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Gene Nov 2023The TBL1XR1 gene encodes the protein transducin-beta-like 1 receptor1, widely distributed in the pituitary, hypothalamus, white and brown adipose tissue, muscle, and... (Review)
Review
BACKGROUND
The TBL1XR1 gene encodes the protein transducin-beta-like 1 receptor1, widely distributed in the pituitary, hypothalamus, white and brown adipose tissue, muscle, and liver. Current evidence suggests that heterozygous TBL1XR1 pathogenic variants can lead to a wide spectrum of phenotypes. This study aims to reveal the clinical phenotype and genetic profiles of de novo TBL1XR1 variations and summarize the relevant clinical and genetic features.
METHODS
We analyzed four new cases harboring de novo TBL1XR1 variants and reviewed all reported cases.
RESULTS
All probands suffered from global developmental delay. Moreover, patient 1 exhibited susceptibility to startle, patient 2 had hypovitaminosis D, short stature and hyponatremia, and patients 3 and 4 both presented with ASD (Autism spectrum disorder) and short stature. They all had a de novo TBL1XR1 variant (NM_024665.7), c.1184A > G (p.Tyr395Cys), c.1108G > A (p.Asp370Asn), c.1047 + 1G > C, and c.1097C > T (p.Ser366Phe) respectively. In addition, pooled analysis of 51 cases showed that they had speech impairment (38/39), intellectual developmental disorder (28/28), global developmental delay (42/42), and hypotonia (24/27), and some of them had epilepsy (10/22), ASD (13/25), and developmental regression (4/13).
CONCLUSIONS
We report four new patients with de novo TBL1XR1 variants and provide a comprehensive overview of 47 previously reported individuals with TBL1XR1 variants, enriching the genotypic and phenotypic spectrum of TBL1XR1-related disease. This report further validates the pathogenicity de novo TBL1XR1 variants.
Topics: Humans; Autism Spectrum Disorder; Genotype; Phenotype; Heterozygote; Adipose Tissue, Brown; Repressor Proteins; Receptors, Cytoplasmic and Nuclear
PubMed: 37683765
DOI: 10.1016/j.gene.2023.147777 -
CMAJ : Canadian Medical Association... Mar 2024
Topics: Humans; Continuous Glucose Monitoring; Blood Glucose Self-Monitoring; Blood Glucose
PubMed: 38467414
DOI: 10.1503/cmaj.230572-f -
Frontiers in Microbiology 2024In eukaryotic cells, purine metabolism is the way to the production of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and plays key roles in various biological... (Review)
Review
In eukaryotic cells, purine metabolism is the way to the production of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and plays key roles in various biological processes. Purine metabolism mainly consists of , salvage, and catabolic pathways, and some components of these pathways have been characterized in some plant pathogenic fungi, such as the rice blast fungus and wheat head blight fungus . The enzymatic steps of the pathway are well-conserved in plant pathogenic fungi and play crucial roles in fungal growth and development. Blocking this pathway inhibits the formation of penetration structures and invasive growth, making it essential for plant infection by pathogenic fungi. The salvage pathway is likely indispensable but requires exogenous purines, implying that purine transporters are functional in these fungi. The catabolic pathway balances purine nucleotides and may have a conserved stage-specific role in pathogenic fungi. The significant difference of the catabolic pathway and lead us to further explore and identify the key genes specifically regulating pathogenicity in purine metabolic pathway. In this review, we summarized recent advances in the studies of purine metabolism, focusing on the regulation of pathogenesis and growth in plant pathogenic fungi.
PubMed: 38384269
DOI: 10.3389/fmicb.2024.1352354 -
Molecular Biology and Evolution Sep 2023Mutation rate is a fundamental parameter in population genetics. Apart from being an important scaling parameter for demographic and phylogenetic inference, it allows...
Mutation rate is a fundamental parameter in population genetics. Apart from being an important scaling parameter for demographic and phylogenetic inference, it allows one to understand at what rate new genetic diversity is generated and what the expected level of genetic diversity is in a population at equilibrium. However, except for well-established model organisms, accurate estimates of de novo mutation rates are available for a very limited number of organisms from the wild. We estimated mutation rates (µ) in two marine populations of the nine-spined stickleback (Pungitius pungitius) with the aid of several 2- and 3-generational family pedigrees, deep (>50×) whole-genome resequences and a high-quality reference genome. After stringent filtering, we discovered 308 germline mutations in 106 offspring translating to µ = 4.83 × 10-9 and µ = 4.29 × 10-9 per base per generation in the two populations, respectively. Up to 20% of the mutations were shared by full-sibs showing that the level of parental mosaicism was relatively high. Since the estimated µ was 3.1 times smaller than the commonly used substitution rate, recalibration with µ led to substantial increase in estimated divergence times between different stickleback species. Our estimates of the de novo mutation rate should provide a useful resource for research focused on fish population genetics and that of sticklebacks in particular.
