-
Genome Biology and Evolution Jun 2024Recent studies in the rice genome-wide have established that de novo genes, evolving from noncoding sequences, enhance protein diversity through a stepwise process....
Recent studies in the rice genome-wide have established that de novo genes, evolving from noncoding sequences, enhance protein diversity through a stepwise process. However, the pattern and rate of their evolution in protein structure over time remain unclear. Here, we addressed these issues within a surprisingly short evolutionary timescale (<1 million years for 97% of Oryza de novo genes) with comparative approaches to gene duplicates. We found that de novo genes evolve faster than gene duplicates in the intrinsically disordered regions (such as random coils), secondary structure elements (such as α helix and β strand), hydrophobicity, and molecular recognition features. In de novo proteins, specifically, we observed an 8% to 14% decay in random coils and intrinsically disordered region lengths and a 2.3% to 6.5% increase in structured elements, hydrophobicity, and molecular recognition features, per million years on average. These patterns of structural evolution align with changes in amino acid composition over time as well. We also revealed higher positive charges but smaller molecular weights for de novo proteins than duplicates. Tertiary structure predictions showed that most de novo proteins, though not typically well folded on their own, readily form low-energy and compact complexes with other proteins facilitated by extensive residue contacts and conformational flexibility, suggesting a faster-binding scenario in de novo proteins to promote interaction. These analyses illuminate a rapid evolution of protein structure in de novo genes in rice genomes, originating from noncoding sequences, highlighting their quick transformation into active, protein complex-forming components within a remarkably short evolutionary timeframe.
Topics: Evolution, Molecular; Oryza; Plant Proteins; Gene Duplication; Hydrophobic and Hydrophilic Interactions
PubMed: 38753069
DOI: 10.1093/gbe/evae107 -
Frontiers in Aging Neuroscience 2022Reliable electrophysiological indicators are urgently needed in the precise evaluation of Parkinson's disease (PD). It is still elusive whether oculomotor performance is...
OBJECTIVE
Reliable electrophysiological indicators are urgently needed in the precise evaluation of Parkinson's disease (PD). It is still elusive whether oculomotor performance is impaired or has clinical value in early PD. This study aims to explore oculomotor performance in newly diagnosed, drug-naïve PD and its correlation with clinical phenotype.
METHODS
Seventy-five patients with PD, 75 patients with essential tremor (ET), and 46 gender-and age-matched healthy controls (HCs) were included in this cross-sectional study. All subjects underwent oculomotor test videonystagmography. Visually guided saccade latency, saccadic accuracy and gain in smooth pursuit eye movement (SPEM) at three frequencies of the horizontal axis were compared among the three groups. Patients with PD also received detailed motor and non-motor evaluation by serial scales. The association between key oculomotor parameters and clinical phenotypes were explored in PD patients.
RESULTS
Both PD and ET patients showed prolonged saccadic latency and decreased saccadic accuracy relative to HCs. SPEM gain in PD was uniformly reduced at each frequency. SPEM gain at 0.4 Hz was also decreased in ET compared with HCs. However, there was no significant difference of oculomotor parameters between PD and ET patients. Furthermore, prolonged saccadic latency was correlated with long disease duration, whereas decreased SPEM gain was associated with severe motor symptoms in PD patients.
CONCLUSION
Ocular movements are impaired in , drug naïve PD patients; these changes could be indicators for disease progression in PD.
PubMed: 36437987
DOI: 10.3389/fnagi.2022.985679 -
Nature Communications Jan 2024Recent studies reveal that de novo gene origination from previously non-genic sequences is a common mechanism for gene innovation. These young genes provide an...
Recent studies reveal that de novo gene origination from previously non-genic sequences is a common mechanism for gene innovation. These young genes provide an opportunity to study the structural and functional origins of proteins. Here, we combine high-quality base-level whole-genome alignments and computational structural modeling to study the origination, evolution, and protein structures of lineage-specific de novo genes. We identify 555 de novo gene candidates in D. melanogaster that originated within the Drosophilinae lineage. Sequence composition, evolutionary rates, and expression patterns indicate possible gradual functional or adaptive shifts with their gene ages. Surprisingly, we find little overall protein structural changes in candidates from the Drosophilinae lineage. We identify several candidates with potentially well-folded protein structures. Ancestral sequence reconstruction analysis reveals that most potentially well-folded candidates are often born well-folded. Single-cell RNA-seq analysis in testis shows that although most de novo gene candidates are enriched in spermatocytes, several young candidates are biased towards the early spermatogenesis stage, indicating potentially important but less emphasized roles of early germline cells in the de novo gene origination in testis. This study provides a systematic overview of the origin, evolution, and protein structural changes of Drosophilinae-specific de novo genes.
