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Briefings in Bioinformatics Mar 2022A transcriptome constructed from short-read RNA sequencing (RNA-seq) is an easily attainable proxy catalog of protein-coding genes when genome assembly is unnecessary,... (Review)
Review
A transcriptome constructed from short-read RNA sequencing (RNA-seq) is an easily attainable proxy catalog of protein-coding genes when genome assembly is unnecessary, expensive or difficult. In the absence of a sequenced genome to guide the reconstruction process, the transcriptome must be assembled de novo using only the information available in the RNA-seq reads. Subsequently, the sequences must be annotated in order to identify sequence-intrinsic and evolutionary features in them (for example, protein-coding regions). Although straightforward at first glance, de novo transcriptome assembly and annotation can quickly prove to be challenging undertakings. In addition to familiarizing themselves with the conceptual and technical intricacies of the tasks at hand and the numerous pre- and post-processing steps involved, those interested must also grapple with an overwhelmingly large choice of tools. The lack of standardized workflows, fast pace of development of new tools and techniques and paucity of authoritative literature have served to exacerbate the difficulty of the task even further. Here, we present a comprehensive overview of de novo transcriptome assembly and annotation. We discuss the procedures involved, including pre- and post-processing steps, and present a compendium of corresponding tools.
Topics: Genome; High-Throughput Nucleotide Sequencing; Molecular Sequence Annotation; Sequence Analysis, RNA; Transcriptome; Workflow
PubMed: 35076693
DOI: 10.1093/bib/bbab563 -
Nature Reviews. Chemistry Jan 2022Natural metalloproteins perform many functions - ranging from sensing to electron transfer and catalysis - in which the position and property of each ligand and metal,...
Natural metalloproteins perform many functions - ranging from sensing to electron transfer and catalysis - in which the position and property of each ligand and metal, is dictated by protein structure. De novo protein design aims to define an amino acid sequence that encodes a specific structure and function, providing a critical test of the hypothetical inner workings of (metallo)proteins. To date, de novo metalloproteins have used simple, symmetric tertiary structures - uncomplicated by the large size and evolutionary marks of natural proteins - to interrogate structure-function hypotheses. In this Review, we discuss de novo design applications, such as proteins that induce complex, increasingly asymmetric ligand geometries to achieve function, as well as the use of more canonical ligand geometries to achieve stability. De novo design has been used to explore how proteins fine-tune redox potentials and catalyse both oxidative and hydrolytic reactions. With an increased understanding of structure-function relationships, functional proteins including O-dependent oxidases, fast hydrolases, and multi-proton/multi-electron reductases, have been created. In addition, proteins can now be designed using xeno-biological metals or cofactors and principles from inorganic chemistry to derive new-to-nature functions. These results and the advances in computational protein design suggest a bright future for the de novo design of diverse, functional metalloproteins.
PubMed: 35811759
DOI: 10.1038/s41570-021-00339-5 -
Frontiers in Genetics 2022Mosaicism-the existence of genetically distinct populations of cells in a particular organism-is an important cause of genetic disease. Mosaicism can appear as DNA... (Review)
Review
Mosaicism-the existence of genetically distinct populations of cells in a particular organism-is an important cause of genetic disease. Mosaicism can appear as DNA mutations, epigenetic alterations of DNA, and chromosomal abnormalities. Neurodevelopmental or neuropsychiatric diseases, including autism-often arise by mutations that usually not present in either of the parents. mutations might occur as early as in the parental germline, during embryonic, fetal development, and/or post-natally, through ageing and life. Mutation timing could lead to mutation burden of less than heterozygosity to approaching homozygosity. Developmental timing of somatic mutation attainment will affect the mutation load and distribution throughout the body. In this review, we discuss the timing of mutations, spanning from mutations in the germ lineage (all ages), to post-zygotic, embryonic, fetal, and post-natal events, through aging to death. These factors can determine the tissue specific distribution and load of mutations, which can affect disease. The disease threshold burden of somatic mutations of a particular gene in any tissue will be important to define.
