reflects human demographic history and adaptation to diverse local environments. Part of this genetic variation affects individual responses to exogenous substances, such as food, pollutants and drugs, and plays an important role in drug efficacy and safety. This review provides a synthesis of the evolution of loci implicated in human pharmacological response and metabolism, interpreted within the theoretical framework of population genetics and molecular evolution. In particular, I review and discuss key evolutionary aspects of different pharmacogenes in humans and other species, such as the relationship between the type of substrates and rate of evolution; the selective pressure exerted by landscape variables or dietary habits; expected and observed patterns of rare genetic variation. Finally, I discuss how this knowledge can be translated directly or after the implementation of specific studies, into practical guidelines.
| S-EPMC6834052 | biostudies-literature
Project description:An appropriate model of recent human evolution is not only important to understand our own history, but it is necessary to disentangle the effects of demography and selection on genome diversity. Although most genetic data support the view that our species originated recently in Africa, it is still unclear if it completely replaced former members of the Homo genus, or if some interbreeding occurred during its range expansion. Several scenarios of modern human evolution have been proposed on the basis of molecular and paleontological data, but their likelihood has never been statistically assessed. Using DNA data from 50 nuclear loci sequenced in African, Asian and Native American samples, we show here by extensive simulations that a simple African replacement model with exponential growth has a higher probability (78%) as compared with alternative multiregional evolution or assimilation scenarios. A Bayesian analysis of the data under this best supported model points to an origin of our species approximately 141 thousand years ago (Kya), an exit out-of-Africa approximately 51 Kya, and a recent colonization of the Americas approximately 10.5 Kya. We also find that the African replacement model explains not only the shallow ancestry of mtDNA or Y-chromosomes but also the occurrence of deep lineages at some autosomal loci, which has been formerly interpreted as a sign of interbreeding with Homo erectus.
| S-EPMC2077041 | biostudies-literature