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Protein language models have been tested and proved to be reliable when used on curated datasets but have not yet been applied to full proteomes. Accordingly, we tested how two different machine learning-based methods performed when decoding functional information from the proteomes of selected model organisms. We found that protein language models are more precise and informative than deep learning methods for all the species tested and across the three gene ontologies studied, and that they better recover functional information from transcriptomic experiments. The results obtained indicate that these language models are likely to be suitable for large-scale annotation and downstream analyses, and we recommend a guide for their use., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. We identify four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work illustrates the unique flexibility of GR's LBD and suggests different dimeric conformations within cells. In addition, we unveil pathophysiologically relevant quaternary assemblies of the receptor with important implications for glucocorticoid action and drug design., (Published by Oxford University Press on behalf of Nucleic Acids Research 2022.)

Polycyclic triterpenes are members of the terpene family produced by the cyclization of squalene. The most representative polycyclic triterpenes are hopanoids and sterols, the former are mostly found in bacteria, whereas the latter are largely limited to eukaryotes, albeit with a growing number of bacterial exceptions. Given their important role and omnipresence in most eukaryotes, contrasting with their scant representation in bacteria, sterol biosynthesis was long thought to be a eukaryotic innovation. Thus, their presence in some bacteria was deemed to be the result of lateral gene transfer from eukaryotes. Elucidating the origin and evolution of the polycyclic triterpene synthetic pathways is important to understand the role of these compounds in eukaryogenesis and their geobiological value as biomarkers in fossil records. Here, we have revisited the phylogenies of the main enzymes involved in triterpene synthesis, performing gene neighborhood analysis and phylogenetic profiling. Squalene can be biosynthesized by two different pathways containing the HpnCDE or Sqs proteins. Our results suggest that the HpnCDE enzymes are derived from carotenoid biosynthesis ones and that they assembled in an ancestral squalene pathway in bacteria, while remaining metabolically versatile. Conversely, the Sqs enzyme is prone to be involved in lateral gene transfer, and its emergence is possibly related to the specialization of squalene biosynthesis. The biosynthesis of hopanoids seems to be ancestral in the Bacteria domain. Moreover, no triterpene cyclases are found in Archaea, invoking a potential scenario in which eukaryotic genes for sterol biosynthesis assembled from ancestral bacterial contributions in early eukaryotic lineages., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

The DNA damage response (DDR) is a crucial signaling network that preserves the integrity of the genome. This network is an ensemble of distinct but often overlapping subnetworks, where different components fulfill distinct functions in precise spatial and temporal scenarios. To understand how these elements have been assembled together in humans, we performed comparative genomic analyses in 47 selected species to trace back their emergence using systematic phylogenetic analyses and estimated gene ages. The emergence of the contribution of posttranslational modifications to the complex regulation of DDR was also investigated. This is the first time a systematic analysis has focused on the evolution of DDR subnetworks as a whole. Our results indicate that a DDR core, mostly constructed around metabolic activities, appeared soon after the emergence of eukaryotes, and that additional regulatory capacities appeared later through complex evolutionary process. Potential key posttranslational modifications were also in place then, with interacting pairs preferentially appearing at the same evolutionary time, although modifications often led to the subsequent acquisition of new targets afterwards. We also found extensive gene loss in essential modules of the regulatory network in fungi, plants, and arthropods, important for their validation as model organisms for DDR studies.

The implantation process begins with attachment of the trophectoderm (TE) of the blastocyst to the maternal endometrial epithelium. Herein we have investigated the transcriptome of mural TE cells from 13 human blastocysts and compared these with those of human embryonic stem cell (hESC)-derived-TE (hESC(troph)). The transcriptomes of hESC(troph) at Days 8, 10, and 12 had the greatest consistency with TE. Among genes coding for secreted proteins of the TE of human blastocysts and of hESC(troph) are several molecules known to be involved in the implantation process, as well as novel ones, such as CXCL12, HBEGF, inhibin A, DKK3, WNT5A, and follistatin. The similarities between the two lineages underscore some of the known mechanisms and offer discovery of new mechanisms and players in the process of the very early stages of human implantation. We propose that the hESC(troph) is a viable functional model of human trophoblasts to study trophoblast-endometrial interactions. Furthermore, the data derived herein offer the promise of novel diagnostics and therapeutics aimed at practical challenges in human infertility and pregnancy disorders associated with abnormal embryonic implantation.

There is a huge quantity of information generated in Life Sciences, and it is dispersed in many databases and repositories. Despite the broad availability of the information, there is a great demand for methods that are able to look for, gather and display distributed data in a standardized and friendly way. CARGO (Cancer And Related Genes Online) is a configurable biological web portal designed as a tool to facilitate, integrate and visualize results from Internet resources, independently of their native format or access method. Through the use of small agents, called widgets, supported by a Rich Internet Application (RIA) paradigm based on AJAX, CARGO provides pieces of minimal, relevant and descriptive biological information. The tool is designed to be used by experimental biologists with no training in bioinformatics. In the current state, the system presents a list of human cancer genes. Available at http://cargo.bioinfo.cnio.es.

