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Cell Reports Jan 2024Dynamic chromosome remodeling and nuclear compartmentalization take place during mammalian meiotic prophase I. We report here that the crucial roles of male...
Dynamic chromosome remodeling and nuclear compartmentalization take place during mammalian meiotic prophase I. We report here that the crucial roles of male pachynema-specific protein (MAPS) in pachynema progression might be mediated by its liquid-liquid phase separation in vitro and in cellulo. MAPS forms distinguishable liquid phases, and deletion or mutations of its N-terminal amino acids (aa) 2-9 disrupt its secondary structure and charge properties, impeding phase separation. Maps pachytene spermatocytes exhibit defects in nucleus compartmentalization, including defects in forming sex bodies, altered nucleosome composition, and disordered chromatin accessibility. Maps male mice expressing MAPS protein lacking aa 2-9 phenocopy Maps mice. Moreover, a frameshift mutation in C3orf62, the human counterpart of Maps, is correlated with nonobstructive azoospermia in a patient exhibiting pachynema arrest in spermatocyte development. Hence, the phase separation property of MAPS seems essential for pachynema progression in mouse and human spermatocytes.
Topics: Humans; Male; Mice; Animals; Chromatin; Meiosis; Pachytene Stage; Phase Separation; Meiotic Prophase I; Spermatocytes; Mammals
PubMed: 38175751
DOI: 10.1016/j.celrep.2023.113651 -
Aging Dec 2023To investigate the alteration of PV interneurons in ALS mainly focusing its dynamic changes and its relationship with motor neurons and ErbB4 signaling.
OBJECTIVE
To investigate the alteration of PV interneurons in ALS mainly focusing its dynamic changes and its relationship with motor neurons and ErbB4 signaling.
METHODS
SOD1G93A mice were used as ALS model. ALS animals were divided into different groups according to birth age: symptomatic prophase (50~60 days), symptomatic phase (90~100 days), and symptomatic progression (130~140 days). Immunofluorescence was performed for measurement of PV-positive interneurons, MMP-9, ChAT, NeuN and ErbB4. RT-qPCR and western blot were used to determine the expression of PV and MMP-9.
RESULTS
PV expression was remarkably higher in the anterior horn of gray matter compared with posterior horn and area in the middle of gray matter in control mice. In ALS mice, PV, MMP-9 and ErbB4 levels were gradually decreased along with onset. PV, MMP-9 and ErbB4 levels in ALS mice were significantly down-regulated than control mice after onset, indicating the alteration of PV interneurons, FαMNs and ErbB4. SαMNs levels only decreased remarkably at symptomatic progression in ALS mice compared with control mice, while γMNs levels showed no significant change during whole period in all mice. MMP-9 and ErbB4 were positively correlated with PV. NRG1 treatment significantly enhanced the expression of ErBb4, PV and MMP-9 in ALS mice.
CONCLUSION
PV interneurons decrease is along with FαMNs and ErbB4 decrease in ALS mice.
Topics: Animals; Mice; Amyotrophic Lateral Sclerosis; Interneurons; Matrix Metalloproteinase 9; Mice, Transgenic; Parvalbumins; Receptor, ErbB-4; Neuregulin-1
PubMed: 38157256
DOI: 10.18632/aging.205351 -
MicroPublication Biology 2023Immunofluorescence microscopy is a widely adopted method for studying meiotic prophase in the nematode model organism, . An in-depth examination of specific meiotic...
Immunofluorescence microscopy is a widely adopted method for studying meiotic prophase in the nematode model organism, . An in-depth examination of specific meiotic processes requires the quantitative analysis of immunofluorescence images, which often involves the segmentation of individual cells or nuclei. Here, we introduce our image analysis pipeline to automate significant portions of this task. This pipeline relies on the powerful deep learning model Cellpose 2.0 to segment cellular structures. To further improve the segmentation accuracy for germline nuclei stained for chromatin or synaptonemal complexes, we retrained the generalist Cellpose model and integrated our data processing pipeline into the easy-to-use Cell-ACDC image analysis software. Our pipeline thus makes deep learning-based segmentation of nuclei in the distal germline of accessible for users without coding experience.
PubMed: 38148986
DOI: 10.17912/micropub.biology.001062 -
Journal of Developmental Biology Dec 2023The karyosphere (karyosome) is a structure that forms in the oocyte nucleus-germinal vesicle (GV)-at the diplotene stage of meiotic prophase due to the assembly of all...
