Difficult-to-treat (DTR) harboring Verona-Integron metallo-β-lactamase (): infection management and molecular analysis.

harboring Verona Integron-encoded metallo-β-lactamase enzymes (VIM-CRPA) have been associated with infection outbreaks in several parts of the world. In the US, however, VIM-CRPA remain rare. Starting in December 2018, we identified a cluster of cases in our institution.

Dysregulated naive B cells and de novo autoreactivity in severe COVID-19.

Severe SARS-CoV-2 infection has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential, although their origins and resolution have remained unclear. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity, as a dominant feature of severe and critical COVID-19 (refs.

HACS1 signaling adaptor protein recognizes a motif in the paired immunoglobulin receptor B cytoplasmic domain.

Hematopoietic adaptor containing SH3 and SAM domains-1 (HACS1) is a signaling protein with two juxtaposed protein-protein interaction domains and an intrinsically unstructured region that spans half the sequence. Here, we describe the interaction between the HACS1 SH3 domain and a sequence near the third immunoreceptor tyrosine-based inhibition motif (ITIM3) of the paired immunoglobulin receptor B (PIRB). From surface plasmon resonance binding assays using a mouse and human PIRB ITIM3 phosphopeptides as ligands, the HACS1 SH3 domain and SHP2 N-terminal SH2 domain demonstrated comparable affinities in the micromolar range.

Relaxed peripheral tolerance drives broad autoreactivity in severe COVID-19.

An emerging feature of COVID-19 is the identification of autoreactivity in patients with severe disease that may contribute to disease pathology, however the origin and resolution of these responses remain unclear. Previously, we identified strong extrafollicular B cell activation as a shared immune response feature between both severe COVID-19 and patients with advanced rheumatic disease. In autoimmune settings, this pathway is associated with relaxed peripheral tolerance in the antibody secreting cell compartment and the generation of autoreactive responses.

Acute septic elbow monoarthritis with associated Neisseria gonorrhoeae bacteraemia: an uncommon presentation of an old disease.

Neisseria gonorrhoeae is an uncommon present-day cause of septic arthritis. It is generally seen in the younger patient population and is often difficult to isolate in the lab. Blood cultures performed as routine work are usually negative, and when positive tend to be seen in the classic form of disseminated gonococcal infection.

Diffuse melanosis cutis: a rare manifestation of metastatic melanoma.

Diffuse melanosis cutis (DMC) is an extremely rare and late complication of metastatic melanoma (MM). It involves the progressive blue-grey discolouration of the skin and mucous membranes, occurring approximately 1 year after diagnosis of MM. The pathogenesis of DMC is unknown, although specific growth factors, such as alpha-melanocyte stimulating hormone, hepatocyte growth factor and endothelin-1, released by cancer cells, along with release of melanin precursors in the bloodstream and dermal MM micrometastases producing melanin have been attributed.

Investigation of the structure and dynamic of calmodulin-nitric oxide synthase complexes using NMR spectroscopy.

NMR spectroscopy allows for the determination of high resolution structures, as well as being an efficient method for studying the dynamics of protein-protein and protein-peptide complexes. N relaxation and H/D exchange experiments allow for the analysis of these structural dynamics at a residue specific level. Calmodulin (CaM) is a small cytosolic Ca binding protein that serves as a control element for many enzymes.

Calmodulin regulates Ca3 T-type channels at their gating brake.

Calcium (Ca1 and Ca2) and sodium channels possess homologous CaM-binding motifs, known as IQ motifs in their C termini, which associate with calmodulin (CaM), a universal calcium sensor. Ca3 T-type channels, which serve as pacemakers of the mammalian brain and heart, lack a C-terminal IQ motif. We illustrate that T-type channels associate with CaM using co-immunoprecipitation experiments and single particle cryo-electron microscopy.

Structural Consequences of Calmodulin EF Hand Mutations.

Calmodulin (CaM) is a cytosolic Ca-binding protein that serves as a control element for many enzymes. It consists of two globular domains, each containing two EF hand pairs capable of binding Ca, joined by a flexible central linker region. CaM is able to bind and activate its target proteins in the Ca-replete and Ca-deplete forms.

Structural Studies of a Complex Between Endothelial Nitric Oxide Synthase and Calmodulin at Physiological Calcium Concentration.

The small acidic protein calmodulin (CaM) serves as a Ca sensor and control element for many enzymes including nitric oxide synthase (NOS) enzymes that play major roles in key physiological and pathological processes. CaM binding causes a conformational change in NOS to allow for the electron transfer between the reductase and oxygenase domains through a process that is thought to be highly dynamic. In this report, NMR spectroscopy was used to determine the solution structure of the endothelial NOS (eNOS) peptide in complex with CaM at the lowest Ca concentration (225 nM) required for CaM to bind to eNOS and corresponds to a physiological elevated Ca level found in mammalian cells.

Chemical shift assignments of calmodulin constructs with EF hand mutations.

Calmodulin (CaM) is a ubiquitous cytosolic Ca(2+)-binding protein able to bind and regulate hundreds of different proteins. It consists of two globular domains joined by a flexible central linker region. Each one of these domains contains two EF hand pairs capable of binding to Ca(2+).

Dynamics of nitric oxide synthase-calmodulin interactions at physiological calcium concentrations.

The intracellular Ca²⁺ concentration is an important regulator of many cellular functions. The small acidic protein calmodulin (CaM) serves as a Ca²⁺ sensor and control element for many enzymes. Nitric oxide synthase (NOS) is one of the proteins that is activated by CaM and plays a major role in a number of key physiological and pathological processes.

Chemical shift perturbations induced by residue specific mutations of CaM interacting with NOS peptides.

The regulation of nitric oxide synthase (NOS) by calmodulin (CaM) plays a major role in a number of key physiological and pathological processes. A detailed molecular level picture of how this regulation is achieved is critical for drug development and for our understanding of protein regulation in general. CaM is a small acidic calcium binding protein and is required to fully activate NOS.

Solution structure of calmodulin bound to the target peptide of endothelial nitric oxide synthase phosphorylated at Thr495.

Nitric oxide synthase (NOS) plays a major role in a number of key physiological and pathological processes, and it is important to understand how this enzyme is regulated. The small acidic calcium binding protein, calmodulin (CaM), is required to fully activate the enzyme. The exact mechanism of how CaM activates NOS is not fully understood at this time.

Structure and dynamics of calmodulin (CaM) bound to nitric oxide synthase peptides: effects of a phosphomimetic CaM mutation.

Nitric oxide synthase (NOS) plays a major role in a number of key physiological and pathological processes. Knowledge of how this is regulated is important. The small acidic calcium binding protein, calmodulin (CaM), is required to fully activate the enzyme.

Changes in cardiovascular calcification after parathyroidectomy in patients with ESRD.

Background: The effect of parathyroidectomy on vascular calcification in patients with end-stage renal disease has been a subject of interest for many years, although studies in this area have not been definitive. The purpose of this investigation is to determine changes in vascular calcification after subtotal parathyroidectomy by using fast-gated helical computed axial tomographic imaging to measure coronary and carotid artery calcification.

Methods: Computed tomographic imaging was performed at baseline and in follow-up on 10 patients who had undergone subtotal parathyroidectomy and 10 reference patients who had not undergone parathyroidectomy.