Topics: Animals; Smegmamorpha; Mutation Rate; Phylogeny; Mutation; Germ-Line Mutation
PubMed: 37648662
DOI: 10.1093/molbev/msad192 -
Frontiers in Chemistry 2023Drug Design (dnDD) aims to create new molecules that satisfy multiple conflicting objectives. Since several desired properties can be considered in the optimization... (Review)
Review
Drug Design (dnDD) aims to create new molecules that satisfy multiple conflicting objectives. Since several desired properties can be considered in the optimization process, dnDD is naturally categorized as a many-objective optimization problem (ManyOOP), where more than three objectives must be simultaneously optimized. However, a large number of objectives typically pose several challenges that affect the choice and the design of optimization methodologies. Herein, we cover the application of multi- and many-objective optimization methods, particularly those based on Evolutionary Computation and Machine Learning techniques, to enlighten their potential application in dnDD. Additionally, we comprehensively analyze how molecular properties used in the optimization process are applied as either objectives or constraints to the problem. Finally, we discuss future research in many-objective optimization for dnDD, highlighting two important possible impacts: i) its integration with the development of multi-target approaches to accelerate the discovery of innovative and more efficacious drug therapies and ii) its role as a catalyst for new developments in more fundamental and general methodological frameworks in the field.
PubMed: 38192501
DOI: 10.3389/fchem.2023.1288626 -
Frontiers in Plant Science 2023Plants, unlike animals, possess a unique developmental plasticity, that allows them to adapt to changing environmental conditions. A fundamental aspect of this... (Review)
Review
Plants, unlike animals, possess a unique developmental plasticity, that allows them to adapt to changing environmental conditions. A fundamental aspect of this plasticity is their ability to undergo postembryonic organogenesis. This requires the presence of regulators that trigger and mediate specific spatiotemporal changes in developmental programs. The phytohormone cytokinin has been known as a principal regulator of plant development for more than six decades. In shoot organogenesis and shoot regeneration, cytokinins are the prime candidates for the signal that determines shoot identity. Both processes of shoot apical meristem development are accompanied by changes in gene expression, cell fate reprogramming, and the switching-on of the shoot-specific homeodomain regulator, WUSCHEL. Current understanding about the role of cytokinins in the shoot regeneration will be discussed.
PubMed: 37662179
DOI: 10.3389/fpls.2023.1239133 -
Breast (Edinburgh, Scotland) Oct 2023Information of brain metastasis (BM) in de novo stage IV breast cancer is lacking, which is an unavoidable problem and dilemma in practice. Understanding the current...
OBJECTIVES
Information of brain metastasis (BM) in de novo stage IV breast cancer is lacking, which is an unavoidable problem and dilemma in practice. Understanding the current situation is helpful for the clinical cognition and decision-making.
METHODS
We retrospectively analyzed the clinical and survival information of de novo stage IV breast cancer with BM between 2015 and 2019 from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariable logistic and Cox regression analyses were performed to identify predictors of BM and factors associated with all-cause mortality in de novo stage IV breast cancer, respectively. Overall survival (OS) was calculated using Kaplan-Meier and log-rank tests.
RESULTS
Our cohort consisted of 1366 patients with BM in de novo stage IV breast cancer, with an incidence of 8.38% in patients with metastatic disease to any distant site. Incidence was highest among patients with metastatic disease with HR-HER2+ (12.95%) and HR-HER2- (13.40%) subtypes. The higher the number of extracranial metastases, the higher the BM incidence. The median OS was 12.0 (95%CI: 10.426-13.574) months in BM group; it was longest in HR + HER2+ (19.0[95%CI: 11.793-26.207] months), and shortest in HR-HER2- (7.0 [95%CI:5.354-8.646] months). Marital status, subtype, and abundance of metastatic sites influenced morbidity and OS of BM in de novo stage IV breast cancer.
CONCLUSIONS
Population-based estimates of the incidence and prognosis for patients with BM in de novo stage IV breast cancer were closely associated with subtype and metastatic burden. These findings may be helpful in developing diagnostic strategies, especially for brain screening.
Topics: Humans; Female; Breast Neoplasms; Retrospective Studies; Brain Neoplasms; Brain; Cognition; Prognosis; Neoplasm Metastasis
PubMed: 37499376
DOI: 10.1016/j.breast.2023.07.005 -
BioRxiv : the Preprint Server For... Jun 2023Although previously thought to be unlikely, recent studies have shown that gene origination from previously non-genic sequences is a relatively common mechanism for...
