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Nature Communications Jul 2024ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and a causative gene for KBG syndrome, a rare developmental disorder characterized by multiple organ...
ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and a causative gene for KBG syndrome, a rare developmental disorder characterized by multiple organ abnormalities, including cardiac defects. However, the role of ANKRD11 in heart development is unknown. The neural crest plays a leading role in embryonic heart development, and its dysfunction is implicated in congenital heart defects. We demonstrate that conditional knockout of Ankrd11 in the murine embryonic neural crest results in persistent truncus arteriosus, ventricular dilation, and impaired ventricular contractility. We further show these defects occur due to aberrant cardiac neural crest cell organization leading to outflow tract septation failure. Lastly, knockout of Ankrd11 in the neural crest leads to impaired expression of various transcription factors, chromatin remodelers and signaling pathways, including mTOR, BMP and TGF-β in the cardiac neural crest cells. In this work, we identify Ankrd11 as a regulator of neural crest-mediated heart development and function.
Topics: Animals; Neural Crest; Mice, Knockout; Mice; Heart; Repressor Proteins; Heart Defects, Congenital; Gene Expression Regulation, Developmental; Chromatin; Signal Transduction; Myocardium; Female
PubMed: 38951500
DOI: 10.1038/s41467-024-48955-1 -
Molecular Metabolism Jun 2024Aberrant glucolipid metabolism in the heart is a characteristic factor in diabetic cardiomyopathy (DbCM). Super-enhancers-driven noncoding RNAs (seRNAs) are emerging as...
OBJECTIVE
Aberrant glucolipid metabolism in the heart is a characteristic factor in diabetic cardiomyopathy (DbCM). Super-enhancers-driven noncoding RNAs (seRNAs) are emerging as powerful regulators in the progression of cardiac diseases. However, the functions of seRNAs in DbCM have not been fully elucidated.
METHODS
Super enhancers and their associated seRNAs were screened and identified by H3K27ac ChIP-seq data in the Encyclopedia of DNA Elements (ENCODE) dataset. A dual-luciferase reporter assay was performed to analyze the function of super-enhancers on the transcription of peroxisome proliferator-activated receptor α-related seRNA (PPARα-seRNA). A DbCM mouse model was established using db/db leptin receptor-deficient mice. Adeno-associated virus serotype 9-seRNA (AAV9-seRNA) was injected via the tail vein to evaluate the role of seRNA in DbCM. The underlying mechanism was explored through RNA pull-down, RNA and chromatin immunoprecipitation, and chromatin isolation by RNA purification.
RESULTS
PPARα-seRNA was regulated by super-enhancers and its levels were increased in response to high glucose and palmitic acid stimulation in cardiomyocytes. Functionally, PPARα-seRNA overexpression aggravated lipid deposition, reduced glucose uptake, and repressed energy production. In contrast, PPARα-seRNA knockdown ameliorated metabolic disorder in vitro. In vivo, overexpression of PPARα-seRNA exacerbated cardiac metabolic disorder and deteriorated cardiac dysfunction, myocardial fibrosis, and hypertrophy in DbCM. Mechanistically, PPARα-seRNA bound to the histone demethylase KDM4B (Lysine-specific demethylase 4B) and decreased H3K9me3 levels in the promoter region of PPARα, ultimately enhancing its transcription.
CONCLUSIONS
Our study revealed the pivotal function of a super-enhancer-driven long noncoding RNA (lncRNA), PPARα-seRNA, in the deterioration of cardiac function and the exacerbation of metabolic abnormalities in diabetic cardiomyopathy, which recruited KDM4B to the promoter region of PPARα and repression of its transcription. This suggests a promising therapeutic strategy for the treatment of DbCM.
PubMed: 38950776
DOI: 10.1016/j.molmet.2024.101978 -
Hamostaseologie Jul 2024Bleeding disorder of unknown cause (BDUC) is a diagnosis of exclusion after exhaustive evaluation of plasmatic coagulation and platelet function. This review explores...
