Transforming RN-Baccalaureate Education Using Insights From a National Faculty Needs Assessment.

Background: The recent American Association of Colleges of Nursing (AACN) Essentials revision emphasizes direct clinical experiences across 4 spheres of care in RN-Baccalaureate (RN-B) education, creating challenges for online, asynchronous programs. Differentiating between prelicensure and postlicensure education complicates the integration of these requirements. Understanding RN-B faculty needs is critical for curricular transformation.

Unveiling complexities: Examining the role of traumatic loss in shaping the interplay between black maternal mental health and maternal bonding.

Black women are more likely to experience traumatic birthing events, more likely to experience perinatal depression, and less likely to receive mental health treatment than women of other racial and ethnic backgrounds, and yet largely overlooked in perinatal mental health research. This pilot study seeks to understand how unacceptable racial disparities and adverse perinatal outcomes influence Black maternal depression and maternal bonding by exploring how prior traumatic loss moderates the relationship between depression and bonding during a subsequent pregnancy among a sample of Black mothers. We use survey data collected from 75 Black mothers as part of the Black Fathers, Equal Partners in Promoting Maternal and Infant Health study, a collaboration between the University of Wisconsin Madison and the African American Breastfeeding Network in Milwaukee, Wisconsin, USA.

Land-derived metals impact the survival and settlement of larval mussels.

Global declines in wild mussel populations and production have been linked to the impacts of climate change and pollution. Summer die-offs of mussels (Perna canaliculus), spat retention issues, and a severe decline in mussel spat settlement have been reported in the Marlborough Sounds, an important area for mussel farming in New Zealand. Preliminary evidence suggests that naturally occurring contaminants and changing land use in the surrounding areas, could contribute to the decline of this species.

Single-cell RNA sequencing identifies CXADR as a fate determinant of the placental exchange surface.

The placenta is the critical interface between mother and fetus, and consequently, placental dysfunction underlies many pregnancy complications. Placental formation requires an adequate expansion of trophoblast stem and progenitor cells followed by finely tuned lineage specification events. Here, using single-cell RNA sequencing of mouse trophoblast stem cells during the earliest phases of differentiation, we identify gatekeepers of the stem cell state, notably Nicol1, and uncover unsuspected trajectories of cell lineage diversification as well as regulators of lineage entry points.

The backbone constitution drives passive permeability independent of side chains in depsipeptide and peptide macrocycles inspired by -verticilide.

The number of peptide-like scaffolds found in late-stage drug development is increasing, but a critical unanswered question in the field is whether substituents (side chains) or the backbone drive passive permeability. The backbone is scrutinized in this study. Five series of macrocyclic peptidic compounds were prepared, and their passive permeability was determined (PAMPA, Caco-2), to delineate structure-permeability relationships.

The experiences of occupational therapists supporting children with self-regulation needs: A qualitative descriptive study.

Introduction: Occupational therapists support children with self-regulation needs to engage in meaningful occupations at home, school, and in the community. However, little is known about how Australian practitioners perceive their role working with children with self-regulation needs in the Australian healthcare context. Therefore, we explored the contemporary practice experiences of Australian occupational therapists working with children 4-12 years referred for self-regulation support, to better understand elements constituting efficacious service delivery to enhance occupational engagement.

Backbone-Determined Antiarrhythmic Structure-Activity Relationships for a Mirror Image, Oligomeric Depsipeptide Natural Product.

Cyclic oligomeric depsipeptides (COD) are a structural class within naturally occurring compounds with a wide range of biological activity. Verticilide is a COD (24-membered ring) that was identified by its inhibition of insect ryanodine receptor (RyR). We have since found that the enantiomer of verticilide (-verticilide, ) is a potent inhibitor of mammalian RyR2, a cardiac calcium channel, and therefore a potential antiarrhythmic agent.

High-throughput functional mapping of variants in an arrhythmia gene, KCNE1, reveals novel biology.

Background: KCNE1 encodes a 129-residue cardiac potassium channel (I) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants have insufficient evidence of clinical consequences and thus limited clinical utility.

LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation.

Aims: The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic disorders, including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress.

-Verticilide B1 Inhibits Type 2 Ryanodine Receptor Channels and is Antiarrhythmic in Mice.

Intracellular Ca leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor (+)-verticilide (-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (-(-)-verticilide). Here, we examined its 18-membered ring-size oligomer (-verticilide B1; "-B1") in RyR2 single channel and [H]ryanodine binding assays, and in cardiomyocytes and mice, a gene-targeted model of SCD.

Absence of the primary cilia formation gene Talpid3 impairs muscle stem cell function.

Skeletal muscle stem cells (MuSC) are crucial for tissue homoeostasis and repair after injury. Following activation, they proliferate to generate differentiating myoblasts. A proportion of cells self-renew, re-enter the MuSC niche under the basal lamina outside the myofiber and become quiescent.

RyR2 Binding of an Antiarrhythmic Cyclic Depsipeptide Mapped Using Confocal Fluorescence Lifetime Detection of FRET.

Hyperactivity of cardiac sarcoplasmic reticulum (SR) ryanodine receptor (RyR2) Ca-release channels contributes to heart failure and arrhythmias. Reducing the RyR2 activity, particularly during cardiac relaxation (diastole), is a desirable therapeutic goal. We previously reported that the unnatural enantiomer () of an insect-RyR activator, verticilide, inhibits porcine and mouse RyR2 at diastolic (nanomolar) Ca and has in vivo efficacy against atrial and ventricular arrhythmia.

