Discovery of novel cyclopentane carboxylic acids as potent and selective inhibitors of Na1.7.

Discovery efforts leading to the identification of cyclopentane carboxylic acid 31, a potent inhibitor of Na1.7 that showed high selectivity over Na1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein.

Strategies for optimal management of pediatric acute agitation in emergency settings.

Acute agitation in youth is a challenging presentation to the emergency department. In many cases, however, youth can be behaviorally de-escalated using a combination of environmental modification and verbal de-escalation. In cases where additional strategies such as pharmacologic de-escalation or physical restraint are needed, using the least restrictive means possible, including the youth in the decision-making process, and providing options are important.

Small molecule inhibitor binds to NOD-like receptor family pyrin domain containing 3 and prevents inflammasome activation.

Despite recent advances in the mechanism of oxidized DNA activating NLRP3, the molecular mechanism and consequence of oxidized DNA associating with NLRP3 remains unknown. Cytosolic NLRP3 binds oxidized DNA which has been released from the mitochondria, which subsequently triggers inflammasome activation. Human glycosylase (hOGG1) repairs oxidized DNA damage which inhibits inflammasome activation.

Rapid, biochemical tagging of cellular activity history in vivo.

Intracellular calcium (Ca) is ubiquitous to cell signaling across biology. While existing fluorescent sensors and reporters can detect activated cells with elevated Ca levels, these approaches require implants to deliver light to deep tissue, precluding their noninvasive use in freely behaving animals. Here we engineered an enzyme-catalyzed approach that rapidly and biochemically tags cells with elevated Ca in vivo.

The contribution of Na1.6 to the efficacy of voltage-gated sodium channel inhibitors in wild type and Na1.6 gain-of-function (GOF) mouse seizure control.

Background And Purpose: Inhibitors of voltage-gated sodium channels (Nas) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Na channels as a means of informing the development of improved antiseizure drugs.

Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of Na1.

Rapid, biochemical tagging of cellular activity history in vivo.

Intracellular calcium (Ca) is ubiquitous to cell signaling across all biology. While existing fluorescent sensors and reporters can detect activated cells with elevated Ca levels, these approaches require implants to deliver light to deep tissue, precluding their noninvasive use in freely-behaving animals. Here we engineered an enzyme-catalyzed approach that rapidly and biochemically tags cells with elevated Ca in vivo.

Machine learning-guided engineering of genetically encoded fluorescent calcium indicators.

Here we used machine learning to engineer genetically encoded fluorescent indicators, protein-based sensors critical for real-time monitoring of biological activity. We used machine learning to predict the outcomes of sensor mutagenesis by analyzing established libraries that link sensor sequences to functions. Using the GCaMP calcium indicator as a scaffold, we developed an ensemble of three regression models trained on experimentally derived GCaMP mutation libraries.

Point-of-Care Ultrasound of a Nasal Septal Abscess.

Although nasal septal abscesses (NSA) are rare, complications can be significant and devastating. Thus, timely diagnosis of NSA is critical. In this case report, we describe the use of point-of-care ultrasound in diagnosing NSA in a healthy boy presenting with viral upper respiratory infection symptoms and fever.

Development and application of a multiple reaction monitoring method for the simultaneous quantification of sodium channels Na 1.1, Na 1.2, and Na 1.6 in solubilized membrane proteins from stable HEK293 cell lines, rodents, and human brain tissues.

Rationale: Na 1.1, 1.2, and 1.

Small molecule inhibitor binds to NLRP3 and prevents inflammasome activation.

Unlabelled: Despite recent advances in the mechanism of oxidized DNA activating NLRP3, the molecular mechanism and consequence of oxidized DNA associating with NLRP3 remains unknown. Cytosolic NLRP3 binds oxidized DNA which has been released from the mitochondria, which subsequently triggers inflammasome activation. Human glycosylase (hOGG1) repairs oxidized DNA damage which inhibits inflammasome activation.

Review of pediatric emergency care and the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic posed new challenges in health care delivery for patients of all ages. These included inadequate personal protective equipment, workforce shortages, and unknowns related to a novel virus. Children have been uniquely impacted by COVID-19, both from the system of care and socially.