Bleeding disorder of unknown cause (BDUC) is a diagnosis of exclusion after exhaustive evaluation of plasmatic coagulation and platelet function. This review explores the utility of global hemostatic assays as confirmatory tests and in elucidating the pathophysiology of BDUC. Unlike traditional hemostatic tests that focus on coagulation factors, global assays are conducted both in plasma and also whole blood. These assays provide a more comprehensive understanding of the cell-based model of coagulation, aid in the identification of plasmatic factor abnormalities that may reduce hemostatic capacity, and allow for the assessment of impaired platelet-endothelial interactions under shear stress, as well as hyperfibrinolytic states. While clinical tests such as skin bleeding time and global assays such as PFA-100 exhibit limited diagnostic capacity, the role of viscoelastic testing in identifying hemostatic dysfunction in patients with BDUC remains unclear. Thrombin generation assays have shown variable results in BDUC patients; some studies demonstrate differences compared with healthy controls or reference values, whereas others question its clinical utility. Fibrinolysis assessment in vitro remains challenging, with studies employing euglobulin clot lysis time, plasma clot lysis time, and fluorogenic plasmin generation yielding inconclusive or conflicting results. Notably, recent studies suggest that microfluidic analysis unveils shear-dependent platelet function defects in BDUC patients, undetected by conventional platelet function assays. Overall, global assays might be helpful for exploring underlying hemostatic impairments, when conventional hemostatic laboratory tests yield no results. However, due to limited data and/or discrepant results, further research is needed to evaluate the utility of global assays as screening tools.
PubMed: 38950624
DOI: 10.1055/a-2330-9112 -
The Journal of Clinical Investigation Jun 2024Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for...
Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.
Topics: Humans; Iron-Sulfur Proteins; Male; Female; Neuromuscular Diseases; Child; Cell Nucleus; Cytoplasm; Metallochaperones
PubMed: 38950322
DOI: 10.1172/JCI179559 -
EFORT Open Reviews Jul 2024Over the years, with a better understanding of knee anatomy and biomechanics, superior implant designs, advanced surgical techniques, and the availability of precision... (Review)
Review
Over the years, with a better understanding of knee anatomy and biomechanics, superior implant designs, advanced surgical techniques, and the availability of precision tools such as robotics and navigation, a more personalized approach to total knee arthroplasty (TKA) has emerged. In the presence of extra-articular deformities, performing personalized TKA can be more challenging and specific considerations are required, since one has to deal with an acquired pathological anatomy. Performing personalized TKA surgery in patients with extra-articular deformities, the surgeon can: (1) resurface the joint, omitting the extra-articular deformity; (2) partially compensate the extra-articular deformity with intra-articular correction (hybrid technique), or (3) correct the extra-articular deformity combined with a joint resurfacing TKA (single stage or two-stage procedure). Omitting the acquired lower limb malalignment by resurfacing the knee has the advantages of respecting the joint surface anatomy and preserving soft tissue laxities. On the other hand, it maintains pathological joint load and lower limb kinematics with potentially detrimental outcomes. The hybrid technique can be performed in most cases. It circumvents complications associated with osteotomies and brings lower limb axes closer to native alignment. On the other hand, it creates some intra-articular imbalances, which may require soft tissue releases and/or constrained implants. Correcting the extra-articular deformity (through an osteotomy) in conjunction with joint resurfacing TKA represents the only true kinematic alignment technique, as it aims to reproduce native knee laxity and overall lower limb axis.
PubMed: 38949174
DOI: 10.1530/EOR-23-0215 -
EFORT Open Reviews Jul 2024Adolescent idiopathic scoliosis (AIS) is an abnormal coronal curvature of the spine that most commonly presents in adolescence. While it may be asymptomatic, AIS can... (Review)
Review
Adolescent idiopathic scoliosis (AIS) is an abnormal coronal curvature of the spine that most commonly presents in adolescence. While it may be asymptomatic, AIS can cause pain, cosmetic deformity, and physical and psychological disability with curve progression. As adolescents with AIS enter adulthood, condition outcomes vary with some experiencing curve stabilization and others noting further curve progression, chronic pain, osteoporosis/fractures, declines in pulmonary and functional capacity, among others. Regular monitoring and individualized management by healthcare professionals are crucial to address the diverse challenges and provide appropriate support for a fulfilling adult life with AIS. This review examines the prevalence, risk factors, presenting symptoms, diagnosis, management, and complications of AIS in the adult population, informing targeted interventions by clinicians caring for adult patients with AIS.
