Synthesis and Pharmacological Characterization of Fluorescent Ligands Targeting the Angiotensin II Receptors Derived from Agonists, β-Arrestin-Biased Agonists, and Antagonists.

Angiotensin II (AngII) regulates cerebral circulation and binds with a similar affinity to AT and AT receptors. Biased AT agonists, such as TRV027, which are able to selectively activate β-arrestin while blocking the G pathway, appear promising as new therapeutics. New pharmacological tools are needed to further explore the impact of biased AT agonists on cells or tissues, such as the cerebral vessels.

Travel surveillance uncovers dengue virus dynamics and introductions in the Caribbean.

Dengue is the most prevalent mosquito-borne viral disease in humans, and cases are continuing to rise globally. In particular, islands in the Caribbean have experienced more frequent outbreaks, and all four dengue virus (DENV) serotypes have been reported in the region, leading to hyperendemicity and increased rates of severe disease. However, there is significant variability regarding virus surveillance and reporting between islands, making it difficult to obtain an accurate understanding of the epidemiological patterns in the Caribbean.

The C-type lectin DCIR contributes to the immune response and pathogenesis of colorectal cancer.

Development and progression of malignancies are accompanied and influenced by alterations in the surrounding immune microenvironment. Understanding the cellular and molecular interactions between immune cells and cancer cells has not only provided important fundamental insights into the disease, but has also led to the development of new immunotherapies. The C-type lectin Dendritic Cell ImmunoReceptor (DCIR) is primarily expressed by myeloid cells and is an important regulator of immune homeostasis, as demonstrated in various autoimmune, infectious and inflammatory contexts.

Travel surveillance uncovers dengue virus dynamics and introductions in the Caribbean.

Dengue is the most prevalent mosquito-borne viral disease in humans, and cases are continuing to rise globally. In particular, islands in the Caribbean have experienced more frequent outbreaks, and all four dengue virus (DENV) serotypes have been reported in the region, leading to hyperendemicity and increased rates of severe disease. However, there is significant variability regarding virus surveillance and reporting between islands, making it difficult to obtain an accurate understanding of the epidemiological patterns in the Caribbean.

User-Centered Mobile Applications for Stroke Survivors (MAPPS): A Mixed-Methods Study of Patient Preferences.

Objective: Investigate stroke survivors' (SS) preferences for a hypothetical mHealth app for post-stroke care and to study the influence of demographic variables on these preferences.

Design: Mixed-methods, sequential, observational study.

Setting: Focus groups (phase 1) were conducted to identify SS perceptions and knowledge of mHealth applications (apps).

Natural Peptide Toxins as an Option for Renewed Treatment of Type 2 Vasopressin Receptor-Related Diseases.

The type 2 vasopressin receptor (V2R) is expressed in the kidneys, and it is the keystone of water homeostasis. Under the control of the antidiuretic hormone vasopressin, the V2R ensures vital functions, and any disturbance has dramatic consequences. Despite decades of research to develop drugs capable of activating or blocking V2R function to meet real medical needs, only one agonist and one antagonist are virtually used today.

Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic Aβ Peptides.

Excess brain cholesterol is strongly implicated in the pathogenesis of Alzheimer's disease (AD). Here we evaluated how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of the amyloid precursor protein (APP) regulates its processing. We generated nine point mutations in the APP gene, changing the charge and/or hydrophobicity of the amino-acids which were previously shown as part of the CBS.

From a Cone Snail Toxin to a Competitive MC4R Antagonist.

The melanocortin 4 receptor (MC4R) plays a role in energy homeostasis and represents a target for treating energy balance disorders. For decades, synthetic ligands have been derived from MC4R endogenous agonists and antagonists, such as setmelanotide used to treat rare forms of genetic obesity. Recently, animal venoms have demonstrated their capacity to provide melanocortin ligands with toxins from a scorpion and a spider.

MT9, a natural peptide from black mamba venom antagonizes the muscarinic type 2 receptor and reverses the M2R-agonist-induced relaxation in rat and human arteries.

All five muscarinic receptors have important physiological roles. The endothelial M2 and M3 subtypes regulate arterial tone through direct coupling to Gq or Gi/o proteins. Yet, we lack selective pharmacological drugs to assess the respective contribution of muscarinic receptors to a given function.

Binding properties to nicotinic acetylcholine receptors can explain differential toxicity of neonicotinoid insecticides in Chironomidae.

Neonicotinoids are neuroactive insecticides commonly detected in freshwater ecosystems. Recent studies have indicated that these compounds are markedly toxic to Chironomidae, a widespread family of ecologically important aquatic insects. However, despite their sensitivity, the pharmacological mechanisms driving neonicotinoid toxicity have yet to be characterized in these insect species.

A snake toxin as a theranostic agent for the type 2 vasopressin receptor.

