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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 -
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 -
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 -
The Journal of Craniofacial Surgery Sep 2022To confirm this hypothesis, this study aimed to explore the pathogenic factors, prognosis, and their relationship in de novo aneurysms and to reach a consensus on their...
OBJECTIVE
To confirm this hypothesis, this study aimed to explore the pathogenic factors, prognosis, and their relationship in de novo aneurysms and to reach a consensus on their management.
METHODS
First, the clinical data of 5 patients with de novo aneurysms from April 1998 to October 2021 were analyzed retrospectively. Then, the English literature on de novo aneurysms reported in Pubmed from 1985 to 2021 was systematically reviewed, and 18 case reports from 17 articles and 16 case series were identified. Univariate and multivariate analyses and modified Fisher test were used to analyze the relationship between pathogenic factors and prognosis.
RESULTS
Hypertension was noted in 60% of our clinical cases, 50% of the case series identified in the literature review, and 66.7% of the case reports in the literature review. In the case reports identified from our literature review, the proportion of original aneurysms in the anterior circulation was 96.3%. Moreover, in our 5 cases, all original aneurysms occurred in the anterior circulation. The rupture rate of original aneurysms in our 5 cases was 100%, and that of the cases reported in the literature review was 88.9%. Univariate logistic analysis showed that the time interval was related to the prognosis of de novo aneurysms with a P value of 0.048 and an odds ratio of 0.968 (95% confidence interval 0.938-1.000). Modified Fisher exact tests showed that patient age at the occurrence of de novo aneurysm P = 0.029) was related to the prognosis of de novo aneurysms.
CONCLUSIONS
Hypertension, an original aneurysms located in the anterior circulation and rupture represent the pathogenic factors associated with de novo aneurysms. The time interval to de novo aneurysm and patient age at the occurrence of de novo aneurysm are predictive of prognosis. Based on the above information, we can prevent and improve the prognosis of de novo aneurysms.
Topics: Aneurysm, Ruptured; Humans; Intracranial Aneurysm; Prognosis; Retrospective Studies; Risk Factors; Virulence Factors
PubMed: 34974461
DOI: 10.1097/SCS.0000000000008451 -
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 -
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 -
European Journal of Neurology Sep 2022Hypertension is a risk factor for subarachnoid hemorrhage and is also considered a risk factor for saccular intracranial aneurysm (sIA) formation. However, there is...
BACKGROUND AND PURPOSE
Hypertension is a risk factor for subarachnoid hemorrhage and is also considered a risk factor for saccular intracranial aneurysm (sIA) formation. However, there is little direct evidence that antihypertensive medication will reduce sIA formation.
METHODS
The impact of antihypertensive medication on de novo sIA formation was studied in an angiographically followed cohort of 1419 patients. Patients were identified from our population-based Kuopio Intracranial Aneurysm Database, and data on the purchases of antihypertensive medication were obtained from a national registry. Univariate and multivariate analyses were used to investigate the risk factors.
RESULTS
Of the 966 sIA patients who were prescribed with antihypertensive medication, 841 patients used the medication regularly; 20 of them had de novo sIA. One hundred and twenty-five patients used the medication irregularly and 12 of them developed de novo sIAs. Four hundred and fifty-three patients did not use antihypertensive medication even though 27 of them had a diagnosis of hypertension, and 10 of them developed de novo sIAs. In the multivariate analysis antihypertensive medication did not significantly reduce de novo sIA formation (hazard ratio [HR] 1.60, 95% confidence interval [CI] 0.84-3.06). Age at primary diagnosis (HR: 0.95, 95%: CI 0.93-0.98) and smoking history (HR: 5.53, 95% CI: 2.77-11.05) were significant risk factors for de novo sIA formation. Also, irregular usage of antihypertensive medication was a significant risk factor (HR: 3.84, 95% CI: 1.59-9.29) for de novo sIA formation.
CONCLUSIONS
Antihypertensive agents were not associated with a reduction of de novo sIA formation, but irregular use of antihypertensive agents was associated with an increased risk of de novo sIA formation.
Topics: Aneurysm, Ruptured; Antihypertensive Agents; Cohort Studies; Humans; Hypertension; Intracranial Aneurysm; Subarachnoid Hemorrhage
PubMed: 35652754
DOI: 10.1111/ene.15430 -
International Journal of Biological... Jul 2023Patients with Alzheimer's disease (AD) display both peripheral tissue and brain insulin resistance, the later could be a potential risk factor for cognitive dysfunction.... (Review)
Review
Patients with Alzheimer's disease (AD) display both peripheral tissue and brain insulin resistance, the later could be a potential risk factor for cognitive dysfunction. While certain degree of inflammation is required for inducing insulin resistance, underlying mechanism(s) remains unclear. Evidence from diverse research domains suggest that elevated intracellular fatty acids of de novo pathway can induce insulin resistance even without triggering inflammation; however, the effect of saturated fatty acids (SFAs) could be detrimental due the development of proinflammatory cues. In this context, evidence suggest that while lipid/fatty acid accumulation is a characteristic feature of brain pathology in AD, dysregulated de novo lipogenesis could be a potential source for lipid/fatty acid accumulation. Therefore, therapies aimed at regulating de novo lipogenesis could be effective in improving insulin sensitivity and cognitive function in patients with AD.
Topics: Humans; Insulin Resistance; Lipogenesis; Liver; Alzheimer Disease; Fatty Acids; Inflammation
PubMed: 37187418
DOI: 10.1016/j.ijbiomac.2023.124859 -
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