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CNS Neuroscience & Therapeutics Mar 2024Can we better understand the unique mechanisms of de novo abilities in light of our current knowledge of the psychological and neuroscientific literature on creativity?... (Review)
Review
Can we better understand the unique mechanisms of de novo abilities in light of our current knowledge of the psychological and neuroscientific literature on creativity? This review outlines the state-of-the-art in the neuroscience of creativity and points out crucial aspects that still demand further exploration, such as brain plasticity. The progressive development of current neuroscience research on creativity presents a multitude of prospects and potentials for furnishing efficacious therapy in the context of health and illness. Therefore, we discuss directions for future studies, identifying a focus on pinpointing the neglected beneficial practices for creative therapy. We emphasize the neglected neuroscience perspective of creativity on health and disease and how creative therapy could offer limitless possibilities to improve our well-being and give hope to patients with neurodegenerative diseases to compensate for their brain injuries and cognitive impairments by expressing their hidden creativity.
Topics: Humans; Creativity; Neurosciences; Cognitive Dysfunction
PubMed: 37305955
DOI: 10.1111/cns.14266 -
Genome Biology Jul 2023Chromosome-level haplotype-resolved genome assembly is an important resource in molecular biology. However, current de novo haplotype assemblers require parental data or...
Chromosome-level haplotype-resolved genome assembly is an important resource in molecular biology. However, current de novo haplotype assemblers require parental data or reference genomes and often fail to provide chromosome-level results. We present GreenHill, a novel scaffolding and phasing tool that considers various assemblers' contigs as input to reconstruct chromosome-level haplotypes using Hi-C without parental or reference data. Its unique functions include new error correction based on Hi-C contacts and the simultaneous use of Hi-C and long reads. Benchmarks reveal that GreenHill outperforms other approaches in contiguity and phasing accuracy, and the majority of chromosome arms are entirely phased.
Topics: Tool Use Behavior; Benchmarking; Haplotypes
PubMed: 37434204
DOI: 10.1186/s13059-023-03006-8 -
BMC Genomics Jul 2023Bacteria of the Borrelia burgdorferi sensu lato (s.l.) complex can cause Lyme borreliosis. Different B. burgdorferi s.l. genospecies vary in their host and vector...
BACKGROUND
Bacteria of the Borrelia burgdorferi sensu lato (s.l.) complex can cause Lyme borreliosis. Different B. burgdorferi s.l. genospecies vary in their host and vector associations and human pathogenicity but the genetic basis for these adaptations is unresolved and requires completed and reliable genomes for comparative analyses. The de novo assembly of a complete Borrelia genome is challenging due to the high levels of complexity, represented by a high number of circular and linear plasmids that are dynamic, showing mosaic structure and sequence homology. Previous work demonstrated that even advanced approaches, such as a combination of short-read and long-read data, might lead to incomplete plasmid reconstruction. Here, using recently developed high-fidelity (HiFi) PacBio sequencing, we explored strategies to obtain gap-free, complete and high quality Borrelia genome assemblies. Optimizing genome assembly, quality control and refinement steps, we critically appraised existing techniques to create a workflow that lead to improved genome reconstruction.
RESULTS
Despite the latest available technologies, stand-alone sequencing and assembly methods are insufficient for the generation of complete and high quality Borrelia genome assemblies. We developed a workflow pipeline for the de novo genome assembly for Borrelia using several types of sequence data and incorporating multiple assemblers to recover the complete genome including both circular and linear plasmid sequences.
CONCLUSION
Our study demonstrates that, with HiFi data and an ensemble reconstruction pipeline with refinement steps, chromosomal and plasmid sequences can be fully resolved, even for complex genomes such as Borrelia. The presented pipeline may be of interest for the assembly of further complex microbial genomes.
