CRISPR-Cas9 to induce fetal hemoglobin for the treatment of sickle cell disease.

Genome editing is potentially a curative technique available to all individuals with β-hemoglobinopathies, including sickle cell disease (SCD). Fetal hemoglobin (HbF) inhibits sickle hemoglobin (HbS) polymerization, and it is well described that naturally occurring hereditary persistence of HbF (HPFH) alleviates disease symptoms; therefore, reawakening of developmentally silenced HbF in adult red blood cells (RBCs) has long been of interest as a therapeutic strategy. Recent advances in genome editing platforms, particularly with the use of CRISPR-Cas9, have paved the way for efficient HbF induction through the creation of artificial HPFH mutations, editing of transcriptional HbF silencers, and modulating epigenetic intermediates that govern HbF expression.

Multiparametric Cardiovascular Magnetic Resonance in Acute Myocarditis: Comparison of 2009 and 2018 Lake Louise Criteria With Endomyocardial Biopsy Confirmation.

Cardiac magnetic resonance (CMR) has been shown to improve the diagnosis of myocarditis, but no systematic comparison of this technique is currently available. The purpose of this study was to compare the 2009 and 2018 Lake Louise Criteria (LLC) for the diagnosis of acute myocarditis using 3.0 T MRI with endomyocardial biopsy (EMB) as a reference and to provide the cutoff values for multiparametric CMR techniques.

Intracellular imaging of metmyoglobin and oxygen using new dual purpose probe EYFP-Myoglobin-mCherry.

The biological relevance of nitric oxide (NO) and reactive oxygen species (ROS) in signaling, metabolic regulation, and disease treatment has become abundantly clear. The dramatic change in NO/ROS processing that accompanies a changing oxygen landscape calls for new imaging tools that can provide cellular details about both [O ] and the production of reactive species. Myoglobin oxidation to the met state by NO/ROS is a known sensor with absorbance changes in the visible range.

Evaluation of Hepatic Iron Overload Using a Contemporary 0.55 T MRI System.

Background: MRI T2* and R2* mapping have gained clinical acceptance for noninvasive assessment of iron overload. Lower field MRI may offer increased measurement dynamic range in patients with high iron concentration and may potentially increase MRI accessibility, but it is compromised by lower signal-to-noise ratio that reduces measurement precision.

Purpose: To characterize a high-performance 0.

Utility of plasma cell-free DNA for detection and quantification of clonal hematopoiesis.

Although cell-free DNA (cfDNA) tests have emerged as a potential non-invasive alternative to bone marrow biopsies for monitoring clonal hematopoiesis in hematologic diseases, whether commercial cfDNA assays can be implemented for the detection and quantification of de novo clonal hematopoiesis in place of blood cells is uncertain. In this study, peripheral plasma cfDNA samples available from patients with aplastic anemia (n=25) or myelodysplastic syndromes (n=27) and a healthy cohort (n=107) were screened for somatic variants in genes related to hematologic malignancies using a Clinical Laboratory Improvement Amendments-certified panel. Results were further compared to DNA sequencing of matched blood cells.

The NIH Lipo-COVID Study: A Pilot NMR Investigation of Lipoprotein Subfractions and Other Metabolites in Patients with Severe COVID-19.

A complex interplay exists between plasma lipoproteins and inflammation, as evidenced from studies on atherosclerosis. Alterations in plasma lipoprotein levels in the context of infectious diseases, particularly respiratory viral infections, such as SARS-CoV-2, have become of great interest in recent years, due to their potential utility as prognostic markers. Patients with severe COVID-19 have been reported to have low levels of total cholesterol, HDL-cholesterol, and LDL-cholesterol, but elevated levels of triglycerides.

The role of 4D flow MRI for clinical applications in cardiovascular disease: current status and future perspectives.

Magnetic resonance imaging (MRI) four-dimensional (4D) flow is a type of phase-contrast (PC) MRI that uses blood flow encoded in 3 directions, which is resolved relative to 3 spatial and temporal dimensions of cardiac circulation. It can be used to simultaneously quantify and visualize hemodynamics or morphology disorders. 4D flow MRI is more comprehensive and accurate than two-dimensional (2D) PC MRI and echocardiography.

NOTCH-mediated ex vivo expansion of human hematopoietic stem and progenitor cells by culture under hypoxia.

Activation of NOTCH signaling in human hematopoietic stem/progenitor cells (HSPCs) by treatment with an engineered Delta-like ligand (DELTA1 [DXI]) has enabled ex vivo expansion of short-term HSPCs, but the effect on long-term repopulating hematopoietic stem cells (LTR-HSCs) remains uncertain. Here, we demonstrate that ex vivo culture of human adult HSPCs with DXI under low oxygen tension limits ER stress in LTR-HSCs and lineage-committed progenitors compared with normoxic cultures. A distinct HSC gene signature was upregulated in cells cultured with DXI in hypoxia and, after 21 days of culture, the frequency of LTR-HSCs increased 4.

