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Cancer Causes & Control : CCC Mar 2021Myelodysplastic syndromes (MDS) are classified as de novo and therapy-related (tMDS). We evaluated associations between MDS risk factors separately for de novo and tMDS.
PURPOSE
Myelodysplastic syndromes (MDS) are classified as de novo and therapy-related (tMDS). We evaluated associations between MDS risk factors separately for de novo and tMDS.
METHODS
The study population included 346 de novo MDS cases, 37 tMDS cases and 682 population controls frequency matched by age and sex. Polytomous logistic regression was performed to calculate odds ratios (OR) and 95% confidence intervals (CI).
RESULTS
After adjustment, former smoking status (OR = 1.45, 95% CI: 1.10-1.93), personal history of autoimmune disease (OR = 1.34, 95% CI: 0.99-1.82) and exposure to benzene (OR = 1.48, 95% CI: 1.00-2.19) were associated with de novo MDS. Risk estimates for the associations between smoking, autoimmune disease, and benzene exposure were similar in magnitude but non-significant in tMDS cases. Among individuals with a previous diagnosis of cancer, de novo MDS cases and controls were more likely to have had a previous solid tumor, while tMDS cases more commonly had a previous hematologic malignancy.
CONCLUSIONS
We observed similar associations between smoking, history of autoimmune disease and benzene exposure in de novo and tMDS although estimates for tMDS were imprecise due to small sample sizes. Future analyses with larger sample sizes will be required to confirm whether environmental factors influence risk of tMDS.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Autoimmune Diseases; Benzene; Environmental Exposure; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasms; Risk Factors; Smoking
PubMed: 33392905
DOI: 10.1007/s10552-020-01378-x -
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 -
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 -
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 -
Ecancermedicalscience 2022Limited data exists for non-small cell lung cancer (NSCLC) patients harbouring T790M mutation.
INTRODUCTION
Limited data exists for non-small cell lung cancer (NSCLC) patients harbouring T790M mutation.
METHODS
NSCLC patients, with T790M, who registered at our institute between 01/03/2015 and 31/12/2019, were considered for retrospective analysis of treatment pattern and clinical outcomes, i.e., progression-free survival (PFS) and overall survival (OS).
RESULTS
Of 1,542 epidermal growth factor receptor ()-mutated patients, 40 (2.59%) had T790M. Most were male (27, 67.5%) and smokers (23, 57.5%). The commonest site of metastasis was the lungs (31, 77.5%), while 7 (17.5%) had central nervous system (CNS) involvement. Additional gene mutations and anaplastic lymphoma kinase (ALK) positivity were observed in 20 (50.0%) and 4 (10.0%) cases, respectively. The first-line systemic therapy and the number of patients receiving it were as follows: osimertinib by 14 (35.0%), first-generation tyrosine kinase inhibitors (TKIs) by 10 (25.0%), gefitinib + chemotherapy by 3 (7.5%), chemotherapy by 7 (17.5%) and gefitinib + bevacizumab by 2 (5%). One patient defaulted before starting any treatment. Hence, 39 were considered for survival analysis. The median PFS and OS for the entire cohort were 10.4 (95% CI = 7.6-19.7) months and 24.9 (95% CI = 15.7-NA) months, respectively. The median PFS for patients on osimertinib was 19.8 (95% CI = 11.6-28.0) months versus 8.8 (95% CI = 6.6-10.9) months for those on other systemic therapy. No CNS involvement, use of osimertinib or first-generation TKI plus chemotherapy or ALK inhibitor in ALK-positive cases prognosticated better PFS. When compared to other systemic therapies, osimertinib improved PFS in patients with or without additional mutations, although it was statistically significant for the former group only ( = 0.002).
CONCLUSION
The incidence of T790M is low. Osimertinib in frontline therapy provides promising outcomes.
PubMed: 35919239
DOI: 10.3332/ecancer.2022.1385 -
Genes Apr 2022The discovery and characterization of transposable element (TE) families are crucial tasks in the process of genome annotation. Careful curation of TE libraries for each... (Review)
Review
The discovery and characterization of transposable element (TE) families are crucial tasks in the process of genome annotation. Careful curation of TE libraries for each organism is necessary as each has been exposed to a unique and often complex set of TE families. methods have been developed; however, a fully automated and accurate approach to the development of complete libraries remains elusive. In this review, we cover established methods and recent developments in TE analysis. We also present various methodologies used to assess these tools and discuss opportunities for further advancement of the field.
Topics: DNA Transposable Elements
PubMed: 35456515
DOI: 10.3390/genes13040709 -
ACM-BCB ... ... : the ... ACM... Sep 2023The high-throughput short-reads RNA-seq protocols often produce paired-end reads, with the middle portion of the fragments being unsequenced. We explore if the...
The high-throughput short-reads RNA-seq protocols often produce paired-end reads, with the middle portion of the fragments being unsequenced. We explore if the full-length fragments can be computationally reconstructed from the sequenced two ends in the absence of the reference genome-a problem here we refer to as bridging. Solving this problem provides longer, more informative RNA-seq reads, and benefits downstream RNA-seq analysis such as transcript assembly, expression quantification, and splicing differential analysis. However, bridging is a challenging and complicated task owing to alternative splicing, transcript noises, and sequencing errors. It remains unclear if the data provides sufficient information for accurate bridging, let alone efficient algorithms that determine the true bridges. Methods have been proposed to bridge paired-end reads in the presence of reference genome (called reference-based bridging), but the algorithms are far away from scaling for bridging as the underlying compacted de Bruijn graph (cdBG) used in the latter task often contains millions of vertices and edges. We designed a new truncated Dijkstra's algorithm for this problem, and proposed a novel algorithm that reuses the shortest path tree to avoid running the truncated Dijkstra's algorithm from scratch for all vertices for further speeding up. These innovative techniques result in scalable algorithms that can bridge all paired-end reads in a cdBG with millions of vertices. Our experiments showed that paired-end RNA-seq reads can be accurately bridged to a large extent. The resulting tool is freely available at https://github.com/Shao-Group/rnabridge-denovo.
PubMed: 38045531
DOI: 10.1145/3584371.3612987 -
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 -
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