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BioRxiv : the Preprint Server For... Jun 2024In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) are thought to receive fewer excitatory synaptic inputs and to have...
UNLABELLED
In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) are thought to receive fewer excitatory synaptic inputs and to have lower expression levels of activity-dependent genes and of genes involved in mitochondrial energy production. In concert, these findings from previous studies suggest that DLPFC L3PNs are hypoactive in schizophrenia, disrupting the patterns of activity that are crucial for working memory, which is impaired in the illness. However, whether lower PN activity produces alterations in inhibitory and/or excitatory synaptic strength has not been tested in the primate DLPFC. Here, we decreased PN excitability in rhesus monkey DLPFC using adeno-associated viral vectors (AAVs) to produce Cre recombinase-mediated overexpression of Kir2.1 channels, a genetic silencing tool that efficiently decreases neuronal excitability. In acute slices prepared from DLPFC 7-12 weeks post-AAV microinjections, Kir2.1-overexpressing PNs had a significantly reduced excitability largely attributable to highly specific effects of the AAV-encoded Kir2.1 channels. Moreover, recordings of synaptic currents showed that Kir2.1-overexpressing DLPFC PNs had reduced strength of excitatory synapses whereas inhibitory synaptic inputs were not affected. The decrease in excitatory synaptic strength was not associated with changes in dendritic spine number, suggesting that excitatory synapse quantity was unaltered in Kir2.1-overexpressing DLPFC PNs. These findings suggest that, in schizophrenia, the excitatory synapses on hypoactive L3PNs are weaker and thus might represent a substrate for novel therapeutic interventions.
SIGNIFICANCE STATEMENT
In schizophrenia, dorsolateral prefrontal cortex (DLPFC) pyramidal neurons (PNs) have both transcriptional and structural alterations that suggest they are hypoactive. PN hypoactivity is thought to produce synaptic alterations in schizophrenia, however the effects of lower neuronal activity on synaptic function in primate DLPFC have not been examined. Here, we used, for the first time in primate neocortex, adeno-associated viral vectors (AAVs) to reduce PN excitability with Kir2.1 channel overexpression and tested if this manipulation altered the strength of synaptic inputs onto the Kir2.1-overexpressing PNs. Recordings in DLPFC slices showed that Kir2.1 overexpression depressed excitatory (but not inhibitory), synaptic currents, suggesting that, in schizophrenia, the hypoactivity of PNs might be exacerbated by reduced strength of the excitatory synapses they receive.
PubMed: 38915638
DOI: 10.1101/2024.06.12.598658 -
BioRxiv : the Preprint Server For... Jun 2024Inverted formin-2 (INF2) gene mutations are among the most common causes of genetic focal segmental glomerulosclerosis (FSGS) with or without Charcot-Marie-Tooth (CMT)...
Inverted formin-2 (INF2) gene mutations are among the most common causes of genetic focal segmental glomerulosclerosis (FSGS) with or without Charcot-Marie-Tooth (CMT) disease. Recent studies suggest that INF2, through its effects on actin and microtubule arrangement, can regulate processes including vesicle trafficking, cell adhesion, mitochondrial calcium uptake, mitochondrial fission, and T-cell polarization. Despite roles for INF2 in multiple cellular processes, neither the human pathogenic R218Q INF2 point mutation nor the INF2 knock-out allele is sufficient to cause disease in mice. This discrepancy challenges our efforts to explain the disease mechanism, as the link between INF2-related processes, podocyte structure, disease inheritance pattern, and their clinical presentation remains enigmatic. Here, we compared the kidney responses to puromycin aminonucleoside (PAN) induced injury between R218Q INF2 point mutant knock-in and INF2 knock-out mouse models and show that R218Q INF2 mice are susceptible to developing proteinuria and FSGS. This contrasts with INF2 knock-out mice, which show only a minimal kidney phenotype. Co-localization and co-immunoprecipitation analysis of wild-type and mutant INF2 coupled with measurements of cellular actin content revealed that the R218Q INF2 point mutation confers a gain-of-function effect by altering the actin cytoskeleton, facilitated in part by alterations in INF2 localization. Differential analysis of RNA expression in PAN-stressed heterozygous R218Q INF2 point-mutant and heterozygous INF2 knock-out mouse glomeruli showed that the adhesion and mitochondria-related pathways were significantly enriched in the disease condition. Mouse podocytes with R218Q INF2, and an INF2-mutant human patient's kidney organoid-derived podocytes with an S186P INF2 mutation, recapitulate the defective adhesion and mitochondria phenotypes. These results link INF2-regulated cellular processes to the onset and progression of glomerular disease. Thus, our data demonstrate that gain-of-function mechanisms drive INF2-related FSGS and explain the autosomal dominant inheritance pattern of this disease.
