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Current Opinion in Cell Biology Oct 2023Membrane-bound organelles allow cells to traffic cargo and separate and regulate metabolic pathways. While many organelles are generated by the growth and division of... (Review)
Review
Membrane-bound organelles allow cells to traffic cargo and separate and regulate metabolic pathways. While many organelles are generated by the growth and division of existing organelles, some can also be produced de novo, often in response to metabolic cues. This review will discuss recent advances in our understanding of the early steps in the de novo biogenesis of peroxisomes, lipid droplets, lipoproteins, and autophagosomes. These organelles play critical roles in cellular lipid metabolism and other processes, and their dysfunction causes or is linked to several human diseases. The de novo biogenesis of these organelles occurs in or near the endoplasmic reticulum membrane. This review summarizes recent progress and highlights open questions.
Topics: Humans; Peroxisomes; Lipid Droplets; Autophagosomes; Endoplasmic Reticulum; Lipid Metabolism; Lipoproteins
PubMed: 37531895
DOI: 10.1016/j.ceb.2023.102210 -
Frontiers in Genetics 2023Intellectual disability (ID) is defined by cognitive and social adaptation defects. Variants in the gene, which encodes the brain-specific cytoplasmic protein SYNGAP1,...
Intellectual disability (ID) is defined by cognitive and social adaptation defects. Variants in the gene, which encodes the brain-specific cytoplasmic protein SYNGAP1, are commonly associated with ID. The aim of this study was to identify novel gene variants in Chinese individuals with ID and evaluate the pathogenicity of the detected variants. Whole exome sequencing (WES) was performed on 113 patients diagnosed with ID. In the study, two variants in were identified. Sanger sequencing was used to confirm these variants. Minigene assays were used to verify whether the intronic variant in influenced the normal splicing of mRNA. Two heterozygous pathogenic variants in c.333del and c.664-2A>G, were identified in two ID patients separately. The c.333del variant has been reported previously as a finding in a child with ID, while the c.664-2A>G variant was novel intronic variant, which has not been reported in the literature. Functional studies showed that c.664-2A>G could cause aberrant splicing, resulting in exon 7 skipping and a 16bp deletion within exon 7. We identified two pathogenic heterozygous variants in in two patients with ID, among which the c.664-2A>G variant was a novel pathogenic variant. Our findings further enrich the variant spectrum of the gene and provide a research basis for the genetic diagnosis of ID.
PubMed: 37928246
DOI: 10.3389/fgene.2023.1270175 -
International Journal of Cardiology Dec 2023Data on the incidence and factors associated with de novo atrial fibrillation (AF) in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is limited....
BACKGROUND
Data on the incidence and factors associated with de novo atrial fibrillation (AF) in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is limited. We described the incidence and factors associated with de novo AF in patients diagnosed with ATTRwt-CA to drive tailored arrhythmia screening.
METHODS
Multicenter, retrospective, observational cohort study performed in six referral centers for CA. All consecutive patients diagnosed with ATTRwt-CA between 2004 and 2020 with >6-month follow up (FU) were enrolled and divided into three groups according to presence of AF: (1)patients with 'known AF'; (2)patients in 'sinus rhythm' and (3)patients developing 'de novo AF' during FU. Incidence and factors associated with AF in patients with ATTRwt were the primary outcomes.
RESULTS
Overall, 266 patients were followed for a median of 19 [11-33] months: 148 (56%) with known AF, 84 (31.6%) with sinus rhythm, and 34 (12.8%) with de novo AF. At Fine-Gray competing risk analysis to account for mortality, PR (sub-distribution hazard ratio [SHR] per Δms: 1.008, 95% C.I. 1.001-1.013, p = 0.008), QRS (SHR per Δms: 1.012, 95% C.I. 1.001-1.022, p = 0.046) and left atrial diameter ≥ 50 mm (SHR: 2.815,95% C.I. 1.483-5.342, p = 0.002) were associated with de novo AF. Patients with at least two risk factors (PR ≥ 200 ms, QRS ≥ 120 ms or LAD≥50 mm) had a higher risk of developing de novo AF compared to patients with no risk factors (HR 14.918 95% C.I. 3.242-31.646, p = 0.008).
CONCLUSIONS
At the end of the study almost 70% patients had AF. Longer PR and QRS duration and left atrial dilation are associated with arrhythmia onset.
PubMed: 37689398
DOI: 10.1016/j.ijcard.2023.131346 -
Human Genetics Jul 2023The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition,...
The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier-Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo MCM6 variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo MCM6 variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of MCM6 variants in the diagnostic arsenal of NDD.