Eicosanoid-Regulated Myeloid ENaC and Isolevuglandin Formation in Human Salt-Sensitive Hypertension.

Background: The mechanisms by which salt increases blood pressure in people with salt sensitivity remain unclear. Our previous studies found that high sodium enters antigen-presenting cells (APCs) via the epithelial sodium channel and leads to the production of isolevuglandins and hypertension. In the current mechanistic clinical study, we hypothesized that epithelial sodium channel-dependent isolevuglandin-adduct formation in APCs is regulated by epoxyeicosatrienoic acids (EETs) and leads to salt-sensitive hypertension in humans.

-Verticilide B1 inhibits type 2 ryanodine receptor channels and is antiarrhythmic in Casq2-/- mice.

Unlabelled: Ca leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor (+)-verticilide ( -1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product ( -(-)-verticilide). Here, we examined its 18-membered ring-size oligomer ( -verticilide B1; " -B1") in single RyR2 channel assays, [ H]ryanodine binding assays, and in cardiomyocytes and mice, a gene-targeted model of SCD.

RyR2 inhibition with dantrolene is antiarrhythmic, prevents further pathological remodeling, and improves cardiac function in chronic ischemic heart disease.

Diastolic Ca leak due to cardiac ryanodine receptor (RyR2) hyperactivity has been widely documented in chronic ischemic heart disease (CIHD) and may contribute to ventricular tachycardia (VT) risk and progressive left-ventricular (LV) remodeling. Here we test the hypothesis that targeting RyR2 hyperactivity can suppress VT inducibility and progressive heart failure in CIHD by the RyR2 inhibitor dantrolene. METHODS AND RESULTS: CIHD was induced in C57BL/6 J mice by left coronary artery ligation.

High-throughput functional mapping of variants in an arrhythmia gene, , reveals novel biology.

Background: encodes a 129-residue cardiac potassium channel (I) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants have insufficient evidence of clinical consequences and thus limited clinical utility.

The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and morbidity. The strongest genetic risk factors for AF in humans are variants on chromosome 4q25, near the paired-like homeobox transcription factor 2 gene PITX2. Although mice deficient in Pitx2 (Pitx2+/-) have increased AF susceptibility, the mechanism remains controversial.

In Vivo Pharmacokinetic and Pharmacodynamic Properties of the Antiarrhythmic Molecule -Verticilide.

The unnatural verticilide enantiomer (-verticilide) is a selective and potent inhibitor of cardiac ryanodine receptor (RyR2) calcium release channels and exhibits antiarrhythmic activity in a murine model of catecholaminergic polymorphic ventricular tachycardia (CPVT). To determine verticilide's pharmacokinetic and pharmacodynamic properties in vivo, we developed a bioassay to measure - and -verticilide in murine plasma and correlated plasma concentrations with antiarrhythmic efficacy in a mouse model of CPVT. -Verticilide rapidly degraded in plasma in vitro, showing >95% degradation within 5 minutes, whereas verticilide showed <1% degradation over 6 hours.

Defects in placental syncytiotrophoblast cells are a common cause of developmental heart disease.

Placental abnormalities have been sporadically implicated as a source of developmental heart defects. Yet it remains unknown how often the placenta is at the root of congenital heart defects (CHDs), and what the cellular mechanisms are that underpin this connection. Here, we selected three mouse mutant lines, Atp11a, Smg9 and Ssr2, that presented with placental and heart defects in a recent phenotyping screen, resulting in embryonic lethality.

Black fathers' contributions to maternal mental health.

This mixed-methods research study aimed to assess the contribution of interparental relationship quality and paternal support for mothers to maternal mental health among Black parents in a metro area characterized by severe racial disparities. We also explored Black parents' understanding of meaningful paternal support for mothers. Using survey data collected from Black mothers (N = 75), we examined correlations among the study variables, then conducted mediation and moderation analyses to examine whether relationship quality would mediate the association between paternal support and maternal mental health and to test whether relationship quality would moderate the association between paternal support and maternal self-reported overall health.

Structure-Activity Relationships for the -Me- Versus -H-Amide Modification to Macrocyclic -Verticilide Antiarrhythmics.

The synthesis of all -Me and -H analogues of -verticilide is described, enabling a structure-activity relationship study based on cardiac ryanodine receptor (RyR2) calcium ion channel inhibition. The use of permeabilized cardiomyocytes allowed us to correlate the degree of -methylation with activity without concern for changes in passive membrane permeability that these modifications can cause. A key hypothesis was that the minimal pharmacophore may be repeated in this cyclic oligomeric octadepsipeptide (a 24-membered macrocycle), opening the possibility that target engagement will not necessarily be lost with a single -Me → -H modification.

Impaired Dynamic Sarcoplasmic Reticulum Ca Buffering in Autosomal Dominant CPVT2.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal cardiac arrhythmia syndrome triggered by catecholamines released during exercise, stress, or sudden emotion. Variants in the calsequestrin-2 gene (), encoding the major calcium (Ca) binding protein in the sarcoplasmic reticulum (SR), are the second most common cause of CPVT. Recently, several gene variants, such as -K180R, have been linked to an autosomal dominant form of Casq2-linked CPVT (CPVT2), but the underlying mechanism is not known.