A5083885931- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- Cell death mechanisms and regulation
- Genomics and Rare Diseases
- Congenital heart defects research
- Inflammasome and immune disorders
- Immunodeficiency and Autoimmune Disorders
- Renal and related cancers
- Neurogenetic and Muscular Disorders Research
- Emergency and Acute Care Studies
- RNA Research and Splicing
- Kawasaki Disease and Coronary Complications
- Cardiomyopathy and Myosin Studies
- RNA regulation and disease
- dental development and anomalies
- Genetic and Kidney Cyst Diseases
- Mitochondrial Function and Pathology
- RNA and protein synthesis mechanisms
- Healthcare Policy and Management
- NF-κB Signaling Pathways
- Respiratory Support and Mechanisms
- Genetic factors in colorectal cancer
- Autophagy in Disease and Therapy
- IL-33, ST2, and ILC Pathways
- Protein Tyrosine Phosphatases
Yale University
2016-2025
ID Genomics (United States)
2025
University of New Haven
2024
Peace Arch Hospital
2024
Walton Centre
2012-2023
University of Liverpool
2012-2023
Government Communications Headquarters
2020
Pediatrics and Genetics
2019
RELX Group (United States)
2019
Columbia University Irving Medical Center
2018
The current model of apoptosis holds that upstream signals lead to activation downstream effector caspases. We generated mice deficient in the two effectors, caspase 3 and 7, which died immediately after birth with defects cardiac development. Fibroblasts lacking both enzymes were highly resistant mitochondrial death receptor-mediated apoptosis, displayed preservation membrane potential, had defective nuclear translocation apoptosis-inducing factor (AIF). Furthermore, early apoptotic events...
Macrophage JNK in Metabolic Disease Inflammation is thought to be an important driver of diet-induced obesity and insulin resistance. Proinflammatory, M1 phenotype macrophages the c-jun NH 2 terminal kinases (JNK) are central players this process. But whether expression specifically required inside unclear. In mice containing a macrophage-specific deletion both Jnk1 Jnk2 , Han et al. (p. 218 published online 6 December; see Perspective by Ferrante Jr. ) found that were protected against many...
Caspase-3 is a critical enzyme for apoptosis and cell survival. Here we report delayed ossification decreased bone mineral density in caspase-3–deficient (Casp3–/– Casp3+/–) mice due to an attenuated osteogenic differentiation of marrow stromal stem cells (BMSSCs). The mechanism involved the impaired BMSSCs due, at least partially, overactivated TGF-β/Smad2 signaling pathway upregulated expressions p53 p21 along with downregulated Cdk2 Cdc2, ultimately increased replicative senescence. In...
Caspase-3 is a critical enzyme for apoptosis and cell survival. Here we report delayed ossification decreased bone mineral density in caspase-3–deficient (Casp3–/– Casp3+/–) mice due to an attenuated osteogenic differentiation of marrow stromal stem cells (BMSSCs). The mechanism involved the impaired BMSSCs due, at least partially, overactivated TGF-β/Smad2 signaling pathway upregulated expressions p53 p21 along with downregulated Cdk2 Cdc2, ultimately increased replicative senescence. In...
Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 have been identified humans with congenital malformations defined as deficiency disorder (CNDD). Here, we 13 further individuals predicted to be damaging, phenotypes ranging from multiple severe complete absence malformation. Enzymatic assessment variant...
Extremely premature infants (EPIs) who are born before 30 weeks of gestation susceptible to infection; however, the trajectory their peripheral immunity is poorly understood. Here, we undertook longitudinal analyses immune cells from 250 μl whole blood at 1 week, month, and 2 months 10 EPIs compared these with samples healthy adults preterm full-term cord samples. Single-cell suspensions individual were split perform single-cell RNA sequencing, T B cell receptor phosphoprotein mass...
Abstract Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after severe acute respiratory coronavirus 2 (SARS-CoV-2) exposure. To investigate functions, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key response initiators. We found severely dampened cytokine and elevated gene...