The karyosphere (karyosome) is a structure that forms in the oocyte nucleus-germinal vesicle (GV)-at the diplotene stage of meiotic prophase due to the assembly of all chromosomes in a limited portion of the GV. In some organisms, the karyosphere has an extrachromosomal external capsule, the marker protein of which is nuclear F-actin. Despite many years of theories about the formation of the karyosphere capsule (KC) in the GV of the common frog , we present data that cast doubt on its existence, at least in this species. Specific extrachromosomal strands, which had been considered the main elements of the frog's KC, do not form a continuous layer around the karyosphere and, according to immunogold labeling, do not contain structural proteins, such as actin and lamin B. At the same time, F-actin is indeed noticeably concentrated around the karyosphere, creating the illusion of a capsule at the light microscopy/fluorescence level. The barrier-to-autointegration factor (BAF) and one of its functional partners-LEMD2, an inner nuclear membrane protein-are not localized in the strands, suggesting that the strands are not functional counterparts of the nuclear envelope. The presence of characteristic strands in the GV of late oocytes may reflect an excess of SMC1 involved in the structural maintenance of diplotene oocyte chromosomes at the karyosphere stage, since SMC1 has been shown to be the most abundant protein in the strands. Other characteristic microstructures-the so-called , very similar in ultrastructure to the nuclear pore complexes-do not contain nucleoporins Nup35 and Nup93, and, therefore, they cannot be considered autonomous pore complexes, as previously thought. Taken together, our data indicate that traditional ideas about the existence of the KC as a special structural compartment of the GV are to be revisited.
PubMed: 38132712
DOI: 10.3390/jdb11040044 -
Schizophrenia (Heidelberg, Germany) Dec 2023Quantification of treatment response is crucial to optimize outcomes for patients with schizophrenia. In this study, we evaluated the relationship between quantitative...
Quantification of treatment response is crucial to optimize outcomes for patients with schizophrenia. In this study, we evaluated the relationship between quantitative measures of clinician-rated symptom severity and self-rated side effects, well-being, and functioning among inpatients with schizophrenia using the six-item version of the Positive and Negative Syndrome Scale (PANSS-6), the Glasgow Antipsychotic Side-effect Scale (GASS), the WHO-Five Well-being Index (WHO-5), and the Sheehan Disability Scale (SDS). All measurements were conducted as close to admission and discharge as possible. Well-being and functioning were found to be most strongly associated with the additive effect of symptoms and side effects, while changes in side effects, well-being, and functioning appeared to be relatively independent from changes in symptom severity. The use of both symptom and side effect measures should inform clinical decision-making in the treatment of schizophrenia, as it has the potential to optimize functioning and well-being.
PubMed: 38104195
DOI: 10.1038/s41537-023-00420-6 -
Frontiers in Cell and Developmental... 2023Actin is a multi-functional protein that is involved in numerous cellular processes including cytoskeleton regulation, cell migration, and cellular integrity. In these... (Review)
Review
Actin is a multi-functional protein that is involved in numerous cellular processes including cytoskeleton regulation, cell migration, and cellular integrity. In these processes, actin's role in respect to its structure, complex mechanical, and protein-binding properties has been studied primarily in the cytoplasmic and cellular membrane compartments. However, its role in somatic cell nuclei has recently become evident where it participates in transcription, chromatin remodeling, and DNA damage repair. What remains enigmatic is the involvement of nuclear actin in physiological processes that lead to the generation of germ cells, in general, and primary spermatocytes, in particular. Here, we will discuss the possible role and nuclear localization of actin during meiotic prophase I and its interaction with chromatin remodeling complexes, the latter being essential for the control of pairing of homologous chromosomes, cross-over formation, and recombination. It is our hope that this perspective article will extend the scope of actin's nuclear function in germ cells undergoing meiotic division.
PubMed: 38078006
DOI: 10.3389/fcell.2023.1295452 -
Schizophrenia Research Jun 2024Pharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs). (Comparative Study)
Comparative Study
BACKGROUND
Pharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs).
OBJECTIVE
In a 2021 article, the United Kingdom (UK) had >90 % of European clozapine-related fatal outcomes in VigiBase, the World Health Organization's pharmacovigilance database. Two possibly opposing hypotheses could explain this disparity: 1) fewer reported fatal outcomes in other Western European countries mainly reflect underreporting to VigiBase, and 2) the higher number of UK reports reflects higher real relative mortality.
METHODS
VigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions.
RESULTS
The UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label "death" was the top cause in the world (46 %) and in the UK (33 %). "Pneumonia" was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1-10 % of the UK clozapine fatal outcome number.
CONCLUSIONS
Different Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases.
Topics: Clozapine; Humans; Antipsychotic Agents; Europe; United Kingdom; Pharmacovigilance; Adverse Drug Reaction Reporting Systems; Adult; Male; Databases, Factual; Female; Middle Aged
PubMed: 38065799
DOI: 10.1016/j.schres.2023.11.010 -
Proceedings of the National Academy of... Dec 2023Successful chromosome segregation into gametes depends on tightly regulated interactions between the parental chromosomes. During meiosis, chromosomes are aligned...
