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The Journal of Cell Biology May 2021Centrioles form centrosomes and cilia. In most proliferating cells, centrioles assemble through canonical duplication, which is spatially, temporally, and numerically...
Centrioles form centrosomes and cilia. In most proliferating cells, centrioles assemble through canonical duplication, which is spatially, temporally, and numerically regulated by the cell cycle and the presence of mature centrioles. However, in certain cell types, centrioles assemble de novo, yet by poorly understood mechanisms. Herein, we established a controlled system to investigate de novo centriole biogenesis, using Drosophila melanogaster egg explants overexpressing Polo-like kinase 4 (Plk4), a trigger for centriole biogenesis. We show that at a high Plk4 concentration, centrioles form de novo, mature, and duplicate, independently of cell cycle progression and of the presence of other centrioles. Plk4 concentration determines the temporal onset of centriole assembly. Moreover, our results suggest that distinct biochemical kinetics regulate de novo and canonical biogenesis. Finally, we investigated which other factors modulate de novo centriole assembly and found that proteins of the pericentriolar material (PCM), and in particular γ-tubulin, promote biogenesis, likely by locally concentrating critical components.
Topics: Animals; Cell Cycle; Cell Cycle Proteins; Cell Division; Cells, Cultured; Centrioles; Centrosome; Drosophila Proteins; Drosophila melanogaster; Female; Male; Protein Serine-Threonine Kinases; Tubulin
PubMed: 33760919
DOI: 10.1083/jcb.202008090 -
Frontiers in Pediatrics 2021encodes an α1 isoform of Na/K-ATPase, which is expressed abundantly in kidneys and central nervous system. variants may cause Na/K-ATPase loss of function and lead...
encodes an α1 isoform of Na/K-ATPase, which is expressed abundantly in kidneys and central nervous system. variants may cause Na/K-ATPase loss of function and lead to a wide spectrum of phenotypes. This study aims to summarize the clinical and genetic features of mutation-related disorders and explore the potential correlations between phenotypes and genotypes. We analyzed two new cases harboring novel variants and reviewed all reported cases. Both our probands had developmental delay, patient 1 accompanied with sleep disorders, irritability, and patient 2 with refractory seizures. They each had a novel heterozygous missense variant, c.2797G>A[p.Asp933Asn] (NM_000701) and c.2590G>A[p.Gly864Arg] (NM_000701) respectively. Four patients with variants have been reported in two previous papers. Among them, three patients had refractory seizures and one patient had complex hereditary spastic paraplegia (HSP). Therefore, all six patients had developmental delay, and four of them had epilepsy. All variants located in the transmembrane regions M3, M4, M7, and M8 of ATP1A1 protein. Four patients with mutations in M3 and M7 had more severe phenotypes, including developmental delay and epileptic encephalopathy, three of them with hypomagnesemia, whereas two patients with mutations in M4 and M8 had milder phenotypes, only with mild developmental delay, without seizures or hypomagnesemia. Correcting hypomagnesemia had not controlled those seizures. Two novel variants identified in two patients here enriched the genotypic and phenotypic spectrum of mutation-related disorder. Our findings suggest that hypomagnesemia in this disorder might relate to more severe phenotype and indicate more severe Na/K-ATPase dysfunction. Variations in M3 and M7 transmembrane regions were related to more severe phenotype than those in M4 and M8, which suggested that variations in M3 and M7 might cause more severe functional defect.
PubMed: 33968856
DOI: 10.3389/fped.2021.657256 -
BioRxiv : the Preprint Server For... Jun 2023Although previously thought to be unlikely, recent studies have shown that gene origination from previously non-genic sequences is a relatively common mechanism for...
Although previously thought to be unlikely, recent studies have shown that gene origination from previously non-genic sequences is a relatively common mechanism for gene innovation in many species and taxa. These young genes provide a unique set of candidates to study the structural and functional origination of proteins. However, our understanding of their protein structures and how these structures originate and evolve are still limited, due to a lack of systematic studies. Here, we combined high-quality base-level whole genome alignments, bioinformatic analysis, and computational structure modeling to study the origination, evolution, and protein structure of lineage-specific genes. We identified 555 gene candidates in that originated within the lineage. We found a gradual shift in sequence composition, evolutionary rates, and expression patterns with their gene ages, which indicates possible gradual shifts or adaptations of their functions. Surprisingly, we found little overall protein structural changes for genes in the lineage. Using Alphafold2, ESMFold, and molecular dynamics, we identified a number of gene candidates with protein products that are potentially well-folded, many of which are more likely to contain transmembrane and signal proteins compared to other annotated protein-coding genes. Using ancestral sequence reconstruction, we found that most potentially well-folded proteins are often born folded. Interestingly, we observed one case where disordered ancestral proteins become ordered within a relatively short evolutionary time. Single-cell RNA-seq analysis in testis showed that although most genes are enriched in spermatocytes, several young genes are biased in the early spermatogenesis stage, indicating potentially important but less emphasized roles of early germline cells in the gene origination in testis. This study provides a systematic overview of the origin, evolution, and structural changes of -specific genes.
