No barrier to emergence of bathyal king crabs on the Antarctic shelf

Cold-water conditions have excluded durophagous (skeleton-breaking) predators from the Antarctic seafloor for millions of years. Rapidly warming seas off the western Antarctic Peninsula could now facilitate their return to the continental shelf, with profound consequences for the endemic fauna. Among the likely first arrivals are king crabs (Lithodidae), which were discovered recently on the adjacent continental slope. During the austral summer of 2010‒2011, we used underwater imagery to survey a slope-dwelling population of the lithodid Paralomis birsteini off Marguerite Bay, western Antarctic Peninsula for environmental or trophic impediments to shoreward expansion. The population density averaged ∼4.5 individuals × 1,000 m(−2) within a depth range of 1,100‒1,500 m (overall observed depth range 841–2,266 m). Images of juveniles, discarded molts, and precopulatory behavior, as well as gravid females in a trapping study, suggested a reproductively viable population on the slope. At the time of the survey, there was no thermal barrier to prevent the lithodids from expanding upward and emerging on the outer shelf (400- to 550-m depth); however, near-surface temperatures remained too cold for them to survive in inner-shelf and coastal environments (<200 m). Ambient salinity, composition of the substrate, and the depth distribution of potential predators likewise indicated no barriers to expansion of lithodids onto the outer shelf. Primary food resources for lithodids—echinoderms and mollusks—were abundant on the upper slope (550–800 m) and outer shelf. As sea temperatures continue to rise, lithodids will likely play an increasingly important role in the trophic structure of subtidal communities closer to shore

Transforming the Muncie Mall into a Community Sustainability Hub

Students in this course have worked to develop proposals to transform the Muncie Mall into a sustainability center for the Muncie community. Interdisciplinary student teams used specialized disciplinary knowledge and skills to plan projects that they have presented and discussed with local business and government leaders

A <i>CACNA1C</i> Variant Associated with Reduced Voltage-Dependent Inactivation, Increased Ca_V1.2 Channel Window Current, and Arrhythmogenesis

<div><p>Mutations in <i>CACNA1C</i> that increase current through the Ca_V1.2 L-type Ca²⁺ channel underlie rare forms of long QT syndrome (LQTS), and Timothy syndrome (TS). We identified a variant in <i>CACNA1C</i> in a male child of Filipino descent with arrhythmias and extracardiac features by candidate gene sequencing and performed functional expression studies to electrophysiologically characterize the effects of the variant on Ca_V1.2 channels. As a baby, the subject developed seizures and displayed developmental delays at 30 months of age. At age 5 years, he displayed a QTc of 520 ms and experienced recurrent VT. Physical exam at 17 years of age was notable for microcephaly, short stature, lower extremity weakness and atrophy with hyperreflexia, spastic diplegia, multiple dental caries and episodes of rhabdomyolysis. Candidate gene sequencing identified a G>C transversion at position 5731 of <i>CACNA1C</i> (rs374528680) predicting a glycine>arginine substitution at residue 1911 (p.G1911R) of Ca_V1.2. The allele frequency of this variant is 0.01 in Malays, but absent in 984 Caucasian alleles and in the 1000 genomes project. In electrophysiological analyses, the variant decreased voltage-dependent inactivation, thus causing a gain of function of Ca_V1.2. We also observed a negative shift of V_1/2 of activation and positive shift of V_1/2 of channel inactivation, resulting in an increase of the window current. Together, these suggest a gain-of-function effect on Ca_V1.2 and suggest increased susceptibility for arrhythmias in certain clinical settings. The p.G1911R variant was also identified in a case of sudden unexplained infant death (SUID), for which an increasing number of clinical observations have demonstrated can be associated with arrhythmogenic mutations in cardiac ion channels. In summary, the combined effects of the <i>CACNA1C</i> variant to diminish voltage-dependent inactivation of Ca_V1.2 and increase window current expand our appreciation of mechanisms by which a gain of function of Ca_V1.2 can contribute to QT prolongation.</p></div

Location of the p.G1911R variant in the α_1C subunit of Ca_V1.2.

<p>A: Schematic of the Ca_V1.2 channel pore-forming α_1C subunit and the auxiliary α₂δ and β subunit. The p.G1911R variant is in the C-terminus close to the calcineurin (CaN) binding site. The location of other mutations in α_1C previously associated with TS are also indicated, including the most commonly reported p.G402R and p.G406R in the loop between DI and DII, and A1473G in the transmembrane segment 6 in the DIV. AID, α1 subunit interacting domain. B: Sanger sequencing of a normal control (WT) and the patient’s DNA showing the p.G1911R variant (arrow). C: Amino acid alignment shows conservation among species of glycine (G) at position 1911 also showing the CaN binding domain.</p

Electrophysiological parameters for the wild type and p.G1911R mutant channel.

<p>Numbers tested are in parentheses.</p><p>*p<0.05 vs WT.</p><p>Electrophysiological parameters for the wild type and p.G1911R mutant channel.</p

Long QT and ventricular tachycardia.

<p>A: Baseline electrocardiogram showing prolonged QT interval. The heart rate is 97. The QTc is 504 ms. The ECG was recorded at 25 mm/s. B: Leads I and II showing monomorphic ventricular tachycardia on an ECG rhythm strip recorded in the Emergency Department.</p

p.G1911R affects Ca_V1.2 availability and VDI.

<p>A–B: Current-voltage relationship and representative current traces showing an increase in current density at more negative potentials. C: voltage-dependence of activation and steady-state inactivation curves showing a hyperpolarizing and depolarizing shift, respectively leading to increased availability and window current. D: p.G1911R decreases voltage-dependent inactivation as measured by fitting a single exponential and comparing the tau value. Summarized in E. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106982#pone-0106982-t001" target="_blank">Table 1</a> for values. *p<0.05.</p

Single-cell RNA sequencing profiling of mouse endothelial cells in response to pulmonary arterial hypertension.

AIMS: Endothelial cell (EC) dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension (PAH). We aimed to characterize EC dynamics in PAH at single-cell resolution. METHODS AND RESULTS: We carried out single-cell RNA sequencing (scRNA-seq) of lung ECs isolated from an EC lineage-tracing mouse model in Control and SU5416/hypoxia-induced PAH conditions. EC populations corresponding to distinct lung vessel types, including two discrete capillary populations, were identified in both Control and PAH mice. Differential gene expression analysis revealed global PAH-induced EC changes that were confirmed by bulk RNA-seq. This included upregulation of the major histocompatibility complex class II pathway, supporting a role for ECs in the inflammatory response in PAH. We also identified a PAH response specific to the second capillary EC population including upregulation of genes involved in cell death, cell motility, and angiogenesis. Interestingly, four genes with genetic variants associated with PAH were dysregulated in mouse ECs in PAH. To compare relevance across PAH models and species, we performed a detailed analysis of EC heterogeneity and response to PAH in rats and humans through whole-lung PAH scRNA-seq datasets, revealing that 51% of up-regulated mouse genes were also up-regulated in rat or human PAH. We identified promising new candidates to target endothelial dysfunction including CD74, the knockdown of which regulates EC proliferation and barrier integrity in vitro. Finally, with an in silico cell ordering approach, we identified zonation-dependent changes across the arteriovenous axis in mouse PAH and showed upregulation of the Serine/threonine-protein kinase Sgk1 at the junction between the macro- and microvasculature. CONCLUSION: This study uncovers PAH-induced EC transcriptomic changes at a high resolution, revealing novel targets for potential therapeutic candidate development