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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 -
The Journal of Clinical Investigation Jun 2024Research advances over the past 30 years have confirmed a critical role for genetics in the etiology of dilated cardiomyopathies (DCMs). However, full knowledge of the...
Research advances over the past 30 years have confirmed a critical role for genetics in the etiology of dilated cardiomyopathies (DCMs). However, full knowledge of the genetic architecture of DCM remains incomplete. We identified candidate DCM causal gene, C10orf71, in a large family with 8 patients with DCM by whole-exome sequencing. Four loss-of-function variants of C10orf71 were subsequently identified in an additional group of492 patients with sporadic DCM from 2 independent cohorts. C10orf71 was found to be an intrinsically disordered protein specifically expressed in cardiomyocytes. C10orf71-KO mice had abnormal heart morphogenesis during embryonic development and cardiac dysfunction as adults with altered expression and splicing of contractile cardiac genes. C10orf71-null cardiomyocytes exhibited impaired contractile function with unaffected sarcomere structure. Cardiomyocytes and heart organoids derived from human induced pluripotent stem cells with C10orf71 frameshift variants also had contractile defects with normal electrophysiological activity. A rescue study using a cardiac myosin activator, omecamtiv mecarbil, restored contractile function in C10orf71-KO mice. These data support C10orf71 as a causal gene for DCM by contributing to the contractile function of cardiomyocytes. Mutation-specific pathophysiology may suggest therapeutic targets and more individualized therapy.
Topics: Humans; Animals; Cardiomyopathy, Dilated; Mice; Myocytes, Cardiac; Mice, Knockout; Frameshift Mutation; Organoids; Male; Female; Myocardial Contraction; Adult; Disease Models, Animal
PubMed: 38950288
DOI: 10.1172/JCI177172 -
PLoS Neglected Tropical Diseases Jul 2024Giardiasis and zinc deficiency have been identified as serious health problems worldwide. Although Zn depletion is known to occur in giardiasis, no work has investigated...
BACKGROUND
Giardiasis and zinc deficiency have been identified as serious health problems worldwide. Although Zn depletion is known to occur in giardiasis, no work has investigated whether changes occur in brain structures.
METHODS
Three groups of gerbils were used: control (1), orogastrically inoculated on day 3 after birth with trophozoites of two isolates of Giardia intestinalis (HGINV/WB) group (2 and 3). Estimates were made at five ages covering: establishment of infection, Giardia population growth, natural parasite clearance and a post-infection age. QuantiChrome zinc assay kit, cresyl violet staining and TUNEL technique were used.
RESULTS
A significant decrease (p<0.01) in tissue zinc was observed and persisted after infection. Cytoarchitectural changes were observed in 75% of gerbils in the HGINV or WB groups. Ectopic pyramidal neurons were found in the cornus ammonis (CA1-CA3). At 60 and 90 days of age loss of lamination was clearly visible in CA1. In the dentate gyrus (DG), thinning of the dorsal lamina and abnormal thickening of the ventral lamina were observed from 30 days of age. In the cerebellum, we found an increase (p<0.01) in the thickness of the external granular layer (EGL) at 14 days of age that persisted until day 21 (C 3 ± 0.3 μm; HGINV 37 ± 5 μm; WB 28 ± 3 μm); Purkinje cell population estimation showed a significant decrease; a large number of apoptotic somas were observed scattered in the molecular layer; in 60 and 90 days old gerbils we found granular cell heterotopia and Purkinje cell ectopia. The pattern of apoptosis was different in the cerebellum and hippocampus of parasitized gerbils.
CONCLUSION
The morphological changes found suggest that neuronal migration is affected by zinc depletion caused by giardiasis in early postnatal life; for the first time, the link between giardiasis-zinc depletion and damaged brain structures is shown. This damage may explain the psychomotor/cognitive delay associated with giardiasis. These findings are alarming. Alterations in zinc metabolism and signalling are known to be involved in many brain disorders, including autism.
PubMed: 38950061
DOI: 10.1371/journal.pntd.0012302 -
PloS One 2024Diabetic foot ulcers (DFUs) pose a significant challenge in diabetes care. Yet, a comprehensive understanding of the underlying biological disparities between healing...
Diabetic foot ulcers (DFUs) pose a significant challenge in diabetes care. Yet, a comprehensive understanding of the underlying biological disparities between healing and non-healing DFUs remains elusive. We conducted bioinformatics analysis of publicly available transcriptome sequencing data in an attempt to elucidate these differences. Our analysis encompassed differential analysis to unveil shifts in cell composition and gene expression profiles between non-healing and healing DFUs. Cell communication alterations were explored employing the Cellchat R package. Pseudotime analysis and cytoTRACE allowed us to dissect the heterogeneity within fibroblast subpopulations. Our findings unveiled disruptions in various cell types, localized low-grade inflammation, compromised systemic antigen processing and presentation, and extensive extracellular matrix signaling disarray in non-healing DFU patients. Some of these anomalies partially reverted in healing DFUs, particularly within the abnormal ECM-receptor signaling pathway. Furthermore, we distinguished distinct fibroblast subpopulations in non-healing and healing DFUs, each with unique biological functions. Healing-associated fibroblasts exhibited heightened extracellular matrix (ECM) remodeling and a robust wound healing response, while non-healing-associated fibroblasts showed signs of cellular senescence and complement activation, among other characteristics. This analysis offers profound insights into the wound healing microenvironment, identifies pivotal cell types for DFU healing promotion, and reveals potential therapeutic targets for DFU management.
Topics: Diabetic Foot; Humans; Wound Healing; Single-Cell Analysis; Fibroblasts; Transcriptome; Extracellular Matrix; Gene Expression Profiling; Signal Transduction
PubMed: 38950058
DOI: 10.1371/journal.pone.0306248 -
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 2024Skeletal scintigraphy has a pivotal role in detecting a number of bone pathologies, but it has its own limitations because of 2D image acquisition. Hybrid imaging acts...
Skeletal scintigraphy has a pivotal role in detecting a number of bone pathologies, but it has its own limitations because of 2D image acquisition. Hybrid imaging acts as a savior in these cases where it is difficult to distinguish between benign and malignant lesions just on the basis of planar images. We present one such case of known breast carcinoma with abnormal increased radiotracer uptake in the skull which was difficult to characterize as benign lesion such as hyperostosis frontalis or metastatic osseous lesion. The importance of describing this case is to have a thorough understanding of hyperostosis patterns and to not confuse it with metastatic deposits in patients with known malignancies.
Topics: Humans; Female; Breast Neoplasms; Diagnosis, Differential; Hyperostosis Frontalis Interna; Single Photon Emission Computed Tomography Computed Tomography; Middle Aged; Bone Neoplasms
PubMed: 38949003
DOI: 10.47391/JPMA.24-48 -
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