Topics: Humans; Borrelia; Genome, Bacterial; Phylogeny; Borrelia burgdorferi; Lyme Disease; Borrelia burgdorferi Group
PubMed: 37460975
DOI: 10.1186/s12864-023-09500-4 -
Frontiers in Genetics 2024Autism spectrum disorder (ASD) is characterized by aberrations in social interaction and communication associated with repetitive behaviors and interests, with strong...
Autism spectrum disorder (ASD) is characterized by aberrations in social interaction and communication associated with repetitive behaviors and interests, with strong clinical heterogeneity. Genetic factors play an important role in ASD, but about 75% of ASD cases have an undetermined genetic risk. We extensively investigated an ASD cohort made of 102 families from the Middle Eastern population of Qatar. First, we investigated the copy number variations (CNV) contribution using genome-wide SNP arrays. Next, we employed Next Generation Sequencing (NGS) to identify or inherited variants contributing to the ASD etiology and its associated comorbid conditions in families with complete trios (affected child and the parents). Our analysis revealed 16 CNV regions located in genomic regions implicated in ASD. The analysis of the 88 ASD cases identified 41 genes in 39 ASD subjects with de novo (n = 24) or inherited variants (n = 22). We identified three novel variants in new candidate genes for ASD (, , and ). Also, we have identified 15 variants in genes that were previously implicated in ASD or related neurodevelopmental disorders (, , , , , , , , , , , , , and ). Additionally, we defined eight novel recessive variants (, , , , , and ), four of which were X-linked. Despite the ASD multifactorial etiology that hinders ASD genetic risk discovery, the number of identified novel or known putative ASD genetic variants was appreciable. Nevertheless, this study represents the first comprehensive characterization of ASD genetic risk in Qatar's Middle Eastern population.
PubMed: 38572415
DOI: 10.3389/fgene.2024.1363849 -
BioRxiv : the Preprint Server For... Nov 2023A hallmark of Idiopathic Pulmonary Fibrosis is the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive...
A hallmark of Idiopathic Pulmonary Fibrosis is the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by lung fibroblasts requires synthesis of glycine, the most abundant amino acid in collagen protein. TGF-β upregulates the expression of the enzymes of the serine/glycine synthesis pathway in lung fibroblasts through mTORC1 and ATF4-dependent transcriptional programs. SHMT2, the final enzyme of the serine/glycine synthesis pathway, transfers a one-carbon unit from serine to tetrahydrofolate (THF), producing glycine and 5,10-methylene-THF (meTHF). meTHF is converted back to THF in the mitochondrial one-carbon (1C) pathway through the sequential actions of MTHFD2 (which converts meTHF to 10-formyl-THF), and either MTHFD1L, which produces formate, or ALDH1L2, which produces CO. It is unknown how the mitochondrial 1C pathway contributes to glycine biosynthesis or collagen protein production in fibroblasts, or fibrosis . Here, we demonstrate that TGF-β induces the expression of , , and in human lung fibroblasts. expression was required for TGF-β-induced cellular glycine accumulation and collagen protein production. Combined knockdown of both and also inhibited glycine accumulation and collagen protein production downstream of TGF-β; however knockdown of either protein alone had no inhibitory effect, suggesting that lung fibroblasts can utilize either enzyme to regenerate THF. Pharmacologic inhibition of MTHFD2 recapitulated the effects of knockdown in lung fibroblasts and ameliorated fibrotic responses after intratracheal bleomycin instillation . Our results provide insight into the metabolic requirements of lung fibroblasts and provide support for continued development of MTHFD2 inhibitors for the treatment of IPF and other fibrotic diseases.