PubMed: 38949156
DOI: 10.1530/EOR-23-0162 -
EFORT Open Reviews Jul 2024Total joint arthroplasty (TJA) is rising globally, with an associated increase in associated complications, necessitating increased efforts in prevention of these... (Review)
Review
Total joint arthroplasty (TJA) is rising globally, with an associated increase in associated complications, necessitating increased efforts in prevention of these complications with pre-operative optimisation. Malnutrition has been highlighted as one of the most important pre-operative modifiable risk factors to be addressed in TJA, with the term malnutrition in orthopaedic surgery having a broad definition that encompasses a wide range of nutritional abnormalities from undernutrition to overnutrition contributing to the outcomes of TJA. Complications associated with malnutrition include periprosthetic joint infection (PJI), periprosthetic fracture, dislocations, aseptic loosening, anaemia, prolonged length of stay (LOS), increased mortality, and raised health care costs. Standardised nutritional scoring tools, anthropometric measurements, and serological markers are all options available in pre-operative nutritional assessment in TJA, but there is no consensus yet regarding the standardisation of what parameters to assess and how to assess them. Abnormal parameters identified using any of the assessment methods results in the diagnosis of malnutrition, and correction of these parameters of overnutrition or undernutrition have shown to improve outcomes in TJA. With the multiple nutritional parameters contributing to the success of total joint arthroplasty, it is imperative that orthopaedic surgeon has a thorough knowledge regarding nutritional peri-operative optimisation in TJA.
PubMed: 38949153
DOI: 10.1530/EOR-23-0192 -
The Journal of Clinical Investigation Jul 2024
Topics: Animals; Mice; Signal Transduction; Macrophages; Receptors, CCR2; NF-kappa B; Disease Models, Animal; Myocardium; Humans; Arrhythmogenic Right Ventricular Dysplasia; Mice, Knockout
PubMed: 38949031
DOI: 10.1172/JCI183441 -
The Journal of Clinical Investigation Jul 2024Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I...
Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.
Topics: Humans; Zebrafish; Leigh Disease; Cilia; Animals; Mitochondria; Kidney Diseases, Cystic; Electron Transport Complex I; Armadillo Domain Proteins; Retina; Eye Abnormalities; Mice; Abnormalities, Multiple; Cerebellum; Mitochondrial Proteins; Zebrafish Proteins; Male
PubMed: 38949024
DOI: 10.1172/JCI175560 -
JPMA. the Journal of the Pakistan... Jun 2024Isolated Left Ventricular Non-compaction (LVNC) is a type of cardiomyopathy that usually has a genetic origin. Its diagnosis is based on finding such as deep...
Isolated Left Ventricular Non-compaction (LVNC) is a type of cardiomyopathy that usually has a genetic origin. Its diagnosis is based on finding such as deep intertrabecular recesses or sinusoids and ventricular trabeculations communicating with the left ventricular cavity. LVNC was first clinically recognised almost four decades ago, yet its diagnostic and management challenges persist. In this report, we present the case of an 18-year-old boy, who presented at the National Institute of Cardiovascular Diseases, Karachi, in March 2023, with complaints of dizziness, pedal oedema, and shortness of breath. Echocardiography revealed signs suggestive of LVNC, which were confirmed conclusively on Cardiovascular Magnetic Resonance (CMR) (NC/C ratio>2.4). The patient underwent implantable cardioverter defibrillator (ICD) placement, was discharged after a smooth post-procedure recovery, and is doing well on follow-ups. Hence, ICD and guideline-directed medical therapy as a combination have turned out to have satisfactory outcomes in decreasing morbidity and providing mortality benefits for such patients.
Topics: Humans; Male; Adolescent; Defibrillators, Implantable; Isolated Noncompaction of the Ventricular Myocardium; Echocardiography; Dyspnea; Dizziness
PubMed: 38948997
DOI: 10.47391/JPMA.10034