Successful chromosome segregation into gametes depends on tightly regulated interactions between the parental chromosomes. During meiosis, chromosomes are aligned end-to-end by an interface called the synaptonemal complex, which also regulates exchanges between them. However, despite the functional and ultrastructural conservation of this essential interface, how protein-protein interactions within the synaptonemal complex regulate chromosomal interactions remains poorly understood. Here, we describe a genetic interaction in the synaptonemal complex, comprised of short segments of three proteins, SYP-1, SYP-3, and SYP-4. We identified the interaction through a saturated suppressor screen of a mutant that destabilizes the synaptonemal complex. The specificity and tight distribution of suppressors suggest a charge-based interface that promotes interactions between synaptonemal complex subunits and, in turn, allows intimate interactions between chromosomes. Our work highlights the power of genetic studies to illuminate the mechanisms that underlie meiotic chromosome interactions.
Topics: Animals; Caenorhabditis elegans; Synaptonemal Complex; Caenorhabditis elegans Proteins; Chromosomal Proteins, Non-Histone; Meiosis; Chromosome Pairing; Nuclear Proteins
PubMed: 38055743
DOI: 10.1073/pnas.2314335120 -
BMJ Open Nov 2023Given the high prevalence of mental health disorders and their significant socioeconomic burden, there is a need to develop improved treatments, and to evaluate them...
INTRODUCTION
Given the high prevalence of mental health disorders and their significant socioeconomic burden, there is a need to develop improved treatments, and to evaluate them through placebo-controlled trials. However, the magnitude of the placebo response in randomised controlled trials to test medications may be substantial, affecting their interpretation. Therefore, improved understanding of the patient, trial and mental disorder factors that influence placebo responses would inform clinical trial design to better detect active treatment effects. There is a growing literature exploring the placebo response within specific mental health disorders, but no overarching synthesis of this research has been produced to date. We present a protocol for an umbrella review of systematic reviews and/or meta-analyses in which we aim to understand the effect size and potential predictors of placebo response within, and across, mental health disorders.
METHODS AND ANALYSIS
We will systematically search databases (Medline, PsycINFO, EMBASE+EMBASE Classic, Web of Knowledge) for systematic reviews and/or meta-analyses that report placebo effect size in clinical trials in patients with mental health disorders (initial search date 23 October 2022). Screening of abstracts and full texts will be done in pairs. We will extract data to qualitatively examine how placebo effect size varies across mental health disorders. We also plan to qualitatively summarise predictors of increased placebo response identified either quantitatively (eg, through meta-regression) or qualitatively. Risk of bias will be assessed using the AMSTAR-2 tool. We aim to not only summarise the current literature but also to identify gaps in knowledge and generate further hypotheses.
ETHICS AND DISSEMINATION
We do not believe there are any specific ethical considerations relevant to this study. We will publish the results in a peer-reviewed journal.
Topics: Humans; Mental Disorders; Mental Health; Placebo Effect; Systematic Reviews as Topic; Review Literature as Topic
PubMed: 38035741
DOI: 10.1136/bmjopen-2023-073946 -
Vavilovskii Zhurnal Genetiki I Selektsii Oct 2023Germline-restricted chromosomes (GRCs) are present in the genomes of germline cells and absent from somatic cells. A GRC is found in all species of the songbirds...
Germline-restricted chromosomes (GRCs) are present in the genomes of germline cells and absent from somatic cells. A GRC is found in all species of the songbirds (Passeri) and in none of the other bird orders studied to date. This indicates that GRC originated in the common ancestor of the songbirds. The germline-restricted chromosome is permanently absent from somatic cells of the songbird, while female germline cells usually contain two copies of GRC and male ones have one copy. In females, GRCs undergo synapsis and restricted recombination in their terminal regions during meiotic prophase. In males, it is almost always eliminated from spermatocytes. Thus, GRC is inherited almost exclusively through the maternal lineage. The germline-restricted chromosome is a necessary genomic element in the germline cells of songbirds. To date, the GRC genetic composition has been studied in four species only. Some GRC genes are actively expressed in female and male gonads, controlling the development of germline cells and synthesis of the proteins involved in the organization of meiotic chromosomes. Songbird species vary in GRC size and genetic composition. The GRC of each bird species consists of amplified and modified copies of genes from the basic genome of that species. The level of homology between GRCs of different species is relatively low, indicating a high rate of genetic evolution of this chromosome. Transmission through the maternal lineage and suppression of the recombination contribute significantly to the accelerated evolution of GRCs. One may suggest that the rapid coordinated evolution between the GRC genes and the genes of the basic genome in the songbirds might be responsible for the explosive speciation and adaptive radiation of this most species-rich and diverse infraorder of birds.
PubMed: 38023808
DOI: 10.18699/VJGB-23-75