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Chromatin remodeler CHD8 is required for spermatogonial proliferation and early meiotic progression.Nucleic Acids Research Apr 2024Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The...
Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The chromatin remodeling mechanisms underpinning early meiotic stages remain poorly understood. Here we focus on the function of one of the major autism genes, CHD8, in spermatogenesis, based on the epidemiological association between autism and low fertility rates. Specific ablation of Chd8 in germ cells results in gradual depletion of undifferentiated spermatogonia and the failure of meiotic double-strand break (DSB) formation, leading to meiotic prophase I arrest and cell death. Transcriptional analyses demonstrate that CHD8 is required for extensive activation of spermatogenic genes in spermatogonia, necessary for spermatogonial proliferation and meiosis. CHD8 directly binds and regulates genes crucial for meiosis, including H3K4me3 histone methyltransferase genes, meiotic cohesin genes, HORMA domain-containing genes, synaptonemal complex genes, and DNA damage response genes. We infer that CHD8 contributes to meiotic DSB formation and subsequent meiotic progression through combined regulation of these meiosis-related genes. Our study uncovers an essential role of CHD8 in the proliferation of undifferentiated spermatogonia and the successful progression of meiotic prophase I.
Topics: Male; Cell Proliferation; Chromatin; Meiosis; Spermatogenesis; Spermatogonia; Animals; Mice
PubMed: 38224953
DOI: 10.1093/nar/gkad1256 -
Cell Death & Disease Jul 2023Mammalian oocytes spend most of their life in a unique state of cell cycle arrest at meiotic prophase I, during which time they are exposed to countless DNA-damaging...
Mammalian oocytes spend most of their life in a unique state of cell cycle arrest at meiotic prophase I, during which time they are exposed to countless DNA-damaging events. Recent studies have shown that DNA double-strand break repair occurs predominantly via the homologous recombination (HR) pathway in small non-growing meiotically arrested oocytes (primordial follicle stage). However, the DNA repair mechanisms employed by fully grown meiotically arrested oocytes (GV-stage) have not been studied in detail. Here we established a conditional knockout mouse model to explore the role of Ku80, a critical component of the nonhomologous end joining (NHEJ) pathway, in the repair of DNA damage in GV oocytes. GV oocytes lacking Ku80 failed to repair etoposide-induced DNA damage, even when only low levels of damage were sustained. This indicates Ku80 is needed to resolve DSBs and that HR cannot compensate for a compromised NHEJ pathway in fully-grown oocytes. When higher levels of DNA damage were induced, a severe delay in M-phase entry was observed in oocytes lacking XRCC5 compared to wild-type oocytes, suggesting that Ku80-dependent repair of DNA damage is important for the timely release of oocytes from prophase I and resumption of meiosis. Ku80 was also found to be critical for chromosome integrity during meiotic maturation following etoposide exposure. These data demonstrate that Ku80, and NHEJ, are vital for quality control in mammalian GV stage oocytes and reveal that DNA repair pathway choice differs in meiotically arrested oocytes according to growth status.
Topics: Animals; Mice; DNA Damage; DNA End-Joining Repair; DNA Repair; Etoposide; Mammals; Meiosis; Oocytes
PubMed: 37407587
DOI: 10.1038/s41419-023-05886-x -
Nucleic Acids Research Sep 2023RAD54 family DNA translocases partner with RAD51 recombinases to ensure stable genome inheritance, exhibiting biochemical activities both in promoting recombinase...
RAD54 family DNA translocases partner with RAD51 recombinases to ensure stable genome inheritance, exhibiting biochemical activities both in promoting recombinase removal and in stabilizing recombinase association with DNA. Understanding how such disparate activities of RAD54 paralogs align with their biological roles is an ongoing challenge. Here we investigate the in vivo functions of Caenorhabditis elegans RAD54 paralogs RAD-54.L and RAD-54.B during meiotic prophase, revealing distinct contributions to the dynamics of RAD-51 association with DNA and to the progression of meiotic double-strand break repair (DSBR). While RAD-54.L is essential for RAD-51 removal from meiotic DSBR sites to enable recombination progression, RAD-54.B is largely dispensable for meiotic DSBR. However, RAD-54.B is required to prevent hyperaccumulation of RAD-51 on unbroken DNA during the meiotic sub-stage when DSBs and early recombination intermediates form. Moreover, DSB-independent hyperaccumulation of RAD-51 foci in the absence of RAD-54.B is RAD-54.L-dependent, revealing a hidden activity of RAD-54.L in promoting promiscuous RAD-51 association that is antagonized by RAD-54.B. We propose a model wherein a division of labor among RAD-54 paralogs allows germ cells to ramp up their capacity for efficient homologous recombination that is crucial to successful meiosis while counteracting potentially deleterious effects of unproductive RAD-51 association with unbroken DNA.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Carrier Proteins; DNA; DNA Repair; Germ Cells; Meiosis; Prophase; Rad51 Recombinase; DNA Helicases
PubMed: 37548405
DOI: 10.1093/nar/gkad638 -
Psychological Medicine Jul 2023Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use as monotherapy and adjunctive therapy.