PubMed: 37425675
DOI: 10.1101/2023.03.13.532420 -
Stem Cells International 2017The advent of cellular reprogramming technology has revolutionized biomedical research. human cardiac myocytes can now be obtained from direct reprogramming of somatic... (Review)
Review
The advent of cellular reprogramming technology has revolutionized biomedical research. human cardiac myocytes can now be obtained from direct reprogramming of somatic cells (such as fibroblasts), from induced pluripotent stem cells (iPSCs, which are reprogrammed from somatic cells), and from human embryonic stem cells (hESCs). Such human cardiac myocytes hold great promise for disease modeling and drug screening and cell therapy of heart disease. Here, we review the technique advancements for generating human cardiac myocytes. We also discuss several challenges for the use of such cells in research and regenerative medicine, such as the immature phenotype and heterogeneity of cardiac myocytes obtained with existing protocols. We focus on the recent advancements in addressing such challenges.
PubMed: 28303153
DOI: 10.1155/2017/4528941 -
Nature Ecology & Evolution Apr 2023De novo gene emergence provides a route for new proteins to be formed from previously non-coding DNA. Proteins born in this way are considered random sequences and...
De novo gene emergence provides a route for new proteins to be formed from previously non-coding DNA. Proteins born in this way are considered random sequences and typically assumed to lack defined structure. While it remains unclear how likely a de novo protein is to assume a soluble and stable tertiary structure, intersecting evidence from random sequence and de novo-designed proteins suggests that native-like biophysical properties are abundant in sequence space. Taking putative de novo proteins identified in human and fly, we experimentally characterize a library of these sequences to assess their solubility and structure propensity. We compare this library to a set of synthetic random proteins with no evolutionary history. Bioinformatic prediction suggests that de novo proteins may have remarkably similar distributions of biophysical properties to unevolved random sequences of a given length and amino acid composition. However, upon expression in vitro, de novo proteins exhibit moderately higher solubility which is further induced by the DnaK chaperone system. We suggest that while synthetic random sequences are a useful proxy for de novo proteins in terms of structure propensity, de novo proteins may be better integrated in the cellular system than random expectation, given their higher solubility.
Topics: Humans; Proteins; Proteomics; Computational Biology
PubMed: 37024625
DOI: 10.1038/s41559-023-02010-2 -
ENeuro Oct 2023The levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of the and salvage synthesis pathways. In the...
The levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of the and salvage synthesis pathways. In the embryonic central nervous system (CNS), the pathway is considered crucial to meet the requirements for the active proliferation of neural stem/progenitor cells (NSPCs). However, how these two pathways are balanced or separately used during CNS development remains poorly understood. In this study, we showed a dynamic shift in pathway utilization, with greater reliance on the pathway during embryonic stages and on the salvage pathway in postnatal-adult mouse brain. The pharmacological effects of various purine synthesis inhibitors and the expression profile of purine synthesis enzymes indicated that NSPCs in the embryonic cerebrum mainly use the pathway. Simultaneously, NSPCs in the cerebellum require both the and the salvage pathways. administration of inhibitors resulted in severe hypoplasia of the forebrain cortical region, indicating a gradient of purine demand along the anteroposterior axis of the embryonic brain, with cortical areas of the dorsal forebrain having higher purine requirements than ventral or posterior areas such as the striatum and thalamus. This histologic defect of the neocortex was accompanied by strong downregulation of the mechanistic target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase (S6K)/S6 signaling cascade, a crucial pathway for cell metabolism, growth, and survival. These findings indicate the importance of the spatiotemporal regulation of both purine pathways for mTORC1 signaling and proper brain development.