Topics: Male; Animals; Drosophila; Drosophila melanogaster; Evolution, Molecular; Testis; Spermatogenesis
PubMed: 38280868
DOI: 10.1038/s41467-024-45028-1 -
Frontiers in Cell and Developmental... 2019Sphingolipids are a class of lipids that share a sphingoid base backbone. They exert various effects in eukaryotes, ranging from structural roles in plasma membranes to...
Sphingolipids are a class of lipids that share a sphingoid base backbone. They exert various effects in eukaryotes, ranging from structural roles in plasma membranes to cellular signaling. sphingolipid synthesis takes place in the endoplasmic reticulum (ER), where the condensation of the activated C fatty acid palmitoyl-CoA and the amino acid L-serine is catalyzed by serine palmitoyltransferase (SPT). The product, 3-ketosphinganine, is then converted into more complex sphingolipids by additional ER-bound enzymes, resulting in the formation of ceramides. Since sphingolipid homeostasis is crucial to numerous cellular functions, improved assessment of sphingolipid metabolism will be key to better understanding several human diseases. To date, no assay exists capable of monitoring synthesis sphingolipid in its entirety. Here, we have established a cell-free assay utilizing rat liver microsomes containing all the enzymes necessary for bottom-up synthesis of ceramides. Following lipid extraction, we were able to track the different intermediates of the sphingolipid metabolism pathway, namely 3-ketosphinganine, sphinganine, dihydroceramide, and ceramide. This was achieved by chromatographic separation of sphingolipid metabolites followed by detection of their accurate mass and characteristic fragmentations through high-resolution mass spectrometry and tandem-mass spectrometry. We were able to distinguish, unequivocally, between synthesized sphingolipids and intrinsic species, inevitably present in the microsome preparations, through the addition of stable isotope-labeled palmitate-d and L-serine-d. To the best of our knowledge, this is the first demonstration of a method monitoring the entirety of ER-associated sphingolipid biosynthesis. Proof-of-concept data was provided by modulating the levels of supplied cofactors (e.g., NADPH) or the addition of specific enzyme inhibitors (e.g., fumonisin B). The presented microsomal assay may serve as a useful tool for monitoring alterations in sphingolipid synthesis in cells or tissues. Additionally, our methodology may be used for metabolism studies of atypical substrates - naturally occurring or chemically tailored - as well as novel inhibitors of enzymes involved in sphingolipid synthesis.
PubMed: 31632963
DOI: 10.3389/fcell.2019.00210 -
G3 (Bethesda, Md.) Jul 2019Homology is a fundamental concept in comparative biology. It is extensively used at the sequence level to make phylogenetic hypotheses and functional inferences....
Homology is a fundamental concept in comparative biology. It is extensively used at the sequence level to make phylogenetic hypotheses and functional inferences. Nonetheless, the majority of eukaryotic genomes contain large numbers of orphan genes lacking homologs in other taxa. Generally, the fraction of orphan genes is higher in genomically undersampled clades, and in the absence of closely related genomes any hypothesis about their origin and evolution remains untestable. Previously, we sequenced ten genomes with an underlying ladder-like phylogeny to establish a phylogenomic framework for studying genome evolution in diplogastrid nematodes. Here, we use this deeply sampled data set to understand the processes that generate orphan genes in our focal species Based on phylostratigraphic analysis and additional bioinformatic filters, we obtained 29 high-confidence candidate genes for which mechanisms of orphan origin were proposed based on manual inspection. This revealed diverse mechanisms including annotation artifacts, chimeric origin, alternative reading frame usage, and gene splitting with subsequent gain of exons. In addition, we present two cases of complete origination from non-coding regions, which represents one of the first reports of genes in nematodes. Thus, we conclude that emergence, divergence, and mixed mechanisms contribute to novel gene formation in nematodes.