Topics: Humans; Autism Spectrum Disorder; Cysteine; Neurodevelopmental Disorders; Cell Cycle Proteins; DNA Helicases; Microcephaly; Phenotype; Zinc; Intellectual Disability; Minichromosome Maintenance Complex Component 6
PubMed: 37198333
DOI: 10.1007/s00439-023-02569-7 -
Chinese Clinical Oncology Aug 2023Nasopharyngeal carcinoma (NPC) with de novo distant metastasis (M1) is classified as stage IVB in the 8th edition of the staging system jointly adopted by the American... (Review)
Review
BACKGROUND AND OBJECTIVE
Nasopharyngeal carcinoma (NPC) with de novo distant metastasis (M1) is classified as stage IVB in the 8th edition of the staging system jointly adopted by the American Joint Committee on Cancer and the International Union against Cancer Control. Patients with M1 disease generally have a relatively short life expectancy. This review discusses the personalized and intensified treatment strategies for de novo metastatic NPC.
METHODS
A literature search was conducted on PubMed to identify peer-reviewed publications on subdivisions of M1 disease and treatment of de novo metastatic NPC. Clinicaltrials.gov and Chinese Clinical Trial Register were searched to identify ongoing clinical trials evaluating systemic or local therapy of previously untreated metastatic NPC.
KEY CONTENT AND FINDINGS
M1 encompasses a diverse group of diseases. Several important factors, including tumor burden, EBV-DNA levels, location of involvement, the number of metastasis, and treatment strategies, influence the prognosis of NPC patients. Researchers have attempted to define M1 subcategorization to reflect the underlying risk profile and tailor personalized treatment. Recent advancements have brought new hope for this otherwise incurable condition. In the era of immunotherapy, checkpoint inhibitors have become the first-line systemic treatment for metastatic NPC in JUPITER-02, CAPTAIN-1st, and RATIONALE-309. Additionally, the value of radical locoregional radiation therapy and ablative treatment to distant metastatic sites should not be overlooked in patients with de novo metastatic diseases. Locoregional radiation with concurrent chemotherapy, maintenance chemotherapy, and radical local treatment to metastatic sites are emerging as potential treatment options.
CONCLUSIONS
Given the diversity of metastatic NPC, a multimodality approach incorporating chemotherapy, immunotherapy, locoregional radiation and ablative treatment to metastatic sites has been shown to improve overall control. Further research is needed to determine the efficacy and optimal duration of maintenance therapy.
Topics: Humans; Immunotherapy; Multimodal Imaging; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Metastasis
PubMed: 37699604
DOI: 10.21037/cco-23-32 -
Proteins Jun 2024Understanding the emergence and structural characteristics of de novo and random proteins is crucial for unraveling protein evolution and designing novel enzymes....
Understanding the emergence and structural characteristics of de novo and random proteins is crucial for unraveling protein evolution and designing novel enzymes. However, experimental determination of their structures remains challenging. Recent advancements in protein structure prediction, particularly with AlphaFold2 (AF2), have expanded our knowledge of protein structures, but their applicability to de novo and random proteins is unclear. In this study, we investigate the structural predictions and confidence scores of AF2 and protein language model-based predictor ESMFold for de novo and conserved proteins from Drosophila and a dataset of comparable random proteins. We find that the structural predictions for de novo and random proteins differ significantly from conserved proteins. Interestingly, a positive correlation between disorder and confidence scores (pLDDT) is observed for de novo and random proteins, in contrast to the negative correlation observed for conserved proteins. Furthermore, the performance of structure predictors for de novo and random proteins is hampered by the lack of sequence identity. We also observe fluctuating median predicted disorder among different sequence length quartiles for random proteins, suggesting an influence of sequence length on disorder predictions. In conclusion, while structure predictors provide initial insights into the structural composition of de novo and random proteins, their accuracy and applicability to such proteins remain limited. Experimental determination of their structures is necessary for a comprehensive understanding. The positive correlation between disorder and pLDDT could imply a potential for conditional folding and transient binding interactions of de novo and random proteins.
Topics: Animals; Protein Folding; Conserved Sequence; Drosophila Proteins; Databases, Protein; Models, Molecular; Computational Biology; Proteins; Intrinsically Disordered Proteins; Protein Conformation; Amino Acid Sequence; Algorithms; Drosophila
PubMed: 38226524
DOI: 10.1002/prot.26652 -
Cancers Oct 2023De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since... (Review)
Review
De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities for de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have modified the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road toward personalized treatment for de novo mHSPC is still long, considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that did not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as a predictive biomarker requires further validation, and it remains to be ascertained how the genomic variants detected in mHSPC, which are regarded as predictive in the castration-resistant disease, can be exploited in the mHSPC setting.
PubMed: 37894312
DOI: 10.3390/cancers15204945 -
MedRxiv : the Preprint Server For... Apr 2024Insertion of active retroelements-L1s, s, and SVAs-can disrupt proper genome function and lead to various disorders including cancer. However, the role of retroelements...