MQ1, a snake toxin which targets with high nanomolar affinity and absolute selectivity for the type 2 vasopressin receptor (V2R), is a drug candidate for renal diseases and a molecular probe for imaging cells or organs expressing V2R. MQ1's pharmacological properties were characterized and applied to a rat model of hyponatremia. Its PK/PD parameters were determined as well as its therapeutic index.

A Venomics Approach Coupled to High-Throughput Toxin Production Strategies Identifies the First Venom-Derived Melanocortin Receptor Agonists.

Animal venoms are rich in hundreds of toxins with extraordinary biological activities. Their exploitation is difficult due to their complexity and the small quantities of venom available from most venomous species. We developed a Venomics approach combining transcriptomic and proteomic characterization of 191 species and identified 20,206 venom toxin sequences.

Can IM-MS Collision Cross Sections of Biomolecules Be Rationalized Using Collision Cross-Section Trends of Polydisperse Synthetic Homopolymers?

In the past, we developed a method inferring physicochemical properties from ion mobility mass spectrometry (IM-MS) data from polydisperse synthetic homopolymers. We extend here the method to biomolecules that are generally monodisperse. Similarities in the IM-MS behavior were illustrated on proteins and peptides.

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.

Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen.

Combination of Capillary Zone Electrophoresis-Mass Spectrometry, Ion Mobility-Mass Spectrometry, and Theoretical Calculations for Cysteine Connectivity Identification in Peptides Bearing Two Intramolecular Disulfide Bonds.

Disulfide bonds between cysteine residues are commonly involved in the stability of numerous peptides and proteins and are crucial for providing biological activities. In such peptides, the appropriate cysteine connectivity ensures the proper conformation allowing an efficient binding to their molecular targets. Disulfide bond connectivity characterization is still challenging and is a critical issue in the analysis of structured peptides/proteins targeting pharmaceutical or pharmacological utilizations.

Evaluation of the Spider ( genus) Phlotoxin 1 and Synthetic Variants as Antinociceptive Drug Candidates.

Over the two last decades, venom toxins have been explored as alternatives to opioids to treat chronic debilitating pain. At present, approximately 20 potential analgesic toxins, mainly from spider venoms, are known to inhibit with high affinity the Na1.7 subtype of voltage-gated sodium (Na) channels, the most promising genetically validated antinociceptive target identified so far.

Medical Mobile Applications for Stroke Survivors and Caregivers.

Background: Recent studies estimate nearly half of the US population can access mobile medical applications (apps) on their smartphones. The are no systematic data available on apps focused on stroke survivors/caregivers.

Objective: To identify apps (a) designed for stroke survivors/caregivers, (b) dealing with a modifiable stroke risk factor (SRF), or (c) were developed for other purposes but could potentially be used by stroke survivors/caregivers.

High-Throughput Production of Oxidized Animal Toxins in Escherichia coli.

High-throughput production (HTP) of synthetic genes is becoming an important tool to explore the biological function of the extensive genomic and meta-genomic information currently available from various sources. One such source is animal venom, which contains thousands of novel bioactive peptides with potential uses as novel therapeutics to treat a plethora of diseases as well as in environmentally benign bioinsecticide formulations. Here, we describe a HTP platform for recombinant bacterial production of oxidized disulfide-rich proteins and peptides from animal venoms.

Ischemic Stroke Predictors in Patients Presenting with Dizziness, Imbalance, and Vertigo.

Objects: To identify predictors of acute ischemic stroke (AIS) among patients presenting to the Emergency Department (ED) with dizziness, imbalance, or vertigo (DIV) based on demographic and clinical characteristics.

Methods: We identified patients admitted to the hospital after presenting to the ED with DIV from the Statewide Planning and Research Cooperative System database of New York from 2010 to 2014. Demographic and clinical characteristics were systematically collected.

Disulfide Connectivity Analysis of Peptides Bearing Two Intramolecular Disulfide Bonds Using MALDI In-Source Decay.

Disulfide connectivity in peptides bearing at least two intramolecular disulfide bonds is highly important for the structure and the biological activity of the peptides. In that context, analytical strategies allowing a characterization of the cysteine pairing are of prime interest for chemists, biochemists, and biologists. For that purpose, this study evaluates the potential of MALDI in-source decay (ISD) for characterizing cysteine pairs through the systematic analysis of identical peptides bearing two disulfide bonds, but not the same cysteine connectivity.

In-Depth Glyco-Peptidomics Approach Reveals Unexpected Diversity of Glycosylated Peptides and Atypical Post-Translational Modifications in Dendroaspis angusticeps Snake Venom.

Animal venoms represent a valuable source of bioactive peptides that can be derived into useful pharmacological tools, or even innovative drugs. In this way, the venom of (DA), the Eastern Green Mamba, has been intensively studied during recent years. It mainly contains hundreds of large toxins from 6 to 9 kDa, each displaying several disulfide bridges.