METHODS
A systematic review and a meta-analysis were conducted on randomized placebo-controlled trials (RCTs) that reported on the efficacy and safety/tolerability of antipsychotics for the treatment of adults with MDD. Data of both monotherapy and adjunctive antipsychotic use were extracted, but analyzed separately using a random-effects model. Co-primary outcomes were study-defined-treatment response and intolerability-related discontinuation. We also illustrated the risk/benefit balance of antipsychotics for MDD, using two-dimensional graphs representing the primary efficacy and safety/tolerability outcome. Secondary outcomes included psychopathology, remission, all-cause-discontinuation, inefficacy-related discontinuation, and adverse events.
RESULTS
Forty-five RCTs with 12 724 patients were included in the analysis. In monotherapy (studies = 13, = 4375), amisulpride [1.99 (1.55-2.55)], sulpiride [1.50 (1.03-2.17)], and quetiapine [1.48 (1.23-1.78)] were significantly superior to placebo regarding treatment response. However, intolerability-related discontinuations were significantly higher compared to placebo with amisulpride and quetiapine. In adjunctive therapy (studies = 32, = 8349), ziprasidone [1.80 (1.07-3.04)], risperidone [1.59 (1.19-2.14)], aripiprazole [1.54 (1.35-1.76)], brexpiprazole [1.41 (1.21-1.66)], cariprazine [1.27 (1.07-1.52)], and quetiapine [1.23 (1.08-1.41)] were significantly superior to placebo regarding treatment response. However, of these antipsychotics that were superior to placebo, only risperidone was equivalent to placebo regarding discontinuation due to intolerability, while the other antipsychotics were inferior.
CONCLUSION
Results suggest that there are significant differences regarding the risk/benefit ratio among antipsychotics for MDD, which should inform clinical care.
Topics: Adult; Humans; Antipsychotic Agents; Quetiapine Fumarate; Risperidone; Depressive Disorder, Major; Amisulpride; Olanzapine; Benzodiazepines; Dibenzothiazepines
PubMed: 35510505
DOI: 10.1017/S0033291722000745 -
The British Journal of Psychiatry : the... Jul 2023Recent research has led to important changes in the concepts and assessment of negative symptoms in schizophrenia. We review current negative symptom concepts and their... (Review)
Review
Recent research has led to important changes in the concepts and assessment of negative symptoms in schizophrenia. We review current negative symptom concepts and their clinical implications, as well as new methods of assessing these symptoms. These changes hold promise for improving our understanding and treatment of negative symptoms.
Topics: Humans; Psychiatric Status Rating Scales; Schizophrenic Psychology; Schizophrenia; Psychometrics
PubMed: 37424200
DOI: 10.1192/bjp.2023.68 -
BioRxiv : the Preprint Server For... Aug 2023In dividing cells, accurate chromosome segregation depends on sister chromatid cohesion, protein linkages that are established during DNA replication. Faithful...
In dividing cells, accurate chromosome segregation depends on sister chromatid cohesion, protein linkages that are established during DNA replication. Faithful chromosome segregation in oocytes requires that cohesion, first established in S phase, remain intact for days to decades, depending on the organism. Premature loss of meiotic cohesion in oocytes leads to the production of aneuploid gametes and contributes to the increased incidence of meiotic segregation errors as women age (maternal age effect). The prevailing model is that cohesive linkages do not turn over in mammalian oocytes. However, we have previously reported that cohesion-related defects arise in Drosophila oocytes when individual cohesin subunits or cohesin regulators are knocked down after meiotic S phase. Here we use two strategies to express a tagged cohesin subunit exclusively during mid-prophase in Drosophila oocytes and demonstrate that newly expressed cohesin is used to form linkages after meiotic S phase. Moreover, nearly complete turnover of chromosome-associated cohesin occurs during meiotic prophase, with faster replacement on the arms than at the centromeres. Unlike S-phase cohesion establishment, the formation of new cohesive linkages during meiotic prophase does not require acetylation of conserved lysines within the Smc3 head. Our findings indicate that maintenance of cohesion between S phase and chromosome segregation in Drosophila oocytes requires an active cohesion rejuvenation program that generates new cohesive linkages during meiotic prophase.
PubMed: 37645916
DOI: 10.1101/2023.08.17.553729 -
The Lancet. Psychiatry Dec 2023The youngest children in a school class are more likely than the oldest to be diagnosed with ADHD, but this relative age effect is less frequent in older than in younger... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The youngest children in a school class are more likely than the oldest to be diagnosed with ADHD, but this relative age effect is less frequent in older than in younger school-grade children. However, no study has explored the association between relative age and the persistence of ADHD diagnosis at older ages. We aimed to quantify the association between relative age and persistence of ADHD at older ages.