PubMed: 38915495
DOI: 10.1101/2024.06.08.598088 -
BMC Biology Jun 2024Horizontal gene transfer (HGT) events have rarely been reported in gymnosperms. Gnetum is a gymnosperm genus comprising 25‒35 species sympatric with angiosperms in...
BACKGROUND
Horizontal gene transfer (HGT) events have rarely been reported in gymnosperms. Gnetum is a gymnosperm genus comprising 25‒35 species sympatric with angiosperms in West African, South American, and Southeast Asian rainforests. Only a single acquisition of an angiosperm mitochondrial intron has been documented to date in Asian Gnetum mitogenomes. We wanted to develop a more comprehensive understanding of frequency and fragment length distribution of such events as well as their evolutionary history in this genus.
RESULTS
We sequenced and assembled mitogenomes from five Asian Gnetum species. These genomes vary remarkably in size and foreign DNA content. We identified 15 mitochondrion-derived and five plastid-derived (MTPT) foreign genes. Our phylogenetic analyses strongly indicate that these foreign genes were transferred from diverse eudicots-mostly from the Rubiaceae genus Coptosapelta and ten genera of Malpighiales. This indicates that Asian Gnetum has experienced multiple independent HGT events. Patterns of sequence evolution strongly suggest DNA-mediated transfer between mitochondria as the primary mechanism giving rise to these HGT events. Most Asian Gnetum species are lianas and often entwined with sympatric angiosperms. We therefore propose that close apposition of Gnetum and angiosperm stems presents opportunities for interspecific cell-to-cell contact through friction and wounding, leading to HGT.
CONCLUSIONS
Our study reveals that multiple HGT events have resulted in massive amounts of angiosperm mitochondrial DNA integrated into Asian Gnetum mitogenomes. Gnetum and its neighboring angiosperms are often entwined with each other, possibly accounting for frequent HGT between these two phylogenetically remote lineages.
Topics: Phylogeny; Gene Transfer, Horizontal; Genome, Mitochondrial; Gnetum; DNA, Plant; Evolution, Molecular; Magnoliopsida
PubMed: 38915079
DOI: 10.1186/s12915-024-01924-y -
BMC Genomics Jun 2024Although, oocytes from prepubertal donors are known to be less developmentally competent than those from adult donors it does not restrain their ability to produce...
BACKGROUND
Although, oocytes from prepubertal donors are known to be less developmentally competent than those from adult donors it does not restrain their ability to produce full-term pregnancies. The transcriptomic profile of embryos could be used as a predictor for embryo's individual developmental competence. The aim of the study was to compare transcriptomic profile of blastocysts derived from prepubertal and pubertal heifers oocytes. Bovine cumulus-oocyte complexes (COCs) were obtained by ovum pick- up method from prepubertal and pubertal heifers. After in vitro maturation COCs were fertilized and cultured to the blastocyst stage. Total RNA was isolated from both groups of blastocysts and RNA-seq was performed. Gene ontology analysis was performed by DAVID (Database for Annotation, Visualization and Integrated Discovery).