Topics: Mice; Animals; Purines; Homeostasis; Brain; Mechanistic Target of Rapamycin Complex 1
PubMed: 37770184
DOI: 10.1523/ENEURO.0159-23.2023 -
Autoimmune hepatitis and liver transplantation: Indications, and recurrent and autoimmune hepatitis.World Journal of Transplantation Mar 2022Autoimmune hepatitis is a chronic inflammatory disease of the liver that is characterized by circulating autoantibodies and elevated serum globulin levels. Liver... (Review)
Review
Autoimmune hepatitis is a chronic inflammatory disease of the liver that is characterized by circulating autoantibodies and elevated serum globulin levels. Liver transplantation may be required for patients with acute liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Recurrence is defined as development of the same disease in the allograft following liver transplantation. Autoimmune hepatitis recurs in 36%-68% of the recipients 5 years after liver transplantation. autoimmune hepatitis is the development of autoimmune hepatitis like clinical and laboratory characteristics in patients who had undergone liver transplantation for causes other than autoimmune hepatitis. Diagnostic work up for recurrent and autoimmune hepatitis is similar to the diagnosis of the original disease, and it is usually difficult. Predniso(lo)ne with or without azathioprine is the main treatment for recurrent and autoimmune hepatitis. Early diagnosis and treatment are vital for patient prognosis because autoimmune hepatitis and recurrent autoimmune hepatitis cause graft loss and result in subsequent retransplantation if medical treatment fails.
PubMed: 35433333
DOI: 10.5500/wjt.v12.i3.59 -
Molecular Genetics & Genomic Medicine Mar 2019Osteogenesis imperfecta (OI) is a rare genetic bone fragility disorder. In the current study, differences between the genotypes and phenotypes of de novo and inherited...
BACKGROUND
Osteogenesis imperfecta (OI) is a rare genetic bone fragility disorder. In the current study, differences between the genotypes and phenotypes of de novo and inherited collagen-related OI were investigated.
METHODS
A comparative analysis was performed of the genotypes and phenotypes of 146 unrelated inherited and de novo collagen I OI cases from Estonia, Ukraine, and Vietnam. Mutational analysis of the subjects and all available parents were performed with Sanger sequencing.
RESULTS
Results showed that 56.16% of the OI cases were caused by de novo pathogenic variants. The proportion of OI types OI1, OI4, and OI3 among subjects with inherited OI was 45.31%, 46.88%, and 7.81%, respectively. Among subjects with de novo OI, the proportions of OI types (OI1, OI4, and OI3) were almost equal. Both inherited and de novo OI pathogenic variants occurred more often in the COL1A1 gene than in the COL1A2. The majority of de novo cases were missense pathogenic variants, whereas inherited OI was mostly caused by loss of function pathogenic variants.
CONCLUSION
In summary, there were significant differences between the phenotypes and genotypes of subjects with de novo and inherited OI. These findings may promote the further understanding of OI etiology, and assist with diagnostics procedures, as well as with family planning.
Topics: Adolescent; Collagen Type I; Collagen Type I, alpha 1 Chain; Female; Humans; Male; Mutation; Osteogenesis Imperfecta
PubMed: 30675999
DOI: 10.1002/mgg3.559 -
World Journal of Hepatology Dec 2021Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new acronym adopted from the consensus of international experts. Given the increasing prevalence of... (Review)
Review
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new acronym adopted from the consensus of international experts. Given the increasing prevalence of MAFLD in pre-transplant settings, and recurrent graft steatosis/MAFLD are common in post-transplant settings. The impact of graft steatosis on long-term outcomes is unclear. The current knowledge of incidence rate, risk factors, diagnosis, long-term outcomes, and management of graft steatosis (both and recurrent) is discussed in this review.
PubMed: 35070003
DOI: 10.4254/wjh.v13.i12.1991 -
Molecular Biology and Evolution May 2023The formation of new genes during evolution is an important motor of functional innovation, but the rate at which new genes originate and the likelihood that they...
The formation of new genes during evolution is an important motor of functional innovation, but the rate at which new genes originate and the likelihood that they persist over longer evolutionary periods are still poorly understood questions. Two important mechanisms by which new genes arise are gene duplication and de novo formation from a previously noncoding sequence. Does the mechanism of formation influence the evolutionary trajectories of the genes? Proteins arisen by gene duplication retain the sequence and structural properties of the parental protein, and thus they may be relatively stable. Instead, de novo originated proteins are often species specific and thought to be more evolutionary labile. Despite these differences, here we show that both types of genes share a number of similarities, including low sequence constraints in their initial evolutionary phases, high turnover rates at the species level, and comparable persistence rates in deeper branchers, in both yeast and flies. In addition, we show that putative de novo proteins have an excess of substitutions between charged amino acids compared with the neutral expectation, which is reflected in the rapid loss of their initial highly basic character. The study supports high evolutionary dynamics of different kinds of new genes at the species level, in sharp contrast with the stability observed at later stages.
Topics: Evolution, Molecular; Proteins; Gene Duplication; Saccharomyces cerevisiae; Phylogeny
PubMed: 37139943
DOI: 10.1093/molbev/msad098