Visualizing Mutation-Specific Differences in the Trafficking-Deficient Phenotype of Kv11.1 Proteins Linked to Long QT Syndrome Type 2

KCNH2 encodes the Kv11.1 α-subunit that underlies the rapidly activating delayed-rectifier K+ current in the heart. Loss-of-function KCNH2 mutations cause long QT syndrome type 2 (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channel protein to the cell surface membrane. Several trafficking-deficient LQT2 mutations (e.g., G601S) generate Kv11.1 proteins that are sequestered in a microtubule-dependent quality control (QC) compartment in the transitional endoplasmic reticulum (ER). We tested the hypothesis that the QC mechanisms that regulate LQT2-linked Kv11.1 protein trafficking are mutation-specific. Confocal imaging analyses of HEK293 cells stably expressing the trafficking-deficient LQT2 mutation F805C showed that, unlike G601S-Kv11.1 protein, F805C-Kv11.1 protein was concentrated in several transitional ER subcompartments. The microtubule depolymerizing drug nocodazole differentially affected G601S- and F805C-Kv11.1 protein immunostaining. Nocodazole caused G601S-Kv11.1 protein to distribute into peripheral reticular structures, and it increased the diffuse immunostaining of F805C-Kv11.1 protein around the transitional ER subcompartments. Proteasome inhibition also affected the immunostaining of G601S- and F805C-Kv11.1 protein differently. Incubating cells in MG132 minimally impacted G601S-Kv11.1 immunostaining, but it dramatically increased the diffuse immunostaining of F805C-Kv11.1 protein in the transitional ER. Similar results were seen after incubating cells in the proteasome inhibitor lactacystin. Differences in the cellular distribution of G601S-Kv11.1 and F805C-Kv11.1 protein persisted in transfected human inducible pluripotent stem cell derived cardiomyocytes. These are the first data to visually demonstrate mutation-specific differences in the trafficking-deficient LQT2 phenotype, and this study has identified a novel way to categorize trafficking-deficient LQT2 mutations based on differences in intracellular retention

Assessment of abdominal fat compartments using DXA in premenopausal women from anorexia nervosa to morbid obesity

Objective: The purpose of this study was to test a newly developed DXA method for abdominal fat depot quantification in subjects with AN, normal weight, and obesity using CT as a gold standard. Design and Methods 135 premenopausal women (overweight/obese: n=89, normal-weight: n=27, AN: n=19); abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and total adipose tissue (TAT) areas determined on CT and DXA. Results: There were strong correlations between DXA and CT measurements of abdominal fat compartments in all groups with the strongest correlation coefficients in the normal-weight and overweight/obese groups. Correlations of DXA and CT VAT measurements were strongest in the obese group and weakest in the AN group. DXA abdominal fat depots were higher in all groups compared to CT, with the largest % mean difference in the AN group and smallest in the obese group. Conclusions: A new DXA technique is able to assess abdominal fat compartments including VAT in premenopausal women across a large weight spectrum However, DXA measurements of abdominal fat were higher than CT, and this percent bias was most pronounced in the AN subjects and decreased with increasing weight, suggesting that this technique may be more useful in obese individuals

Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 \u3cem\u3eKCNH2 (hERG)\u3c/em\u3e Mutations and Identifying New Patients

Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the KCNH2 gene (also known as the human ether-à-go-go-related gene or hERG). Almost half of suspected LQT2-causing mutations are missense mutations, and functional studies suggest that about 90% of these mutations disrupt the intracellular transport, or trafficking, of the KCNH2-encoded Kv11.1 channel protein to the cell surface membrane. In this review, we discuss emerging strategies that improve the trafficking and functional expression of trafficking-deficient LQT2 Kv11.1 channel proteins to the cell surface membrane and how new insights into the structure of the Kv11.1 channel protein will lead to computational approaches that identify which KCNH2 missense variants confer a high-risk for LQT2

Parasite-stress promotes in-group assortative sociality: the cases of strong family ties and heightened religiosity

Throughout the world people differ in the magnitude with which they value strong family ties or heightened religiosity. We propose that this cross-cultural variation is a result of a contingent psychological adaptation that facilitates in-group assortative sociality in the face of high levels of parasite-stress while devaluing in-group assortative sociality in areas with low levels of parasite-stress. This is because in-group assortative sociality is more important for the avoidance of infection from novel parasites and for the management of infection in regions with high levels of parasite-stress compared with regions of low infectious disease stress. We examined this hypothesis by testing the predictions that there would be a positive association between parasite-stress and strength of family ties or religiosity. We conducted this study by comparing among nations and among states in the United States of America. We found for both the international and the interstate analyses that in-group assortative sociality was positively associated with parasite-stress. This was true when controlling for potentially confounding factors such as human freedom and economic development. The findings support the parasite-stress theory of sociality, that is, the proposal that parasite-stress is central to the evolution of social life in humans and other animals