PubMed: 36226191
DOI: 10.3389/fgene.2022.983668 -
Drug Discovery Today Nov 2021Molecular design strategies are integral to therapeutic progress in drug discovery. Computational approaches for de novo molecular design have been developed over the... (Review)
Review
Molecular design strategies are integral to therapeutic progress in drug discovery. Computational approaches for de novo molecular design have been developed over the past three decades and, recently, thanks in part to advances in machine learning (ML) and artificial intelligence (AI), the drug discovery field has gained practical experience. Here, we review these learnings and present de novo approaches according to the coarseness of their molecular representation: that is, whether molecular design is modeled on an atom-based, fragment-based, or reaction-based paradigm. Furthermore, we emphasize the value of strong benchmarks, describe the main challenges to using these methods in practice, and provide a viewpoint on further opportunities for exploration and challenges to be tackled in the upcoming years.
Topics: Artificial Intelligence; Computer Simulation; Drug Design; Drug Discovery; Drug Evaluation, Preclinical; Humans; Machine Learning; Workflow
PubMed: 34082136
DOI: 10.1016/j.drudis.2021.05.019 -
Genes & Diseases Nov 2023nucleotide biosynthetic pathway is a highly conserved and essential biochemical pathway in almost all organisms. Both purine nucleotides and pyrimidine nucleotides are... (Review)
Review
nucleotide biosynthetic pathway is a highly conserved and essential biochemical pathway in almost all organisms. Both purine nucleotides and pyrimidine nucleotides are necessary for cell metabolism and proliferation. Thus, the dysregulation of the nucleotide biosynthetic pathway contributes to the development of many human diseases, such as cancer. It has been shown that many enzymes in this pathway are overactivated in different cancers. In this review, we summarize and update the current knowledge on the nucleotide biosynthetic pathway, regulatory mechanisms, its role in tumorigenesis, and potential targeting opportunities.
PubMed: 37554216
DOI: 10.1016/j.gendis.2022.04.018 -
Epigenomes Aug 2022Every cell of an organism shares the same genome; even so, each cellular lineage owns a different transcriptome and proteome. The Polycomb group proteins (PcG) are... (Review)
Review
Every cell of an organism shares the same genome; even so, each cellular lineage owns a different transcriptome and proteome. The Polycomb group proteins (PcG) are essential regulators of gene repression patterning during development and homeostasis. However, it is unknown how the repressive complexes, PRC1 and PRC2, identify their targets and elicit new Polycomb domains during cell differentiation. Classical recruitment models consider the pre-existence of repressive histone marks; still, target binding overcomes the absence of both H3K27me3 and H2AK119ub. The CpG islands (CGIs), non-core proteins, and RNA molecules are involved in Polycomb recruitment. Nonetheless, it is unclear how targets are identified depending on the physiological context and developmental stage and which are the leading players stabilizing Polycomb complexes at domain nucleation sites. Here, we examine the features of sites and the accessory elements bridging its recruitment and discuss the first steps of Polycomb domain formation and transcriptional regulation, comprehended by the experimental reconstruction of the repressive domains through time-resolved genomic analyses in mammals.
PubMed: 35997371
DOI: 10.3390/epigenomes6030025 -
The New Phytologist Jun 2018Contents Summary 1334 I. Introduction 1334 II. Regeneration-initial cell: the origin of regeneration 1335 III. Acquiring regeneration competency: the essential... (Review)
Review
Contents Summary 1334 I. Introduction 1334 II. Regeneration-initial cell: the origin of regeneration 1335 III. Acquiring regeneration competency: the essential intermediate step for hormone-induced regeneration 1335 IV. Hormonal induction of stem cell regulators: the program for de novo establishment of apical meristems 1337 V. Conclusions and perspectives 1337 Acknowledgements 1338 Author contributions 1338 References 1338 SUMMARY: High cellular plasticity confers remarkable regeneration capacity to plants. Based on the activity of stem cells and their regulators, higher plants are capable of regenerating new individuals. De novo organogenesis exemplifies the regeneration of the whole plant body and is exploited widely in agriculture and biotechnology. In this Tansley insight article, we summarize recent advances that facilitate our understanding of the molecular mechanisms underlying de novo organogenesis. According to our current knowledge, this process can be divided into three steps, including activation of regeneration-initial cells, acquisition of competency and de novo establishment of apical meristems. The functions of stem cells and their regulators are critical to de novo organogenesis, whereas auxin and cytokinin act as triggers and linkers between different steps.