The Utility of a Virtual Emergency Medicine Elective for Visiting Medical Students.

Background Away rotations allow emergency medicine (EM)-bound fourth-year medical students to experience a residency program's educational culture and influence the ranking of residency programs. The financial cost and geographic distance have limited student participation in away electives. In recent years, COVID-19 pandemic-related restrictions on away rotations resulted in the creation of multiple virtual courses.

Novel RXFP3 negative allosteric modulator RLX-33 reduces alcohol self-administration in rats.

There is much interest in identifying novel pharmacotherapeutic targets that improve clinical outcomes for the treatment of alcohol use disorder (AUD). One promising target for therapeutic intervention is the relaxin family peptide 3 (RXFP3) receptor, a cognate receptor for neuropeptide relaxin-3, which has previously been implicated in regulating alcohol drinking behavior. Recently, we developed the first small-molecule RXFP3-selective negative allosteric modulator (NAM) RLX-33.

Structure-function relationship of new peptides activating human Na1.1.

Na1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies.

Curated collections for educators: Nine key articles and article series for teaching qualitative research methods.

Background: Qualitative research explains observations, focusing on how and why phenomena and experiences occur. Qualitative methods go beyond quantitative data and provide critical information inaccessible through quantitative methods. However, at all levels of medical education, there is insufficient exposure to qualitative research.

Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1: Preclinical Efficacy against Iron Overload and Safety Evaluation.

Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or -thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors.

Long-Term Consumption of 10 Food Groups and Cardiovascular Mortality: A Systematic Review and Dose Response Meta-Analysis of Prospective Cohort Studies.

A large body of evidence exists on diet and cardiovascular mortality, but limited studies have investigated the long-term intake of food groups, which may have cumulative effects on cardiovascular health in the long term. This review therefore evaluated the relationship between the long-term consumption of 10 food groups and cardiovascular mortality. We conducted a systematic search in Medline, Embase, Scopus, CINAHL, and Web of Science till January 2022.

Nondestructive and multiplex differentiation of pathogenic microorganisms from spoilage microflora on seafood using paper chromogenic array and neural network.

Non-destructive detection of human foodborne pathogens is critical to ensuring food safety and public health. Here, we report a new method using a paper chromogenic array coupled with a machine learning neural network (PCA-NN) to detect viable pathogens in the presence of background microflora and spoilage microbe in seafood via volatile organic compounds sensing. Morganella morganii and Shewanella putrefaciens were used as the model pathogen and spoilage bacteria.

Pharmacological determination of the fractional block of Nav channels required to impair neuronal excitability and seizures.

Voltage-gated sodium channels (Nav) are essential for the initiation and propagation of action potentials in neurons. Of the nine human channel subtypes, Nav1.1, Nav1.

Comparing Factors Associated With Intimate Partner Violence Among Rural and Urban Women in Northern Uganda.

Intimate partner violence (IPV) is an important public health issue with negative effects at individual and societal levels. In northern Uganda, IPV prevalence is high but literature on it is limited. Northern Uganda has a long history of socio-economic and political upheavals, which are recognized risk factors for IPV.

Prevalence and characteristics of advocacy curricula in Australian public health degrees.

Background: Public health advocacy is a fundamental part of health promotion practice. Advocacy efforts can lead to healthier public policies and positive impacts on society. Public health educators are responsible for equipping graduates with cross-cutting advocacy competencies to address current and future public health challenges.

NBI-921352, a first-in-class, Na1.6 selective, sodium channel inhibitor that prevents seizures in gain-of-function mice, and wild-type mice and rats.

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target Na1.6 channels. Such a molecule provides a precision-medicine approach to target -related epilepsy syndromes (-RES), where gain-of-function (GoF) mutations lead to excess Na1.

Synthetic Analogues of Huwentoxin-IV Spider Peptide With Altered Human Na1.7/Na1.6 Selectivity Ratios.

Huwentoxin-IV (HwTx-IV), a peptide discovered in the venom of the Chinese bird spider , has been reported to be a potent antinociceptive compound due to its action on the genetically-validated Na1.7 pain target. Using this peptide for antinociceptive applications suffers from one major drawback, namely its negative impact on the neuromuscular system.