Topics: Amino Acid Sequence; Animals; Computational Biology; Genes, Protozoan; Genome, Protozoan; Genomics; Molecular Sequence Annotation; Reading Frames; Reproducibility of Results; Rhabditida; Species Specificity
PubMed: 31088903
DOI: 10.1534/g3.119.400326 -
The Neuroradiology Journal Jun 2018Objective A small number of patients has been reported to develop a completely new or de novo arteriovenous malformation (AVM) after brain surgery, haemorrhage, head...
Objective A small number of patients has been reported to develop a completely new or de novo arteriovenous malformation (AVM) after brain surgery, haemorrhage, head trauma or ischaemic stroke. The natural history of these lesions is unknown. In this review, both ruptured and unruptured de novo AVMs and their treatments were reviewed. Methods Published literature in the PubMed database citing 'de novo cerebral arteriovenous malformation' was reviewed. Additional studies were identified through reference searches in each reviewed article. A review was performed using all published cases, the treatment approaches and outcomes. Results A total of 38 patients, including 37 de novo AVMs reported from 1988 to 17 November 2017 and our one patient, was collected. The age at AVM diagnosis was 5-73 years (mean ± SD, 27.6 ± 20.5 years). The duration time, from negative examination to AVM diagnosis, was 2 months to 25 years (mean ± SD, 6.6 ± 4.9 years). The presentation of de novo AVM was headaches in three (7.9%) patients, bleedings in 12 (31.6%), incidental in 14 (36.8%) and seizure in nine (23.7%). The estimated risk of haemorrhage was 4.8% per year. Seventeen (44.7%) patients were treated with surgical resection, 10 (26.3%) were conservatively observed, nine (23.7%) were treated with radiosurgery and two (5.3%) were endovascularly embolised. The morbidity and mortality were reported as 5.3% and 7.9%, respectively. Conclusion Post-natal de novo AVMs have been reported. Their annual haemorrhage risk is 4.8%. Most of them are treated by surgical resection and are associated with morbidity and mortality.
Topics: Adolescent; Adult; Aged; Chi-Square Distribution; Child; Child, Preschool; Embolization, Therapeutic; Female; Headache; Hemorrhage; Humans; Intracranial Arteriovenous Malformations; Longitudinal Studies; Male; Middle Aged; Neuroimaging; PubMed; Treatment Outcome; Young Adult
PubMed: 29469668
DOI: 10.1177/1971400918759811 -
Case Reports in Transplantation 2022Allograft membranous glomerulopathy can be a recurrent or de novo disease. Both instead have different underlying immune pathophysiology and disease pattern. While the...
Allograft membranous glomerulopathy can be a recurrent or de novo disease. Both instead have different underlying immune pathophysiology and disease pattern. While the introduction of ANTI-PLAR2 and THS7A brought new insights into the management of Immune/primary MN, the treatment of de novo MN is not clear. Relapsing de novo MN in a kidney transplant was rarely reported. Here, we present a case of relapsing de novo MN without evidence of rejection and a gratifying response to rituximab.
PubMed: 35547830
DOI: 10.1155/2022/6754520 -
Frontiers in Surgery 2022Postoperative seizures and epilepsy are common complications of craniotomy. In this study, we aimed to investigate the characteristics of seizures and epilepsy after...
OBJECTIVE
Postoperative seizures and epilepsy are common complications of craniotomy. In this study, we aimed to investigate the characteristics of seizures and epilepsy after craniotomy.
METHODS
A total of 293 consecutive craniotomy surgeries were analyzed. Infratentorial surgeries, epilepsy surgeries, surgeries using the same approach conducted for the same patients, and the cases with incomplete clinical data were excluded. A total of 211 surgeries were included in this study. We evaluated the following clinical characteristics in all patients: sex, age, preoperative epilepsy, use of preoperative antiseizure medication (ASM), indication for operation, early postoperative seizure (EPS), delayed postoperative seizure (DPS), and postoperative de novo epilepsy. The day of onset of EPSs was defined as within 7 days post-surgery, and the day of onset of DPSs was defined as later than 7 days and less than 60 days post-surgery.
RESULTS
Twenty-eight patients were previously diagnosed with epilepsy. Nine patients had EPSs (4.3%), and 10 patients had DPSs (4.7%). Seven cases of EPSs and six cases of DPSs were observed in 183 patients without previous epilepsy (3.8% and 3.3%, respectively). Three of the seven patients with EPSs (42.9%) and all six patients with DPSs (100%) developed de novo epilepsy. Postoperative de novo epilepsy was observed in 9 (4.9%) of the 183 patients without epilepsy. EPSs and DPSs were significant risk factors for epilepsy ( < 0.01). The odds ratios of EPSs and DPSs for the development of epilepsy were 12.71 (95% confidence interval [CI]: 3.94-112.80; < 0.01) and 22.88 (95% CI: 5.38-55.72; < 0.01), respectively. ASM was administered prophylactically to 51 patients. The prophylactic use of ASMs did not prevent EPSs or postoperative de novo epilepsy.