PubMed: 37986788
DOI: 10.1101/2023.11.07.566074 -
Biomolecules Jan 2024Cholesterol (CHOL) is a multifaceted lipid molecule. It is an essential structural component of cell membranes, where it cooperates in regulating the intracellular... (Review)
Review
Cholesterol (CHOL) is a multifaceted lipid molecule. It is an essential structural component of cell membranes, where it cooperates in regulating the intracellular trafficking and signaling pathways. Additionally, it serves as a precursor for vital biomolecules, including steroid hormones, isoprenoids, vitamin D, and bile acids. Although CHOL is normally uptaken from the bloodstream, cells can synthesize it de novo in response to an increased requirement due to physiological tissue remodeling or abnormal proliferation, such as in cancer. Cumulating evidence indicated that increased CHOL biosynthesis is a common feature of breast cancer and is associated with the neoplastic transformation of normal mammary epithelial cells. After an overview of the multiple biological activities of CHOL and its derivatives, this review will address the impact of de novo CHOL production on the promotion of breast cancer with a focus on mammary stem cells. The review will also discuss the effect of de novo CHOL production on in situ and invasive carcinoma and its impact on the response to adjuvant treatment. Finally, the review will discuss the present and future therapeutic strategies to normalize CHOL biosynthesis.
Topics: Humans; Cognition; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Bile Acids and Salts; Carcinoma
PubMed: 38254664
DOI: 10.3390/biom14010064 -
PLoS Genetics Aug 2023Establishment of a proper DNA methylation landscape in mammalian oocytes is important for maternal imprinting and embryonic development. De novo DNA methylation in...
Establishment of a proper DNA methylation landscape in mammalian oocytes is important for maternal imprinting and embryonic development. De novo DNA methylation in oocytes is mediated by the DNA methyltransferase DNMT3A, which has an ATRX-DNMT3-DNMT3L (ADD) domain that interacts with histone H3 tail unmethylated at lysine-4 (H3K4me0). The domain normally blocks the methyltransferase domain via intramolecular interaction and binding to histone H3K4me0 releases the autoinhibition. However, H3K4me0 is widespread in chromatin and the role of the ADD-histone interaction has not been studied in vivo. We herein show that amino-acid substitutions in the ADD domain of mouse DNMT3A cause dwarfism. Oocytes derived from homozygous females show mosaic loss of CG methylation and almost complete loss of non-CG methylation. Embryos derived from such oocytes die in mid-to-late gestation, with stochastic and often all-or-none-type CG-methylation loss at imprinting control regions and misexpression of the linked genes. The stochastic loss is a two-step process, with loss occurring in cleavage-stage embryos and regaining occurring after implantation. These results highlight an important role for the ADD domain in efficient, and likely processive, de novo CG methylation and pose a model for stochastic inheritance of epigenetic perturbations in germ cells to the next generation.
Topics: Humans; Female; Mice; Male; Animals; Pregnancy; Histones; DNA Methylation; DNA (Cytosine-5-)-Methyltransferases; Chromosomes, Human, Y; DNA Methyltransferase 3A; Mosaicism; Oocytes; Transcription Factors; DNA Modification Methylases; Mammals
PubMed: 37527244
DOI: 10.1371/journal.pgen.1010855 -
Canadian Journal of Kidney Health and... 2023transplant amyloidosis denotes the condition when a patient develops amyloidosis after transplantation but had not been diagnosed with the disease prior to...
RATIONALE
transplant amyloidosis denotes the condition when a patient develops amyloidosis after transplantation but had not been diagnosed with the disease prior to transplantation. The incidence of amyloidosis in kidney transplants is rare, but few published case reports have described the occurrence of Amyloid A protein (AA) and Light Chain (AL) amyloidosis. However, hereditary fibrinogen A alpha chain (AFib) has not been previously reported.
PATIENT PRESENTATION
We present a 72-year-old man, a kidney transplant recipient, who developed progressive rise in his creatinine about 3 years after transplantation. He has long-standing diabetes mellitus type 2, obesity, and hypertension, so he did not have a kidney biopsy of his native kidneys prior to transplantation.
DIAGNOSIS
A kidney transplant biopsy was done that showed amyloidosis. Mass spectrophotometry confirmed it as AFib amyloidosis. Genetic testing of the patient revealed that he has fibrinogen A alpha gene (FGA) point mutation with a p.E545V variant.
