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SUMMARY: Mitochondrial DNA sequences are used extensively in phylogeographic and phylogenetic studies for a wide range of organisms. With the advent of low-cost, high throughput 'next generation' DNA sequencing, and user-friendly bioinformatics pipelines for generating and annotating whole mitochondrial genome assemblies, the analysis of whole mitochondrial genomes has become an important component of phylogenomic studies for taxa with high species diversity but limited coverage for other genomic resources. An important step in characterizing de novo mitochondrial genome assemblies is to evaluate and describe structural rearrangements relative to reference taxa. Accessible tools are needed to help visualize gene and noncoding feature complement, their order and strand orientation. However, there are few dedicated applications that generate high quality genome diagrams. Here we present circularMT and circularMT-console that allow users to create highly customizable, publication quality images, of linear and circular mitochondrial genome maps, either individually, or integrated into an analysis pipeline. AVAILABILITY AND IMPLEMENTATION: Both applications are implemented in C#, with binaries, source code and user guides available on GitHub (https://github.com/msjimc/circularMT). An archive of the published version is available on Zenodo (https://zenodo.org/records/10912319). SUPPLEMENTARY INFORMATION: This paper has no supplementary data.
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Meta-analysis of genome-wide association study data has implicated PDE4B in the pathogenesis of Alzheimer's disease (AD), the leading cause of senile dementia. PDE4B encodes one of four subtypes of cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase-4 (PDE4A-D). To interrogate the involvement of PDE4B in the manifestation of AD-related phenotypes, the effects of a hypomorphic mutation (Pde4bY358C) that decreases PDE4B's cAMP hydrolytic activity were evaluated in the AppNL-G-F knock-in mouse model of AD using the Barnes maze test of spatial memory, 14C-2-deoxyglucose autoradiography, thioflavin-S staining of ß-amyloid (Aß) plaques, and inflammatory marker assay and transcriptomic analysis (RNA sequencing) of cerebral cortical tissue. At 12 months of age, AppNL-G-F mice exhibited spatial memory and brain metabolism deficits, which were prevented by the hypomorphic PDE4B in AppNL-G-F/Pde4bY358C mice, without a decrease in Aß plaque burden. RNA sequencing revealed that, among the 531 transcripts differentially expressed in AppNL-G-F versus wild-type mice, only 13 transcripts from four genes - Ide, Btaf1, Padi2, and C1qb - were differentially expressed in AppNL-G-F/Pde4bY358C versus AppNL-G-F mice, identifying their potential involvement in the protective effect of hypomorphic PDE4B. Our data demonstrate that spatial memory and cerebral glucose metabolism deficits exhibited by 12-month-old AppNL-G-F mice are prevented by targeted inhibition of PDE4B. To our knowledge, this is the first demonstration of a protective effect of PDE4B subtype-specific inhibition in a preclinical model of AD. It thus identifies PDE4B as a key regulator of disease manifestation in the AppNL-G-F model and a promising therapeutic target for AD.
Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Inhibidores de Fosfodiesterasa 4 , Animales , Masculino , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Aprendizaje por Laberinto/fisiología , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibidores de Fosfodiesterasa 4/farmacología , Placa Amiloide/patología , Placa Amiloide/metabolismo , Memoria Espacial/fisiologíaRESUMEN
Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.