-
Cell Feb 2024Methods from artificial intelligence (AI) trained on large datasets of sequences and structures can now "write" proteins with new shapes and molecular functions de novo,... (Review)
Review
Methods from artificial intelligence (AI) trained on large datasets of sequences and structures can now "write" proteins with new shapes and molecular functions de novo, without starting from proteins found in nature. In this Perspective, I will discuss the state of the field of de novo protein design at the juncture of physics-based modeling approaches and AI. New protein folds and higher-order assemblies can be designed with considerable experimental success rates, and difficult problems requiring tunable control over protein conformations and precise shape complementarity for molecular recognition are coming into reach. Emerging approaches incorporate engineering principles-tunability, controllability, and modularity-into the design process from the beginning. Exciting frontiers lie in deconstructing cellular functions with de novo proteins and, conversely, constructing synthetic cellular signaling from the ground up. As methods improve, many more challenges are unsolved.
Topics: Artificial Intelligence; Protein Conformation; Proteins; Protein Engineering; Deep Learning
PubMed: 38306980
DOI: 10.1016/j.cell.2023.12.028 -
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 -
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 -
Plant & Cell Physiology Nov 2022Most cereal crops were domesticated within the last 12,000 years and subsequently spread around the world. These crops have been nourishing the world by supplying a... (Review)
Review
Most cereal crops were domesticated within the last 12,000 years and subsequently spread around the world. These crops have been nourishing the world by supplying a primary energy and nutrient source, thereby playing a critical role in determining the status of human health and sustaining the global population. Here, we review the major challenges of future agriculture and emphasize the utilization of wild germplasm. De novo domestication is one of the most straightforward strategies to manipulate domestication-related and/or other genes with known function, and thereby introduce desired traits into wild plants. We also summarize known causal variations and their corresponding pathways in order to better understand the genetic basis of crop evolution, and how this knowledge could facilitate de novo domestication. Indeed knowledge-driven de novo domestication has great potential for the development of new sustainable crops that have climate-resilient high yield with low resource input and meet individual nutrient needs. Finally, we discuss current opportunities for and barriers to knowledge-driven de novo domestication.
Topics: Humans; Domestication; Crops, Agricultural; Agriculture; Edible Grain; Phenotype
PubMed: 35762778
DOI: 10.1093/pcp/pcac077 -
Journal of Neurophysiology Apr 2023De novo motor learning is a form of motor learning characterized by the development of an entirely new and distinct motor controller to accommodate a novel motor demand.... (Review)
Review
De novo motor learning is a form of motor learning characterized by the development of an entirely new and distinct motor controller to accommodate a novel motor demand. Inversely, adaptation is a form of motor learning characterized by rapid, unconscious modifications in a previously established motor controller to accommodate small deviations in task demands. As most of the motor learning involves the adaptation of previously established motor controllers, de novo learning can be challenging to isolate and observe. The recent publication from Haith et al. (Haith AM, Yang CS, Pakpoor J, Kita K. J 128: 982-993, 2022.) details a novel method to investigate de novo learning using a complex bimanual cursor control task. This research is especially important in the context of future brain-machine interface devices that will present users with an entirely novel motor learning demand, requiring de novo learning.
Topics: Brain-Computer Interfaces; Learning; Adaptation, Physiological
PubMed: 36883755
DOI: 10.1152/jn.00496.2022 -
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 -
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 -
Trends in Plant Science Mar 2024Most high-yielding crops are susceptible to abiotic and biotic stresses, making them particularly vulnerable to the potential effects of climate change. A possible... (Review)
Review
Most high-yielding crops are susceptible to abiotic and biotic stresses, making them particularly vulnerable to the potential effects of climate change. A possible alternative is to accelerate the domestication of wild plants that are already tolerant to harsh conditions and to increase their yields by methods such as gene editing. We foresee that crops' wild progenitors could potentially compete with the resulting de novo domesticated plants, reducing yields. To improve the recognition of weeds, we propose using gene editing techniques to introduce traits into de novo domesticated crops that will allow for visual recognition of the crops by weeding robots that have been trained by machine learning.
PubMed: 38637173
DOI: 10.1016/j.tplants.2024.03.001 -
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 -
World Neurosurgery May 2023There is a lack of data about the clinicopathological and molecular characteristics of de novo versus secondary dedifferentiated chordoma (DC). This integrated study... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
There is a lack of data about the clinicopathological and molecular characteristics of de novo versus secondary dedifferentiated chordoma (DC). This integrated study aimed to investigate the similarities and differences in clinicopathological manifestations, prognoses, and molecular profiles of these 2 subtypes.
METHODS
We accessed the Surveillance, Epidemiology, and End Results (SEER) Program for DC cases from 1975 to 2020. Three electronic databases were also searched for additional DCs. Individual patient data of DC patients from SEER and published literature were combined in integrated analyses.
RESULTS
After excluding duplicated patients, we identified 14 and 116 DC patients from SEER and published literature, respectively. There were 74 de novo, 39 secondary, and 18 cases with unknown origin. Our results showed that de novo and secondary DCs were not statistically different in terms of age, gender, primary location, tumor size, distant metastasis at diagnosis, extent of resection, and chemotherapy receipt. There was limited available molecular data for de novo and secondary DCs, though examples TP53 mutations were found in both. In addition, the rates of tumor relapse, metastasis during follow-up, and patient mortality were also comparable between the 2 groups. In the multivariate Cox regression model, we demonstrated that gross total removal and radiotherapy use were associated with prolonged survival of DCs.
CONCLUSIONS
De novo and secondary DCs were statistically comparable in terms of patient demographics, clinical manifestations, and prognoses. Gross total excision and radiotherapy were optimal treatments associated with better outcomes of DC patients.
Topics: Humans; Chordoma; Prognosis; Kaplan-Meier Estimate; Proportional Hazards Models; Databases, Factual; SEER Program
PubMed: 36804481
DOI: 10.1016/j.wneu.2023.02.062