CONCLUSION
EPSs and DPSs occurred in 4.3% and 4.7% of the patients, respectively, after craniotomy. Postoperative de novo epilepsy occurred in 4.9% of patients. This study revealed that EPSs and DPSs were risk factors for de novo epilepsy. Previous epilepsy was not a significant risk factor for EPSs. The prophylactic use of ASMs did not prevent EPSs or de novo epilepsy.
PubMed: 35521429
DOI: 10.3389/fsurg.2022.881874 -
The Journal of Physiology Jul 2019Fructose is a commonly ingested dietary sugar which has been implicated in playing a particularly harmful role in the development of metabolic disease. Fructose is... (Review)
Review
Fructose is a commonly ingested dietary sugar which has been implicated in playing a particularly harmful role in the development of metabolic disease. Fructose is primarily metabolised by the liver in humans, and increases rates of hepatic de novo lipogenesis. Fructose increases hepatic de novo lipogenesis via numerous mechanisms: by altering transcriptional and allosteric regulation, interfering with cellular energy sensing, and disrupting the balance between lipid synthesis and lipid oxidation. Hepatic de novo lipogenesis is also upregulated by the inability to synthesise glycogen, either when storage is inhibited in knock-down animal models or storage is saturated in glycogen storage disease. Considering that fructose has the capacity to upregulate hepatic glycogen storage, and replenish these stores more readily following glycogen depleting exercise, the idea that hepatic glycogen storage and hepatic de novo lipogenesis are linked is an attractive prospect. We propose that hepatic glycogen stores may be a key factor in determining the metabolic responses to fructose ingestion, and saturation of hepatic glycogen stores could exacerbate the negative metabolic effects of excessive fructose intake. Since physical activity potently modulates glycogen metabolism, this provides a rationale for considering nutrient-physical activity interactions in metabolic health.
Topics: Animals; Energy Intake; Exercise; Fructose; Humans; Lipogenesis; Liver; Liver Glycogen
PubMed: 30950506
DOI: 10.1113/JP277767 -
Drug Resistance Updates : Reviews and... Mar 2023Nucleotide de novo synthesis is essential to cell growth and survival, and its dysregulation leads to cancers and drug resistance. However, how this pathway is...
AIMS
Nucleotide de novo synthesis is essential to cell growth and survival, and its dysregulation leads to cancers and drug resistance. However, how this pathway is dysregulated in cancer has not been well clarified. This study aimed to identify the regulatory mechanisms of nucleotide de novo synthesis and drug resistance.
METHODS
By combining the ChIP-Seq data from the Cistrome Data Browser, RNA sequencing (RNA-Seq) and a luciferase-based promoter assay, we identified transcription factor FOXK2 as a regulator of nucleotide de novo synthesis. To explore the biological functions and mechanisms of FOXK2 in cancers, we conducted biochemical and cell biology assays in vitro and in vivo. Finally, we assessed the clinical significance of FOXK2 in hepatocellular carcinoma.
RESULTS
FOXK2 directly regulates the expression of nucleotide synthetic genes, promoting tumor growth and cancer cell resistance to chemotherapy. FOXK2 is SUMOylated by PIAS4, which elicits FOXK2 nuclear translocation, binding to the promoter regions and transcription of nucleotide synthetic genes. FOXK2 SUMOylation is repressed by DNA damage, and elevated FOXK2 SUMOylation promotes nucleotide de novo synthesis which causes resistance to 5-FU in hepatocellular carcinoma. Clinically, elevated expression of FOXK2 in hepatocellular carcinoma patients was associated with increased nucleotide synthetic gene expression and correlated with poor prognoses for patients.
CONCLUSION
Our findings establish FOXK2 as a novel regulator of nucleotide de novo synthesis, with potentially important implications for cancer etiology and drug resistance.
Topics: Humans; Carcinoma, Hepatocellular; Cell Proliferation; Liver Neoplasms
PubMed: 36682222
DOI: 10.1016/j.drup.2023.100926