The notion that the cell death machinery is utilized during lens organelle degradation supported by observation well characterized apoptotic substrates are cleaved this process. Here, we test directly role of executioner caspases (caspase-3, -6, and -7) in fiber differentiation. distribution mRNA, protein, enzymatic activity for each caspase was determined mouse lens. Transcripts all three were identified cells real time RT-PCR, although only caspase-6 -7 proteins detected subsequently...
Members of the caspase family are essential for many apoptotic programs. We studied mouse embryonic fibroblasts (MEFs) deficient in caspases 3 and 7 9 to determine role these proteases endoplasmic reticulum (ER) stress-induced apoptosis. Both 3–/–/caspase 7–/– 9–/– MEFs were resistant cytotoxicity induced via ER stress failed exhibit morphology. Specifically, apoptosis by increased intracellular calcium was shown depend only on 9, whereas disruption function depended additionally 7. Caspase...
Background Early infantile epileptic encephalopathies are severe disorders consisting of early-onset refractory seizures accompanied often by significant developmental delay. The increasing availability next-generation sequencing has facilitated the recognition single gene mutations as an underlying aetiology some forms early encephalopathies. Objectives This study was designed to identify candidate genes a potential cause encephalopathy, and then provide genetic functional evidence...
CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including maintenance cell-cell junctions, regulation epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, been implicated human diseases cleft palate blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, 13 participants from nine families presenting with...
Abstract The Dromedary camel has a remarkable history amongst cultures across Asia and northern Africa, serving multiple purposes ranging from providing milk, textiles, racing, acting as pack animals. Recent genetic studies have revealed that many dromedaries are genetically homogenous, indicating they do not represent different breeds, advocating for ‘type’ over ‘breed’. In this study, we leveraged whole genome sequencing (WGS) to sequence 15 Jordanian Alia camels the first time, alongside...
Pregnancy loss is a major problem in clinical medicine with devastating consequences for families. Next generation sequencing has improved our ability to identify underlying molecular causes, though over half of all cases lack clear etiology. Here, we began evaluation combined exome across independent families bi-allelic candidate genetic variants the Programmed Cell Death 2 (PDCD2) gene multiple fetuses nonimmune hydrops fetalis (NIHF). PDCD2 an evolutionarily conserved protein no prior...
Objectives We demonstrate an approach that integrates biomarker analysis with machine learning to identify protein signatures, using the example of SARS-CoV-2-induced Multisystem Inflammatory Syndrome in Children (MIS-C). Methods used plasma samples collected from subjects diagnosed MIS-C and compared them first controls asymptomatic/mild SARS-CoV-2 infection then pneumonia or Kawasaki disease. mass spectrometry proteins. Support vector (SVM) algorithm-based classification schemes were...
Germline gain‐of‐function variants in SAMD9 have been associated with a high risk of mortality and newly recognized constellation symptoms described by the acronym MIRAGE: Myelodysplasia, Infection, Restriction growth, Adrenal insufficiency, Genital phenotypes, Enteropathy. Here, we describe two additional patients currently living syndrome, including one patient novel de novo variant for which provide functional data supporting its pathogenicity. We discuss features dysmorphology,...
Familial dilated cardiomyopathy (DCM), clinically characterized by enlargement and dysfunction of one or both ventricles the heart, can be caused variants in sarcomeric genes, including TNNC1 (encoding cardiac troponin C, cTnC). Here, we report case two siblings with severe, early-onset DCM who were found to have compound heterozygous TNNC1: p.Asp145Glu (D145E) p.Asp132Asn (D132N), which inherited from parents. We began our investigation CRISPR/Cas9 knockout Xenopus tropicalis, resulted a...
The selection of sedative medications for mechanically ventilated pediatric patients remains an ongoing clinical challenge. Although continuous ketamine infusion has been used in this population, support its use largely anecdotal. This study describes a single institution's infusions as part sedation protocol the intensive care unit (PICU).This was retrospective children who received multidrug 12-bed PICU at tertiary children's hospital. Outcomes included effectiveness providing adequate...