Insertion of active retroelements-L1s, s, and SVAs-can disrupt proper genome function and lead to various disorders including cancer. However, the role of retroelements (DNRTs) in birth defects and childhood cancers has not been well characterized due to the lack of adequate data and efficient computational tools. Here, we examine whole-genome sequencing data of 3,244 trios from 12 birth defect and childhood cancer cohorts in the Gabriella Miller Kids First Pediatric Research Program. Using an improved version of our tool xTea (x-Transposable element analyzer) that incorporates a deep-learning module, we identified 162 DNRTs, as well as 2 pseudogene insertions. Several variants are likely to be causal, such as a insertion that led to the ablation of a whole exon in the gene in a proband with brain tumor. We observe a high SVA insertion burden in both high-intolerance loss-of-function genes and exons as well as more frequent insertions of paternal origin. We also identify potential mosaic DNRTs from embryonic stages. Our study reveals the important roles of DNRTs in causing birth defects and predisposition to childhood cancers.
PubMed: 38699361
DOI: 10.1101/2024.04.15.24305733 -
The American Surgeon Nov 2023Necrotizing pancreatitis (NP) may result de novo or following procedures such as ERCP or partial pancreatectomy (post-procedural), and may require surgical debridement....
BACKGROUND
Necrotizing pancreatitis (NP) may result de novo or following procedures such as ERCP or partial pancreatectomy (post-procedural), and may require surgical debridement. Video-assisted retroperitoneal debridement (VARD) is a standard approach for NP that employs a 5 cm incision with varying degrees of blind and open debridement. We describe our technique and outcomes of a modified VARD called laparoscopic-assisted pancreatic necrosectomy (LAPN) performed through a single 12 mm incision that uses direct laparoscopic visualization during debridement.
METHODS
At one medical center, all LAPN patients (2012-2020) were assessed for demographics, disease factors, and outcomes. Bivariate logistic regression analyses were performed to identify factors independently associated with recovery after LAPN for patients with vs post-procedural necrosum.
RESULTS
Over 9 years, 60 patients underwent LAPN for NP. Median age was 57 years (IQR: 47-66) and 43 (69%) were men. Pancreas necrosum was in 39 (63%) patients and post-procedural in 23 (37%). NP resolved with a median of 1 LAPN procedure and median hospitalization was 33 days. The LAPN major morbidity rate and in-hospital mortality rate were 47% and 5%. No significant differences were seen between NP etiology cohorts, although post-procedure NP patients trended towards a faster clinical recovery to baseline compared to patients (193 vs 394 days; -value = .07).
CONCLUSIONS
LAPN offers a smaller incision with excellent visualization and non-inferior outcomes, regardless of etiology, with likely faster recovery for patients with post-procedural vs necrotizing pancreatitis.
Topics: Male; Humans; Middle Aged; Female; Debridement; Pancreas; Laparoscopy; Pancreatitis, Acute Necrotizing; Retroperitoneal Space; Drainage; Treatment Outcome
PubMed: 35575200
DOI: 10.1177/00031348221101495 -
Urogynecology (Philadelphia, Pa.) Jan 2024Data on stress urinary incontinence (SUI) after minimally invasive sacrocolpopexy (SCP) with or without midurethral sling placement are limited.
IMPORTANCE
Data on stress urinary incontinence (SUI) after minimally invasive sacrocolpopexy (SCP) with or without midurethral sling placement are limited.
OBJECTIVE
The aim of the study was to determine the incidence of SUI after minimally invasive sacrocolpopexy.
STUDY DESIGN
This was a secondary analysis of 2 randomized clinical trials of participants undergoing SCP. Participants completed symptom assessment and urodynamic testing. Participants underwent SCP with or without midurethral sling placement. Preoperatively, participants were defined as having symptomatic SUI, occult SUI, or no SUI. Participants completed the Pelvic Floor Distress Inventory-20 at 6 and 12 months postoperatively and were categorized as having persistent SUI in the setting of symptomatic or occult SUI or de novo SUI.
RESULTS
Eighty-one participants were included. Sixty-one participants met inclusion criteria for the persistent SUI analysis: 42 participants with symptomatic SUI and 19 participants with occult SUI. There were 20 participants in the de novo SUI group. The overall incidence of persistent SUI was 26.2% (95% confidence interval [CI], 15.8%-39.1%) with 33.3% (95% CI, 19.6%-49.6%) of symptomatic and 10.5% (95% CI, 1.5%-33.1%) of occult participants. Bothersome symptoms were defined as "moderately" or "quite a bit" bothered postoperatively. Of participants with symptomatic SUI, 14.3% participants were bothered and no participants underwent retreatment. No patient with occult SUI was bothered; however, 1 patient underwent retreatment. The incidence of de novo SUI was 45% (95% CI, 23.1%-68.5%). No patient in the de novo SUI group was bothered or underwent SUI treatment.
CONCLUSIONS
Approximately 1 in 4 participants reported persistent SUI. Almost 50% reported de novo SUI. However, few participants were bothered or underwent treatment.
PubMed: 38212891
DOI: 10.1097/SPV.0000000000001454