Never Out of the Woods: Onset of Events in Long QT Syndrome Late in Life Provoked by Atrial Arrhythmias

The assessment of risk in the asymptomatic patient with long QT syndrome can often be a challenging task, particularly when the available evidence is limited to relatively small retrospective registries, not to mention the need to consider the effect of individual patient factors which are often difficult to quantitate. We describe the relatively uncommon case of a man with a long-standing diagnosis of Long QT 2 syndrome who suffered his first cardiac event in his late 60''s, likely precipitated by the development of paroxysmal atrial tachycardia. A brief review of the available literature on risk assessment in adults with genetically confirmed long QT syndrome who have remained asymptomatic late into adulthood will follow the case.     

Voluntary exercise improves insulin sensitivity and adipose tissue inflammation in diet-induced obese mice

Exercise promotes weight loss and improves insulin sensitivity. However, the molecular mechanisms mediating its beneficial effects are not fully understood. Obesity correlates with increased production of inflammatory cytokines, which in turn, contributes to systemic insulin resistance. To test the hypothesis that exercise mitigates this inflammatory response, thereby improving insulin sensitivity, we developed a model of voluntary exercise in mice made obese by feeding of a high fat/high sucrose diet (HFD). Over four wk, mice fed chow gained 2.3 +/- 0.3 g, while HFD mice gained 6.8 +/- 0.5 g. After 4 wk, mice were subdivided into four groups: chow-no exercise, chow-exercise, HFD-no exercise, HFD-exercise and monitored for an additional 6 wk. Chow-no exercise and HFD-no exercise mice gained an additional 1.2 +/- 0.3 g and 3.3 +/- 0.5 g respectively. Exercising mice had higher food consumption, but did not gain additional weight. As expected, GTT and ITT showed impaired glucose tolerance and insulin resistance in HFD-no exercise mice. However, glucose tolerance improved significantly and insulin sensitivity was completely normalized in HFD-exercise animals. Furthermore, expression of TNF-alpha, MCP-1, PAI-1 and IKKbeta was increased in adipose tissue from HFD mice compared with chow mice, whereas exercise reversed the increased expression of these inflammatory cytokines. In contrast, expression of these cytokines in liver was unchanged among the four groups. These results suggest that exercise partially reduces adiposity, reverses insulin resistance and decreases adipose tissue inflammation in diet-induced obese mice, despite continued consumption of HFD.     

Local force cues for strength and stability in a distributed robotic construction system

Construction of spatially extended, self-supporting structures requires a consideration of structural stability throughout the building sequence. For collective construction systems, where independent agents act with variable order and timing under decentralized control, ensuring stability is a particularly pronounced challenge. Previous research in this area has largely neglected considering stability during the building process. Physical forces present throughout a structure may be usable as a cue to inform agent actions as well as an indirect communication mechanism (stigmergy) to coordinate their behavior, as adding material leads to redistribution of forces which then informs the addition of further material. Here we consider in simulation a system of decentralized climbing robots capable of traversing and extending a two-dimensional truss structure, and explore the use of feedback based on force sensing as a way for the swarm to anticipate and prevent structural failures. We consider a scenario in which robots are tasked with building an unsupported cantilever across a gap, as for a bridge, where the goal is for the swarm to build any stable spanning structure rather than to construct a specific predetermined blueprint. We show that access to local force measurements enables robots to build cantilevers that span significantly farther than those built by robots without access to such information. This improvement is achieved by taking measures to maintain both strength and stability, where strength is ensured by paying attention to forces during locomotion to prevent joints from breaking, and stability is maintained by looking at how loads transfer to the ground to ensure against toppling. We show that swarms that take both kinds of forces into account have improved building performance, in both structured settings with flat ground and unpredictable environments with rough terrain.     

137 DNA nanostructure serum stability: greater than the sum of their parts

DNA cages hold tremendous potential to encapsulate and selectively release therapeutic drugs, and can provide useful tools to probe the size and shape dependence of nucleic acid delivery (McLaughlin & Sleiman, H. F., 2011). These structures have been shown to site-specifically present ligands, small molecule drugs, or antisense/siRNA motifs, in order to increase their therapeutic efficiency (Li & Fan, C. 2012). One of the major barriers towards their in vivo applications is the susceptibility of their strands towards nuclease degradation. A number of chemical strategies have been used to block nuclease digestion of oligonucleotides and improve potency, such as the use of a phosphorothioate backbone, 2´-O-methyl, locked nucleic acids, and short hybrid gapmers. However, the synthesis of these oligonucleotides is often complicated and expensive, driving the need for simple modifications to enhance serum stability and address in vivo biodistribution. We show here a simple method to significantly enhance the nuclease stability of DNA strands, through introduction of commercially available, single-endmodifications (Conway & Sleiman 2013). We use these oligonucleotides to construct DNA cages in a single step and in quantitative yields. Even in single-stranded form, these cages stabilize their component strands towards nucleases, with mean lifetimes as long as 62?h in 10 % (v/v) fetal bovine serum (FBS). We examine the effect of other DNA-end modifications on nuclease susceptibility. Finally, we show the ligation of these single-stranded cages into topologically interesting catenane ‘necklaces,’ with mean lifetimes in serum of ～200?h.     