INTERVENTIONS
Cardiac evaluation showed normal transthoracic echocardiogram. Cardiac magnetic resonance imaging (MRI) showed no involvement by amyloidosis. A peripheral nerve biopsy showed diabetic neuropathy. Thus, the kidney was the only organ involved by the disease. The kidney transplant was managed conservatively with blood pressure and diabetes control in addition to his usual immunosuppression regimen which was not altered. He is being treated with diuretics, angiotensin receptor inhibitors, and sodium glucose transport 2 inhibitors.
OUTCOMES
Kidney transplant function exhibited only slow progression over 18 months since the diagnosis was confirmed. This slow progression is likely because the p.E545V point mutation variant is less aggressive than other gene deletion mutations and because our patient was judged to have been diagnosed early in the course of his disease.
TEACHING POINTS
In this case report, we illustrate the findings and testing that confirmed the diagnosis of AFib amyloidosis. We summarize the clinical aspects, outcomes of the disease, and treatment options. We believe this case report is interesting because it is the first reported case of AFib amyloidosis in a kidney transplant recipient who was not known to have the disease prior to kidney transplantation.
PubMed: 37920778
DOI: 10.1177/20543581231209207 -
The Journal of Clinical Investigation Feb 2024Ten percent of the population worldwide suffers from chronic kidney disease (CKD), but the mechanisms driving CKD pathology are incompletely understood. While...
Ten percent of the population worldwide suffers from chronic kidney disease (CKD), but the mechanisms driving CKD pathology are incompletely understood. While dysregulated lipid metabolism is one hallmark of CKD, the pathogenesis of cellular lipid accumulation remains unclear. In this issue of the JCI, Mukhi et al. Identify acyl-CoA synthetase short-chain family 2 (ACSS2) as a disease risk gene and demonstrate a role for ACSS2 in de novo lipogenesis (DNL). Notably, genetic or pharmacological inhibition of DNL protected against kidney disease progression in mice. These findings warrant evaluation of DNL inhibition with respect to efficacy and safety in people with CKD.
Topics: Humans; Animals; Mice; Lipogenesis; Renal Insufficiency, Chronic; Liver; Non-alcoholic Fatty Liver Disease
PubMed: 38357930
DOI: 10.1172/JCI178125 -
Frontiers in Genetics 2023Charcot-Marie-Tooth disease (CMT) is the most common inherited neurological disorder suffered in childhood. To date, the disease features have not been extensively...
Charcot-Marie-Tooth disease (CMT) is the most common inherited neurological disorder suffered in childhood. To date, the disease features have not been extensively characterized in the Chinese paediatric population. In this study, we aimed to analyse the clinical profiles and genetic distributions of a paediatric CMT cohort in China. A total of 181 paediatric CMT patients were enrolled. After preexcluding duplication/deletion by multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, targeted next-generation sequencing (NGS) or whole-exome sequencing (WES) was performed to obtain a genetic diagnosis. Detailed information was collected to explore the spectrum of subtypes and genotype-phenotype correlations. Pathogenic mutations were identified in 68% of patients in this study; with duplication, MFN2 and were the most frequent disease-causing genes. Of note, respect to the higher prevalence worldwide, CMT1A (18.2%) was relatively lower in our cohort. Besides, the mean age at onset (8.3 ± 5.7 years) was significantly older in our series. In genotype-phenotype analyse, point mutations were considered the most severe genotypes and were mostly . In addition, the mutations were identified in up to 12.7% of all patients, which was higher than that in other studies. We identified a relatively lower detection rate of duplication and a higher frequency of variants among paediatric patients in China. We also identified the genetic and phenotypic heterogeneity of this cohort, which may provide clues for clinicians in directing genetic testing strategies for Chinese patients with early-onset CMT.
PubMed: 37519884
DOI: 10.3389/fgene.2023.1188361