A Fluorescent Probe Enables the Discovery of Improved Antagonists Targeting the Intracellular Allosteric Site of the Chemokine Receptor CCR7.

Intracellular ligands of G protein-coupled receptors (GPCRs) are gaining significant interest in drug discovery. Here, we report the development of the fluorescent ligand Mz437 () targeting the CC chemokine receptor CCR7 at an intracellular allosteric site. We demonstrate its experimental power by applying to identify two improved intracellular CCR7 antagonists, SLW131 () and SLW132 (), developed by converting two weakly active antagonists into single- or double-digit nanomolar ligands with minimal modifications.

Description of two new species from South Korea.

Based on molecular markers, mating experiments, morphological observations and ecological data, two species (Nematoda: Diplogastridae) new to science are described. Both were collected from different Scarabaeoid beetles in South Korea, have a gonochoristic mode of reproduction and fall into a sub-clade of the clade. n.

Transcatheter Closure of Postinfarct VSD With the Amplatzer PIVSD Occluder: Results of a US Study.

Background: A postinfarct ventricular septal defect (PIVSD) is associated with high mortality and morbidity, particularly in patients with hemodynamic instability who are not suitable candidates for surgical repair. The Amplatzer PIVSD Occluder (Abbott) is indicated for transcatheter PIVSD closure in patients who are not satisfactory candidates for surgical repair. The objective of this study was to evaluate associated clinical outcomes.

Aβ38 and Aβ43 do not differentiate between Alzheimer's disease and cerebral amyloid angiopathy.

Differential diagnosis between Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) using cerebrospinal fluid (CSF) biomarkers is challenging. A recent study suggested that the addition of Aβ38 and Aβ43 to a standard AD biomarker panel (Aβ40, Aβ42, t-tau, p-tau) to improve the differential diagnosis. We tested this hypothesis in an independent German cohort of CAA and AD patients and controls using the same analytical techniques.

3-year follow-up of a prospective, multicenter study of the Amplatzer Piccolo™ Occluder for transcatheter patent ductus arteriosus closure in children ≥ 700 grams.

Objective: This study describes 3-year follow-up of 200 infants weighing ≥ 700 grams who underwent transcatheter patent ductus arteriosus (PDA) closure with the Amplatzer Piccolo™ Occluder.

Study Design: Between June 2017 and February 2019, 200 children were enrolled in this U.S.

Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2.

Herein, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of CXC chemokine receptor 2 (CXCR2), a G protein-coupled receptor (GPCR) that has been pursued as a drug target in oncology and inflammation. Starting from the cocrystallized intracellular CXCR2 antagonist 00767013 (), tetramethylrhodamine (TAMRA)-labeled CXCR2 ligands were designed, synthesized, and tested for their suitability as fluorescent reporters to probe binding to the IABS of CXCR2. By means of these studies, we developed Mz438 () as a high-affinity and selective fluorescent CXCR2 ligand, enabling cell-free as well as cellular NanoBRET-based binding studies in a nonisotopic and high-throughput manner.

Anaphylaxis: Advances in the Past 10 Years.

In the past 10 years, anaphylaxis has grown into its own special area of study within Allergy-Immunology, both at the bench and at the bedside. This review focuses on some of the most clinically relevant advances over the past decade. These include simplified and more inclusive diagnostic criteria for adults and children, uniform definition of biphasic anaphylaxis, and improved systems for objective severity grading.

Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy: New Data and Quantitative Meta-Analysis.

Background: To evaluate the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers in patients with probable cerebral amyloid angiopathy (CAA) according to the modified Boston criteria in a retrospective multicentric cohort.

Methods: Beta-amyloid 1-40 (Aβ40), beta-amyloid 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau 181 (p-tau) were measured in 31 patients with probable CAA, 28 patients with Alzheimer's disease (AD), and 30 controls. Receiver-operating characteristics (ROC) analyses were performed for the measured parameters as well as the Aβ42/40 ratio to estimate diagnostic parameters.

Comparative genomics and community curation further improve gene annotations in the nematode Pristionchus pacificus.

Background: Nematode model organisms such as Caenorhabditis elegans and Pristionchus pacificus are powerful systems for studying the evolution of gene function at a mechanistic level. However, the identification of P. pacificus orthologs of candidate genes known from C.

Multimodal imaging reveals a unique autofluorescence signature of Randall's plaque.

Kidney stones frequently develop as an overgrowth on Randall's plaque (RP) which is formed in the papillary interstitium. The organic composition of RP is distinct from stone matrix in that RP contains fibrillar collagen; RP in tissue has also been shown to have two proteins that are also found in stones, but otherwise the molecular constituents of RP are unstudied. We hypothesized that RP contains unique organic molecules that can be differentiated from the stone overgrowth by fluorescence.

Clinical and radiological differences between patients with probable cerebral amyloid angiopathy and mixed cerebral microbleeds.

Background: The key imaging features of cerebral amyloid angiopathy (CAA) are lobar, cortical, or cortico-subcortical microbleeds, macrohaemorrhages and cortical superficial siderosis (cSS). In contrast, hypertensive angiopathy is characterized by (micro) haemorrhages in the basal ganglia, thalami, periventricular white matter or the brain stem. Another distinct form of haemorrhagic microangiopathy is mixed cerebral microbleeds (mixed CMB) with features of both CAA and hypertensive angiopathy.

The Utility of Measuring Urinary Metabolites of Mast Cell Mediators in Systemic Mastocytosis and Mast Cell Activation Syndrome.

Mast cells (MCs) leave evidence of their presence and activation. Aside from increased numbers of MCs in tissues, this evidence includes detecting elevated serum levels of tryptase and discovering increased excretion of urinary metabolites of prostaglandin (PG) D, leukotriene (LT) C, and/or histamine. The importance of measuring these nontryptase mediator metabolites has largely gone unnoticed.

AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management.

Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other pathways are involved; our current understanding of the biomarkers secreted by activated MCs that best discriminate this disorder from other conditions; and the therapeutic drugs that might selectively affect those mediators or MCs themselves. Finding familial or somatic mutations of genes that cause MCs to be hyperactivatable would extend our diagnostic tools and potentially indicate new therapeutic interventions, targeting either the mutated gene product or the associated molecular pathway. In conclusion, we trust that the clinical, laboratory, and therapeutic criteria for primary MC activation syndromes described herein will provide clinicians with practical criteria of sufficient sensitivity and specificity to diagnose most cases without overdiagnosing the disorder in patients who likely have other conditions.

Mast Cell Activation Syndrome: Tools for Diagnosis and Differential Diagnosis.

The current consensus diagnostic criteria for mast cell activation syndrome(s) (MCAS[s]) were first established in 2012 and updated in 2019. This diagnosis has been attached to multiple medical conditions not intended as part of the diagnosis. In this article, the diagnostic criteria are reviewed and other diseases in the differential diagnosis outlined.

Two new Species of (Nematoda: Diplogastridae) include the Gonochoristic Sister Species of .

The genus (Kreis, 1932) consists of more than 30 soil nematode species that are often found in association with scarab beetles. Three major radiations have resulted in the " species group" in America, the " species group" in Asia, and the " species group," which contains species from Europe and Asia. Phylogenetic analysis indicates that a group of three species, including the gonochorists and and the hermaphrodite , is basal to the above-mentioned radiations.