Somatic mosaicism in inherited bone marrow failure syndromes.

Inherited bone marrow failure syndromes (IBMFS) are a heterogenous group of diseases caused by pathogenic germline variants in key pathways associated with haematopoiesis and genomic stability. Germline variants in IBMFS-related genes are known to reduce the fitness of hematopoietic stem and progenitor cells (HSPC), which has been hypothesized to drive clonal selection in these diseases. In many IBMFS, somatic mosaicism predominantly impacts cells by two distinct mechanisms, with contrasting effects.

LFA-1 in T cell priming, differentiation, and effector functions.

The integrin LFA-1 is crucial for T cell entry into mammalian lymph nodes and tissues, and for promoting interactions with antigen-presenting cells (APCs). However, it is increasingly evident that LFA-1 has additional key roles beyond the mere support of adhesion between T cells, the endothelium, and/or APCs. These include roles in homotypic T cell-T cell (T-T) communication, the induction of intracellular complement activity underlying Th1 effector cell polarization, and the support of long-lasting T cell memory.

Role of heat shock proteins in aging and chronic inflammatory diseases.

Advanced age is associated with a decline in response to stress. This contributes to the establishment of chronic inflammation, one of the hallmarks of aging and age-related disease. Heat shock proteins (HSP) are determinants of life span, and their progressive malfunction leads to age-related pathology.

The -Mediated Xq28 Duplication Syndrome: An Intersection between Neurodevelopment, Immunology, and Cancer.

The -mediated Xq28 duplication syndrome is a rare X-linked intellectual disability syndrome (XLIDS) arising from a duplication of the segment between intron 22 homologous regions 1 and 2, on the q28 subregion of the X chromosome. The main clinical features of the syndrome include intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. Due to the X-linked nature of the syndrome, affected males exhibit more severe phenotypes compared with heterozygous females.

Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus.

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction.

Pericardial Fat and the Risk of Heart Failure.

Background: Obesity is a well-established risk factor for heart failure (HF). However, implications of pericardial fat on incident HF is unclear.

Objectives: This study sought to examine the association between pericardial fat volume (PFV) and newly diagnosed HF.

Developing Analysis Protocols for Monitoring Intracellular Oxygenation Using Fluorescence Lifetime Imaging of Myoglobin-mCherry.

Oxygen (O) is a critical metabolite for cellular function as it fuels aerobic cellular metabolism; further, it is a known regulator of gene expression. Monitoring oxygenation within cells and organelles can provide valuable insights into how O, or lack thereof, both influences and responds to cell processes. In recent years, fluorescence lifetime imaging microscopy (FLIM) has been used to track several probe concentration independent intracellular phenomena, such as pH, viscosity, and, in conjunction with Förster resonance energy transfer (FRET), protein-protein interactions.

Analysis of deficiency of adenosine deaminase 2 pathogenesis based on single-cell RNA sequencing of monocytes.

Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disease caused by loss-of-function variants in the ADA2 gene. DADA2 typically presents in childhood and is characterized by vasculopathy, stroke, inflammation, immunodeficiency, as well as hematologic manifestations. ADA2 protein is predominantly present in stimulated monocytes, dendritic cells, and macrophages.

Feeding-induced resistance to acute lethal sepsis is dependent on hepatic BMAL1 and FXR signalling.

In mice, time of day strongly influences lethality in response to LPS, with survival greatest at the beginning compared to the end of the light cycle. Here we show that feeding, rather than light, controls time-of-day dependent LPS sensitivity. Mortality following LPS administration is independent of cytokine production and the clock regulator BMAL1 expressed in myeloid cells.

The Extended Eighth-Shell method for periodic boundary conditions with rotational symmetry.

The Eighth-Shell method for parallelization of molecular dynamics simulations has previously been shown to be the most optimal for efficiency at large process counts. However, in its current formulation only the P1 space group is supported for periodic boundary conditions (PBC) and thus reflection and/or rotational crystal symmetries are not supported. In this work, we outline the development and implementation of the Extended Eighth-Shell (EES) method that allows rotational symmetry by using an extended import region compared to the ES method.

"," Mapping the 25 Year Evolution and Impact of North American Vascular Biology Organization Science Through Publications of its Founding and Current Members.

Scholarly organizations bring together experts to move forward specific areas of scientific endeavor. More than 5,000 scholarly societies exist world-wide yet little is known about the composition, evolution, and collaboration of experts within these organizations. This study presents general methods to study the evolution of a biomedical organization and its impact over time.

SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation.

Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys and gut. Angiotensin converting enzyme (ACE) 2, the best-characterized entry receptor for the disease-causing virus SARS-CoV-2, is highly expressed in the aforementioned tissues. However, the pathways that underlie the disease are still poorly understood.