RESULTS
A higher average blastocyst rate was obtained in the pubertal than in the pre-pubertal group. There were no differences in the quality of blastocysts between the examined groups. We identified 436 differentially expressed genes (DEGs) between blastocysts derived from researched groups, of which 247 DEGs were downregulated in blastocysts derived from pubertal compared to prepubertal heifers oocytes, and 189 DEGs were upregulated. The genes involved in mitochondrial function, including oxidative phosphorylation (OXPHOS) were found to be different in studied groups using Kyoto Encyclopedia of Genes (KEGG) pathway analysis and 8 of those DEGs were upregulated and 1 was downregulated in blastocysts derived from pubertal compared to prepubertal heifers oocytes. DEGs associated with mitochondrial function were found: ATP synthases (ATP5MF-ATP synthase membrane subunit f, ATP5PD- ATP synthase peripheral stalk subunit d, ATP12A- ATPase H+/K + transporting non-gastric alpha2 subunit), NADH dehydrogenases (NDUFS3- NADH: ubiquinone oxidoreductase subunit core subunit S3, NDUFA13- NADH: ubiquinone oxidoreductase subunit A13, NDUFA3- NADH: ubiquinone oxidoreductase subunit A3), cytochrome c oxidase (COX17), cytochrome c somatic (CYCS) and ubiquinol cytochrome c reductase core protein 1 (UQCRC1). We found lower number of apoptotic cells in blastocysts derived from oocytes collected from prepubertal than those obtained from pubertal donors.
CONCLUSIONS
Despite decreased expression of genes associated with OXPHOS pathway in blastocysts from prepubertal heifers oocytes, the increased level of ATP12A together with the lower number of apoptotic cells in these blastocysts might support their survival after transfer.
Topics: Animals; Cattle; Oxidative Phosphorylation; Female; Gene Expression Profiling; Blastocyst; Transcriptome; Sexual Maturation; Oocytes; Gene Expression Regulation, Developmental; Fertilization in Vitro
PubMed: 38914933
DOI: 10.1186/s12864-024-10532-7 -
Scientific Reports Jun 2024Bivalves are an extraordinary class of animals in which species with a doubly uniparental inheritance (DUI) of mitochondrial DNA have been described. DUI is...
Bivalves are an extraordinary class of animals in which species with a doubly uniparental inheritance (DUI) of mitochondrial DNA have been described. DUI is characterized as a mitochondrial homoplasmy of females and heteroplasmy of male individuals where F-type mitogenomes are passed to the progeny with mother egg cells and divergent M-type mitogenomes are inherited with fathers sperm cells. However, in most cases only male individuals retain divergent mitogenome inherited with spermatozoa. Additionally, in many of bivalves, unique mitochondrial features, like additional genes, gene duplication, gene extensions, mitochondrial introns, and recombination, were observed. In this study, we sequenced and assembled male-type mitogenomes of three Donax species. Comparative analysis of mitochondrial sequences revealed a lack of all seven NADH dehydrogenase subunits as well as the presence of three long additional open reading frames lacking identifiable homology to any of the existing genes.
Topics: Animals; Male; Genome, Mitochondrial; Electron Transport Complex I; DNA, Mitochondrial; Female; Spermatozoa; Phylogeny; Open Reading Frames
PubMed: 38914611
DOI: 10.1038/s41598-024-63764-8 -
BMJ Neurology Open 2024Dystonia is a genetic or non-genetic movement disorder with typical patterned and twisting movements due to abnormal muscle contractions that may be associated with...
BACKGROUND
Dystonia is a genetic or non-genetic movement disorder with typical patterned and twisting movements due to abnormal muscle contractions that may be associated with tremor. Genetic and phenotypic heterogeneity leads to variable clinical presentation.
METHODOLOGY
Next-generation sequencing technologies are being currently used in the workup of patients with inherited dystonia to determine the specific cause in the individuals with autosomal dominant, recessive, X-linked or mitochondrial inheritance patterns. Calcium voltage-gated channel subunit alpha1 A (CACNA1A) gene variants are rare in dystonias.
RESULTS
We here present a 20-year-old man with a history of delayed milestones, flexor posturing, dysarthria, dysphagia and a negative family history from consanguineous parents. Neurological examination revealed right lateral scoliosis of the neck and generalised dystonic posturing affecting both upper and lower limbs. MRI of the brain was unremarkable. Molecular genetic results revealed a heterozygous variant in the CACNA1A gene (CHR19: NM_023035.2, c. 1602G>A; p. Met534Ile). Segregation analyses in both the parents revealed wild-type CACNA1A gene suggesting de novo nature of the variant with a likely pathogenic classification.