Topics: Meristem; Organogenesis; Plant Cells; Plant Growth Regulators; Regeneration; Stem Cells
PubMed: 29574802
DOI: 10.1111/nph.15106 -
Frontiers in Cell and Developmental... 2022In cycling cells, new centrioles are assembled in the vicinity of pre-existing centrioles. Although this canonical centriole duplication is a tightly regulated process... (Review)
Review
In cycling cells, new centrioles are assembled in the vicinity of pre-existing centrioles. Although this canonical centriole duplication is a tightly regulated process in animal cells, centrioles can also form in the absence of pre-existing centrioles; this process is termed centriole formation. centriole formation is triggered by the removal of all pre-existing centrioles in the cell in various manners. Moreover, overexpression of polo-like kinase 4 (Plk4), a master regulatory kinase for centriole biogenesis, can induce centriole formation in some cell types. Under these conditions, structurally and functionally normal centrioles can be formed . While centriole formation is normally suppressed in cells with intact centrioles, depletion of certain suppressor proteins leads to the ectopic formation of centriole-related protein aggregates in the cytoplasm. It has been shown that centriole formation also occurs naturally in some species. For instance, during the multiciliogenesis of vertebrate epithelial cells, massive centriole amplification occurs to form numerous motile cilia. In this review, we summarize the previous findings on centriole formation, particularly under experimental conditions, and discuss its regulatory mechanisms.
PubMed: 35445021
DOI: 10.3389/fcell.2022.861864 -
Frontiers in Immunology 2019The prevalence, pathogenesis, predictors, and natural course of patients with recurrent glomerulonephritis (GN) occurring after kidney transplantation remains... (Review)
Review
The prevalence, pathogenesis, predictors, and natural course of patients with recurrent glomerulonephritis (GN) occurring after kidney transplantation remains incompletely understood, including whether there are differences in the outcomes and advances in the treatment options of specific GN subtypes, including those with GN. Consequently, the treatment options and approaches to recurrent disease are largely extrapolated from the general population, with responses to these treatments in those with recurrent or GN post-transplantation poorly described. Given a greater understanding of the pathogenesis of GN and the development of novel treatment options, it is conceivable that these advances will result in an improved structure in the future management of patients with recurrent or GN. This review focuses on the incidence, genetics, characteristics, clinical course, and risk of allograft failure of patients with recurrent or GN after kidney transplantation, ascertaining potential disparities between "high risk" disease subtypes of IgA nephropathy, idiopathic membranous glomerulonephritis, focal segmental glomerulosclerosis, and membranoproliferative glomerulonephritis. We will examine in detail the management of patients with high risk GN, including the pre-transplant assessment, post-transplant monitoring, and the available treatment options for disease recurrence. Given the relative paucity of data of patients with recurrent and GN after kidney transplantation, a global effort in collecting comprehensive in-depth data of patients with recurrent and GN as well as novel trial design to test the efficacy of specific treatment strategy in large scale multicenter randomized controlled trials are essential to address the knowledge deficiency in this disease.
Topics: Glomerulonephritis; Glomerulonephritis, IGA; Glomerulosclerosis, Focal Segmental; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Recurrence; Risk Factors; Transplantation, Homologous
PubMed: 31475005
DOI: 10.3389/fimmu.2019.01944 -
Yeast (Chichester, England) Sep 2022De novo gene birth is the process by which new genes emerge in sequences that were previously noncoding. Over the past decade, researchers have taken advantage of the... (Review)
Review
De novo gene birth is the process by which new genes emerge in sequences that were previously noncoding. Over the past decade, researchers have taken advantage of the power of yeast as a model and a tool to study the evolutionary mechanisms and physiological implications of de novo gene birth. We summarize the mechanisms that have been proposed to explicate how noncoding sequences can become protein-coding genes, highlighting the discovery of pervasive translation of the yeast transcriptome and its presumed impact on evolutionary innovation. We summarize current best practices for the identification and characterization of de novo genes. Crucially, we explain that the field is still in its nascency, with the physiological roles of most young yeast de novo genes identified thus far still utterly unknown. We hope this review inspires researchers to investigate the true contribution of de novo gene birth to cellular physiology and phenotypic diversity across yeast strains and species.
Topics: Evolution, Molecular; Saccharomyces cerevisiae
PubMed: 35959631
DOI: 10.1002/yea.3810