Although previously thought to be unlikely, recent studies have shown that gene origination from previously non-genic sequences is a relatively common mechanism for gene innovation in many species and taxa. These young genes provide a unique set of candidates to study the structural and functional origination of proteins. However, our understanding of their protein structures and how these structures originate and evolve are still limited, due to a lack of systematic studies. Here, we combined high-quality base-level whole genome alignments, bioinformatic analysis, and computational structure modeling to study the origination, evolution, and protein structure of lineage-specific genes. We identified 555 gene candidates in that originated within the lineage. We found a gradual shift in sequence composition, evolutionary rates, and expression patterns with their gene ages, which indicates possible gradual shifts or adaptations of their functions. Surprisingly, we found little overall protein structural changes for genes in the lineage. Using Alphafold2, ESMFold, and molecular dynamics, we identified a number of gene candidates with protein products that are potentially well-folded, many of which are more likely to contain transmembrane and signal proteins compared to other annotated protein-coding genes. Using ancestral sequence reconstruction, we found that most potentially well-folded proteins are often born folded. Interestingly, we observed one case where disordered ancestral proteins become ordered within a relatively short evolutionary time. Single-cell RNA-seq analysis in testis showed that although most genes are enriched in spermatocytes, several young genes are biased in the early spermatogenesis stage, indicating potentially important but less emphasized roles of early germline cells in the gene origination in testis. This study provides a systematic overview of the origin, evolution, and structural changes of -specific genes.
PubMed: 37425675
DOI: 10.1101/2023.03.13.532420 -
ENeuro Oct 2023The levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of the and salvage synthesis pathways. In the...
The levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of the and salvage synthesis pathways. In the embryonic central nervous system (CNS), the pathway is considered crucial to meet the requirements for the active proliferation of neural stem/progenitor cells (NSPCs). However, how these two pathways are balanced or separately used during CNS development remains poorly understood. In this study, we showed a dynamic shift in pathway utilization, with greater reliance on the pathway during embryonic stages and on the salvage pathway in postnatal-adult mouse brain. The pharmacological effects of various purine synthesis inhibitors and the expression profile of purine synthesis enzymes indicated that NSPCs in the embryonic cerebrum mainly use the pathway. Simultaneously, NSPCs in the cerebellum require both the and the salvage pathways. administration of inhibitors resulted in severe hypoplasia of the forebrain cortical region, indicating a gradient of purine demand along the anteroposterior axis of the embryonic brain, with cortical areas of the dorsal forebrain having higher purine requirements than ventral or posterior areas such as the striatum and thalamus. This histologic defect of the neocortex was accompanied by strong downregulation of the mechanistic target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase (S6K)/S6 signaling cascade, a crucial pathway for cell metabolism, growth, and survival. These findings indicate the importance of the spatiotemporal regulation of both purine pathways for mTORC1 signaling and proper brain development.
Topics: Mice; Animals; Purines; Homeostasis; Brain; Mechanistic Target of Rapamycin Complex 1
PubMed: 37770184
DOI: 10.1523/ENEURO.0159-23.2023 -
BioRxiv : the Preprint Server For... Sep 2023The human heart is infamous for not healing after infarction in adults, prompting biomedical interest in species that can regenerate damaged hearts. In such animals as...
The human heart is infamous for not healing after infarction in adults, prompting biomedical interest in species that can regenerate damaged hearts. In such animals as zebrafish and neonatal mice, cardiac repair relies on remaining heart tissue supporting cardiomyocyte proliferation. Natural cardiogenesis in post-embryonic stages thus remains elusive. Here we show that the tunicate , an ascidian among the closest living relatives to the vertebrates, can survive complete chemogenetic ablation of the heart and loss of cardiac function, and recover both cardiac tissue and contractility. As in vertebrates, Ciona heart regeneration relies on Bone Morphogenetic Protein (BMP) signaling-dependent proliferation of cardiomyocytes, providing insights into the evolutionary origins of regenerative cardiogenesis in chordates. Remarkably, prospective lineage tracing by photoconversion of the fluorescent protein Kaede suggested that new cardiomyocytes can emerge from endodermal lineages in post-metamorphic animals, providing an unprecedented case of regenerative cardiogenesis. Finally, while embryos cannot compensate for early losses of the cardiogenic lineage, forming heartless juveniles, developing animals gain their regenerative ability during metamorphosis, uncovering a fundamental transition between deterministic embryogenesis and regulative post-embryonic development.
PubMed: 37781597
DOI: 10.1101/2023.09.19.558507