CONCLUSION
Dystonia is one of the clinical phenotypes that can be associated with CACNA1A gene mutations and we recommend that this gene either be included in the dystonia panel offered or tested when the initial primary genetic result is negative.
PubMed: 38912174
DOI: 10.1136/bmjno-2024-000710 -
Wellcome Open Research 2024We present a genome assembly from an individual male (the White-point; Arthropoda; Insecta; Lepidoptera; Noctuidae). The genome sequence is 698.6 megabases in span....
We present a genome assembly from an individual male (the White-point; Arthropoda; Insecta; Lepidoptera; Noctuidae). The genome sequence is 698.6 megabases in span. Most of the assembly is scaffolded into 31 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 15.38 kilobases in length. Gene annotation of this assembly on Ensembl identified 13,679 protein coding genes.
PubMed: 38911902
DOI: 10.12688/wellcomeopenres.20682.1 -
Mitochondrial DNA. Part B, Resources 2024This study is the first to sequence the complete mitochondrial genome (mitogenome) of Bruguière, 1789 (Balanomorpha: Balanidae). The 15,536-bp long mitogenome...
This study is the first to sequence the complete mitochondrial genome (mitogenome) of Bruguière, 1789 (Balanomorpha: Balanidae). The 15,536-bp long mitogenome contained a typical set of animal mitochondrial genes, along with one control region. The mitogenome had an inverted gene block (-----) between (gct) and . This inverted gene block had been detected six species in three subfamilies of the Balanidae family (Balaninae, Acastinae and Megabalaninae), but our results show that it is also present in Concavinae, in which is included. The phylogenetic tree based on the concatenated sequences of the 13 protein-coding genes and two rRNA genes showed that is closely associated with and within Balanidae.
PubMed: 38911522
DOI: 10.1080/23802359.2024.2368727 -
Mitochondrial DNA. Part B, Resources 2024In this study, we assembled high-quality chloroplast genomes of through a reference-guided approach using high-throughput Illumina sequencing reads. The resulting...
In this study, we assembled high-quality chloroplast genomes of through a reference-guided approach using high-throughput Illumina sequencing reads. The resulting chloroplast genome assembly displayed a typical quadripartite structural organization, comprising a large single-copy (LSC) region of 85,233 bp, two inverted repeat (IR) regions of 25,685 bp each, and a small single-copy (SSC) region of 18,207 bp. The chloroplast genome harbored 141 complete genes, and its overall GC content was 38.0%. In maximum-likelihood (ML) and Bayesian inference (BI) trees, the 19 Solanaceae species formed a monophyletic group, dividing into two main clades. and formed a monophyletic group, suggesting a close relationship between the two species. The cp genome presented in this study lays a good foundation for further genetic and genomic studies of the Solanaceae.
PubMed: 38911521
DOI: 10.1080/23802359.2024.2368213 -
Mitochondrial DNA. Part B, Resources 2024Planchon. ex Franch 1886 is a plant with significant pharmacological effects and ornamental importance. This research unveiled the complete chloroplast (cp) genome...
Planchon. ex Franch 1886 is a plant with significant pharmacological effects and ornamental importance. This research unveiled the complete chloroplast (cp) genome sequence of . The study highlights that the cp genome of possesses a distinct tetrameric structure spanning 162,497 base pairs, comprising a small single-copy (SSC) region of 18,902 base pairs, a large single-copy (LSC) region of 90,441 base pairs, and two inverted-repeat regions (IRs), each 26,577 base pairs in length. The GC content of the SSC, LSC, and IR regions of the genome was 31.80%, 35.16%, and 42.82%, respectively, culminating in an overall GC content of 37.27%. The genome comprised 130 genes, which included eight rRNAs, 36 tRNAs, and 86 protein-coding genes. Through phylogenetic analysis utilizing the maximum-likelihood method, it was established that was closely related to var. , positioning it as a sister species. This report not only provides a scientific reference for understanding the phylogeny of the family Vitaceae but also enriches our genetic information of .
PubMed: 38911520
DOI: 10.1080/23802359.2024.2364753