The TreeDet (Tree Determinant) Server is the first release of a system designed to integrate results from methods that predict functional sites in protein families. These methods take into account the relation between sequence conservation and evolutionary importance. TreeDet fully analyses the space of protein sequences in either user-uploaded or automatically generated multiple sequence alignments. The methods implemented in the server represent three main classes of methods for the detection of family-dependent conserved positions, a tree-based method, a correlation based method and a method that employs a principal component analyses coupled to a cluster algorithm. An additional method is provided to highlight the reliability of the position in the alignments. The server is available at http://www.pdg.cnb.uam.es/servers/treedet.

Solving relevant biological problems requires answering complex questions. Addressing such questions traditionally implied the design of time-consuming experimental procedures which most of the time are not accessible to average-sized laboratories. The current trend is to move towards a multidisciplinary approach integrating both theoretical knowledge and experimental work. This combination creates a powerful tool for shedding light on biological problems. To illustrate this concept, we present here a descriptive example of where computational methods were shown to be a key aspect in detecting crucial players in an important biological problem: the dimerization of chemokine receptors. Using evolutionary based sequence analysis in combination with structural predictions two CCR5 residues were selected as important for dimerization and further validated experimentally. The experimental validation of computational procedures demonstrated here provides a wealth of valuable information not obtainable by any of the individual approaches alone.

Aims: To establish a typing method for tracing the epidemic relationship of 16 strains of Salmonella serotype Havana isolated from captive raptors showing no symptomatology and residing in a wildlife hospital in Spain., Methods and Results: Antimicrobial susceptibility testing, ribotyping, pulsed field gel electrophoresis (PFGE) and amplified fragment length polymorphism (AFLP) methodology were applied. Ten unrelated strains of serotype Havana were included as a control group to provide a basis of for the efficiency of the different markers used. All outbreak-related strains were resistant to nalidixic acid and streptomycin and showed the same ripotype, pulsotype and AFLP pattern., Conclusions: This is the first time that AFLP analysis has been tested with serotype Havana isolates and it has demonstrated to be the most useful epidemiological tool for discriminating between unrelated and outbreak-related strains of this serotype. The results obtained suggest that all the Salmonella serotype Havana isolates represented a common outbreak strain whose origin of contamination could not be established although it is thought that it was the poultry meat used for raptors'diet., Significance and Impact of the Study: Our study suggests the importance of microbiological analysis of these products in order to prevent contamination and dissemination of Salmonellae in this kind of Hospital.

Eosinophils appear in the rat uterus in the presence of estrogen. The level of these cells in the uterus depends on the number of blood eosinophils. Insulin is an eosinopenic hormone in the blood and, therefore, could regulate estrogenic responses mediated by these cells in the uterus. Estrogen-induced uterine edema and eosinophilia at doses of 0.01,. 0.1, 1, 10, and 30 micrograms 17 beta-estradiol (E2)/100 g BW are inhibited by insulin. Estrogen binding by uterine eosinophils in vitro decreases in the presence of insulin, suggesting another explanation for the observations in the uterus in vivo. Injection of insulin alone or in combination with 0.01, 0.01, 0.1, or 1 microgram E2/100 g BW increases uterine RNA and protein contents by 6 h. Inactive insulin does not modify any of these stimulatory effects of estrogen. The results support the idea of two separate receptor systems for estrogens in the rat uterus: the eosinophil receptor system, which mediates estrogen-induced uterine edema, and the cytosol-nuclear receptor system, which mediates estrogen-induced uterine RNA and protein syntheses.

Uterine edema induced by 0.1 microgram 17 beta-estradiol (E2)/100 g BW, as well as uterine eosinophilia induced by 0.01, 0.1, 1, 10, and 30 micrograms E2/100 g BW, decrease in the presence of 20 micrograms T3 or T4/100 g BW in the immature rat. Estrogen binding by uterine eosinophils and the number of eosinophils in the blood also decrease with T3 or T4, suggesting an explanation for the findings in the uterus. Thyroid hormones alone or in the presence of 0.001, 0.01, 0.1 and 1 microgram E2/100 g BW, increase the uterine RNA content 7 h after administration compared with the same doses of E2 alone. This response is not associated with any further increase in the urine protein content. The results show a dissociation between the effects of estrogen on RNA or protein levels, which are decreased by thyroid hormones, and some early estrogenic responses (uterine edema and eosinophilia), which are decreased by thyroid hormones.