METHODS
For this meta-analysis, we searched MEDLINE, Embase, CINAHL, PsycINFO, and PubPsych up to April 1, 2022, with terms related to "cohort" and "ADHD" with no date, publication type, or language restrictions. We gathered individual participant data from prospective cohorts that included at least ten children identified with ADHD before age 10 years. ADHD was defined by either a clinical diagnosis or symptoms exceeding clinical cutoffs. Relative age was recorded as the month of birth in relation to the school-entry cutoff date. Study authors were invited to share raw data or to apply a script to analyse data locally and generate anonymised results. Our outcome was ADHD status at a diagnostic reassessment, conducted at least 4 years after the initial assessment and after age 10 years. No information on sex, gender, or ethnicity was collected. We did a two-stage random-effects individual participant data meta-analysis to assess the association of relative age with persistence of ADHD at follow-up. This study was registered with PROSPERO, CRD42020212650.
FINDINGS
Of 33 119 studies generated by our search, we identified 130 eligible unique studies and were able to gather individual participant data from 57 prospective studies following up 6504 children with ADHD. After exclusion of 16 studies in regions with a flexible school entry system that did not allow confident linkage of birthdate to relative age, the primary analysis included 41 studies in 15 countries following up 4708 children for a period of 4 to 33 years. We found that younger relative age was not statistically significantly associated with ADHD persistence at follow-up (odds ratio 1·02, 95% CI 0·99-1·06; p=0·19). We observed statistically significant heterogeneity in our model (Q=75·82, p=0·0011, I=45%). Participant-level sensitivity analyses showed similar results in cohorts with a robust relative age effect at baseline and when restricting to cohorts involving children with a clinical diagnosis of ADHD or with a follow-up duration of more than 10 years.
INTERPRETATION
The diagnosis of ADHD in younger children in a class is no more likely to be disconfirmed over time than that of older children in the class. One interpretation is that the relative age effect decreases the likelihood of children of older relative age receiving a diagnosis of ADHD, and another is that assigning a diagnostic label of ADHD leads to unexplored carryover effects of the initial diagnosis that persist over time. Future studies should be conducted to explore these interpretations further.
FUNDING
None.
Topics: Child; Humans; Adolescent; Aged; Child, Preschool; Young Adult; Adult; Attention Deficit Disorder with Hyperactivity; Prospective Studies; Attention; Schools
PubMed: 37898142
DOI: 10.1016/S2215-0366(23)00272-9 -
Nature Communications May 2024The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an...
The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA-directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas.
Topics: Humans; Protein Inhibitors of Activated STAT; Animals; Cell Line, Tumor; Mitosis; Mice; Thyroid Neoplasms; RNA Interference; Spindle Apparatus; Molecular Chaperones; Xenograft Model Antitumor Assays; Proteasome Endopeptidase Complex; Sumoylation; Carcinoma; Female
PubMed: 38744818
DOI: 10.1038/s41467-024-47751-1 -
CNS Drugs Apr 2024Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are... (Review)
Review
Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that "extrapyramidal symptoms" is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually.
Topics: Humans; Aged; Dystonia; Cholinergic Antagonists; Psychomotor Agitation; Movement Disorders; Tardive Dyskinesia; Antipsychotic Agents; Neuroleptic Malignant Syndrome; Dystonic Disorders
PubMed: 38502289
DOI: 10.1007/s40263-024-01078-z -
Nature Communications Apr 2024Meiotic prophase progression is differently regulated in males and females. In males, pachytene transition during meiotic prophase is accompanied by robust alteration in...
Meiotic prophase progression is differently regulated in males and females. In males, pachytene transition during meiotic prophase is accompanied by robust alteration in gene expression. However, how gene expression is regulated differently to ensure meiotic prophase completion in males remains elusive. Herein, we identify HSF5 as a male germ cell-specific heat shock transcription factor (HSF) for meiotic prophase progression. Genetic analyzes and single-cell RNA-sequencing demonstrate that HSF5 is essential for progression beyond the pachytene stage under non-stress conditions rather than heat stress. Chromatin binding analysis in vivo and DNA-binding assays in vitro suggest that HSF5 binds to promoters in a subset of genes associated with chromatin organization. HSF5 recognizes a DNA motif different from typical heat shock elements recognized by other canonical HSFs. This study suggests that HSF5 is an atypical HSF that is required for the gene expression program for pachytene transition during meiotic prophase in males.
Topics: Mice; Male; Heat Shock Transcription Factors; Meiotic Prophase I; Mice, Knockout; Mice, Inbred C57BL; Spermatogenesis; Testis; Heat-Shock Response; Female
PubMed: 38684656
DOI: 10.1038/s41467-024-47601-0