Thermal niche variation among individuals of the poison frog,Oophaga pumilio,in forest and converted habitats

The conversion of natural habitats to human land uses often increases local temperatures, creating novel thermal environments for species. The variable responses of ectotherms to habitat conversion, where some species decline while others persist, can partly be explained by variation among species in their thermal niches. However, few studies have examined thermal niche variation within species and across forest‐land use ecotones, information that could provide clues about the capacity of species to adapt to changing temperatures. Here, we quantify individual‐level variation in thermal traits of the tropical poison frog, Oophaga pumilio, in thermally contrasting habitats. Specifically, we examined local environmental temperatures, field body temperatures (T_b), preferred body temperatures (T_pref), critical thermal maxima (CT_max), and thermal safety margins (TSM) of individuals from warm, converted habitats and cool forests. We found that frogs from converted habitats exhibited greater mean T_b and T_pref than those from forests. In contrast, CT_max and TSM did not differ significantly between habitats. However, CT_max did increase moderately with increasing T_b, suggesting that changes in CT_max may be driven by microscale temperature exposure within habitats rather than by mean habitat conditions. Although O. pumilio exhibited moderate divergence in T_pref, CT_max appears to be less labile between habitats, possibly due to the ability of frogs in converted habitats to maintain their T_b below air temperatures that reach or exceed CT_max. Selective pressures on thermal tolerances may increase, however, with the loss of buffering microhabitats and increased frequency of extreme temperatures expected under future habitat degradation and climate warming. Abstract in Spanish is available with online material.     

Adoptive Transfer of Lymphocytes Isolated from Simian Immunodeficiency Virus SIVmac239Δnef-Vaccinated Macaques Does Not Affect Acute-Phase Viral Loads but May Reduce Chronic-Phase Viral Loads in Major Histocompatibility Complex-Matched Recipients

The live attenuated simian immunodeficiency virus (SIV) SIVmac239Δnef is the most effective SIV/human immunodeficiency virus (HIV) vaccine in preclinical testing. An understanding of the mechanisms responsible for protection may provide important insights for the development of HIV vaccines. Leveraging the uniquely restricted genetic diversity of Mauritian cynomolgus macaques, we performed adoptive transfers between major histocompatibility complex (MHC)-matched animals to assess the role of cellular immunity in SIVmac239Δnef protection. We vaccinated and mock vaccinated donor macaques and then harvested between 1.25 × 10⁹ and 3.0 × 10⁹ mononuclear cells from multiple tissues for transfer into 12 naive recipients, followed by challenge with pathogenic SIVmac239. Fluorescently labeled donor cells were detectable for at least 7 days posttransfer and trafficked to multiple tissues, including lung, lymph nodes, and other mucosal tissues. There was no difference between recipient macaques'' peak or postpeak plasma viral loads. A very modest difference in viral loads during the chronic phase between vaccinated animal cell recipients and mock-vaccinated animal cell recipients did not reach significance (P = 0.12). Interestingly, the SIVmac239 challenge virus accumulated escape mutations more rapidly in animals that received cells from vaccinated donors. These results may suggest that adoptive transfers influenced the course of infection despite the lack of significant differences in the viral loads among animals that received cells from vaccinated and mock-vaccinated donor animals.     

Discovery and optimization of aspartate aminotransferase 1 inhibitors to target redox balance in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is extremely refractory to the therapeutic approaches that have been evaluated to date. Recently, it has been demonstrated that PDAC tumors are dependent upon a metabolic pathway involving aspartate aminotransferase 1, also known as glutamate-oxaloacetate transaminase 1 (GOT1), for the maintenance of redox homeostasis and sustained proliferation. As such, small molecule inhibitors targeting this metabolic pathway may provide a novel therapeutic approach for the treatment of this devastating disease. To this end, from a high throughput screen of ～800,000 molecules, 4-(1H-indol-4-yl)-N-phenylpiperazine-1-carboxamide was identified as an inhibitor of GOT1. Mouse pharmacokinetic studies revealed that potency, rather than inherent metabolic instability, would limit immediate cell- and rodent xenograft-based experiments aimed at validating this potential cancer metabolism-related target. Medicinal chemistry-based optimization resulted in the identification of multiple derivatives with >10-fold improvements in potency, as well as the identification of a tryptamine-based series of GOT1 inhibitors.