Counter and Complicit Masculine Discourse Among Men’s Shed Members

Men’s Sheds is a growing international movement aimed at providing men with places and activities that facilitate social connectedness. Despite Men’s Sheds’ focus on males, little attention has been paid to masculinities within the specific context of these settings. The current study used a gender relations framework to explore the ways in which attendees discussed Men’s Sheds, with particular attention to discussions that were complicit and counter to traditional, hegemonic views of masculinity, and diverse positions in between these binaries. The data consisted of transcripts and field notes from four focus groups comprised of mostly older, White, retired male members of a Canadian shed (N = 22). The analysis revealed three overall themes: (1) focus on work, (2) independence, and (3) need for male-focused spaces. These themes and associated subthemes suggest that shed members ascribe to dominant masculine values and ideals, but also support more fluid and flexible views of masculinity. Implications are discussed for how working with an array of masculinities within the Men’s Sheds movement will be helpful with respect to their future growth in Canada and internationally

Jamming at Zero Temperature and Zero Applied Stress: the Epitome of Disorder

We have studied how 2- and 3- dimensional systems made up of particles interacting with finite range, repulsive potentials jam (i.e., develop a yield stress in a disordered state) at zero temperature and applied stress. For each configuration, there is a unique jamming threshold, $\phi_c$, at which particles can no longer avoid each other and the bulk and shear moduli simultaneously become non-zero. The distribution of $\phi_c$ values becomes narrower as the system size increases, so that essentially all configurations jam at the same $\phi$ in the thermodynamic limit. This packing fraction corresponds to the previously measured value for random close-packing. In fact, our results provide a well-defined meaning for "random close-packing" in terms of the fraction of all phase space with inherent structures that jam. The jamming threshold, Point J, occurring at zero temperature and applied stress and at the random close-packing density, has properties reminiscent of an ordinary critical point. As Point J is approached from higher packing fractions, power-law scaling is found for many quantities. Moreover, near Point J, certain quantities no longer self-average, suggesting the existence of a length scale that diverges at J. However, Point J also differs from an ordinary critical point: the scaling exponents do not depend on dimension but do depend on the interparticle potential. Finally, as Point J is approached from high packing fractions, the density of vibrational states develops a large excess of low-frequency modes. All of these results suggest that Point J may control behavior in its vicinity-perhaps even at the glass transition.Comment: 21 pages, 20 figure

Applications of Laboratory Technology in the Evaluation of the Risk of Rabies Transmissions by Biting Dogs and Cats

While rabies is not a common disease in domestic animal species of the United States, potential exposures to rabies in the form of bites are very common and increasing. A nationwide study conducted among general hospitals shows that 1 percent of emergency room visits are for animal bites, of which 80-90 percent are inflicted by the dog (Callaham 1980). This figure is conservative, as the study did not include pediatric hospitals, the bite of victims that progress only to a physician\u27s office, or those that receive no medical care at all. In Missouri alone, this study would infer about 1500 dog bites per year reaching only the general hospital. The number of dog and other animal bites across the country is unknown but may safely be assumed to be staggering in magnitude

Treating cofactors can reverse the expansion of a primary disease epidemic

<p>Abstract</p> <p>Background</p> <p>Cofactors, "nuisance" conditions or pathogens that affect the spread of a primary disease, are likely to be the norm rather than the exception in disease dynamics. Here we present a "simplest possible" demographic model that incorporates two distinct effects of cofactors: that on the transmission of the primary disease from an infected host bearing the cofactor, and that on the acquisition of the primary disease by an individual that is not infected with the primary disease but carries the cofactor.</p> <p>Methods</p> <p>We constructed and analyzed a four-patch compartment model that accommodates a cofactor. We applied the model to HIV spread in the presence of the causal agent of genital schistosomiasis, <it>Schistosoma hematobium</it>, a pathogen commonly co-occurring with HIV in sub-Saharan Africa.</p> <p>Results</p> <p>We found that cofactors can have a range of effects on primary disease dynamics, including shifting the primary disease from non-endemic to endemic, increasing the prevalence of the primary disease, and reversing demographic growth when the host population bears only the primary disease to demographic decline. We show that under parameter values based on the biology of the HIV/<it>S. haematobium </it>system, reduction of the schistosome-bearing subpopulations (e.g. through periodic use of antihelminths) can slow and even reverse the spread of HIV through the host population.</p> <p>Conclusions</p> <p>Typical single-disease models provide estimates of future conditions and guidance for direct intervention efforts relating only to the modeled primary disease. Our results suggest that, in circumstances under which a cofactor affects the disease dynamics, the most effective intervention effort might not be one focused on direct treatment of the primary disease alone. The cofactor model presented here can be used to estimate the impact of the cofactor in a particular disease/cofactor system without requiring the development of a more complicated model which incorporates many other specific aspects of the chosen disease/cofactor pair. Simulation results for the HIV/<it>S. haematobium </it>system have profound implications for disease management in developing areas, in that they provide evidence that in some cases treating cofactors may be the most successful and cost-effective way to slow the spread of primary diseases.</p

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial

Importance: The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. Objective: To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events. Design, Setting, and Participants: A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. Interventions: Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. Main Outcomes and Measures: Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. Results: Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]). Conclusions and Relevance: Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm. Trial Registration: ClinicalTrials.gov Identifier: NCT01191840