Effect of ERCP Utilization and Biliary Complications on Post-Liver-Transplantation Mortality and Graft Survival

Biliary complications after liver transplant are a frequent source of morbidity. However, little recent mortality data exists related to endoscopic management of these complications

Diagnostic Utility of Major Basic Protein, Eotaxin-3 and Leukotriene Enzyme Staining in Eosinophilic Esophagitis

Features of eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD) overlap. We aimed to determine whether staining for tissue biomarkers would differentiate EoE from GERD, suggesting utility for diagnosis of EoE

Esophageal foreign-body impactions: epidemiology, time trends, and the impact of the increasing prevalence of eosinophilic esophagitis

The epidemiology of esophageal foreign-body impaction (EFBI) is poorly described, and the impact of the increasing prevalence of eosinophilic esophagitis (EoE) on this is unknown

Smooth muscle cells affect differential nanoparticle accumulation in disturbed blood flow-induced murine atherosclerosis

Atherosclerosis is a lipid-driven chronic inflammatory disease that leads to the formation of plaques in the inner lining of arteries. Plaques form over a range of phenotypes, the most severe of which is vulnerable to rupture and causes most of the clinically significant events. In this study, we evaluated the efficacy of nanoparticles (NPs) to differentiate between two plaque phenotypes based on accumulation kinetics in a mouse model of atherosclerosis. This model uses a perivascular cuff to induce two regions of disturbed wall shear stress (WSS) on the inner lining of the instrumented artery, low (upstream) and multidirectional (downstream), which, in turn, cause the development of an unstable and stable plaque phenotype, respectively. To evaluate the influence of each WSS condition, in addition to the final plaque phenotype, in determining NP uptake, mice were injected with NPs at intermediate and fully developed stages of plaque growth. The kinetics of artery wall uptake were assessed in vivo using dynamic contrast-enhanced magnetic resonance imaging. At the intermediate stage, there was no difference in NP uptake between the two WSS conditions, although both were different from the control arteries. At the fully-developed stage, however, NP uptake was reduced in plaques induced by low WSS, but not multidirectional WSS. Histological evaluation of plaques induced by low WSS revealed a significant inverse correlation between the presence of smooth muscle cells and NP accumulation, particularly at the plaque-lumen interface, which did not exist with other constituents (lipid and collagen) and was not present in plaques induced by multidirectional WSS. These findings demonstrate that NP accumulation can be used to differentiate between unstable and stable murine atherosclerosis, but accumulation kinetics are not directly influenced by the WSS condition. This tool could be used as a diagnostic to evaluate the efficacy of experimental therapeutics for atherosclerosis

Individual and non‐additive effects of exotic sap‐feeders on root functional and mycorrhizal traits of a shared conifer host

Forest pests drive tree mortality through disruption of functional traits linked to nutrient acquisition, growth and reproduction. The impacts of attack by individual or multiple above‐ground herbivores on root functional traits critical to tree health have received little attention. This is especially true for exotic herbivores, organisms often found in disturbed forests. We excavated whole‐root systems from eastern hemlock (Tsuga canadensis) individuals experimentally infested with hemlock woolly adelgid (HWA: Adelges tsugae) and elongate hemlock scale (EHS: Fiorina externa) individually, or in combination, for periods of 2 and 4 years. Below‐ground root biomass, functional traits and storage nutrients were measured to assess impacts of herbivory. We also quantified ectomycorrhizal fungal (EMF) colonisation of fine roots and used culture‐independent methods to examine EMF diversity. Trees infested with HWA had a greater root mass fraction (root to total biomass ratio), although feeding had no observable effects on root functional traits (e.g. specific root length) or on resource allocation to roots. HWA feeding did significantly reduce EMF colonisation of hemlock fine roots, though surprisingly, EMF diversity and that of other fungal associates were unaffected. In contrast to HWA, EHS (alone or in conjunction with HWA) feeding had no observable effect on below‐ground traits or EMF colonisation alone; however, its presence mediated HWA effects when trees were co‐infested. Simultaneous infestation within the same year yielded significant reductions in EMF colonisation, whereas prior EHS attack weakened HWA effects. Our results collectively suggest that prior EHS attack dampens the impact of HWA on below‐ground functional traits. This highlights how the timing and sequence of herbivore arrival can alter plant‐mediated interactions between herbivores and their effects on above–below‐ground linkages and associated tree health

Modeling-Driven Damage Tolerant Design of Graphene Nanoplatelet/Carbon Fiber/Epoxy Hybrid Composite Panels for Full-Scale Aerospace Structures

The objective of this study is to design a new nano graphenecarbon fiberpolymer hybrid composite that can be used for the NASA SLS Composite Exploration Upper Stage (CEUS) forward skirt structure. The new material will improve the resistance to open-hole compression failure of the structure relative to traditional polymer fiber composites. The material is designed rapidly and with little cost using the Integrated Computational Materials Engineering (ICME) approach. Multiscale modeling and experiments are used to synergistically optimize the material design to yield improved properties and performance by controlling key processing parameters for manufacturing nano-enhanced materials. Specifically, the nanocomposite panel showed a 22 reduction in mass relative to the traditional composite panel, while both designs are equal in terms of ease of manufacture. This potential mass savings corresponds to an estimated 45 savings in materials and manufacturing costs. The multiscale ICME workflow developed for this project can be readily applied to the development of nano-enhanced composite materials and large aerospace structures. In addition, all key aspects of ICME were employed to complete this project including multiscale modeling, experimental characterization and visualization, data management, visualization, error and uncertainty quantification, and education. The results presented herein indicate a dramatic level of success, as well as the power and potential of ICME approach and multiscale modeling for composite materials

Epidemiology and management of oesophageal coin impaction in children

The epidemiology of oesophageal coin impaction in children is poorly understood. We aimed to assess characteristics of patients with coin impaction and identify predictors of type of coin impacted and management strategies

A high affinity, partial antagonist effect of 3,4-diaminopyridine mediates action potential broadening and enhancement of transmitter release at NMJs

3,4-Diaminopyridine (3,4-DAP) increases transmitter release from neuromuscular junctions (NMJs), and low doses of 3,4-DAP (estimated to reach ∼1 μM in serum) are the Food and Drug Administration (FDA)-Approved treatment for neuro muscular weakness caused by Lambert-Eaton myasthenic syn drome. Canonically, 3,4-DAP is thought to block voltage-gated potassium (Kv) channels, resulting in prolongation of the pre synaptic action potential (AP). However, recent reports have shown that low millimolar concentrations of 3,4-DAP have an off-Target agonist effect on the Cav1 subtype ( L-Type ) of voltage-gated calcium (Cav) channels and have speculated that this agonist effect might contribute to 3,4-DAP effects on transmitter release at the NMJ. To address 3,4-DAPs mecha nism(s) of action, we first used the patch-clamp electrophysi ology to characterize the concentration-dependent block of 3,4-DAP on the predominant presynaptic Kv channel subtypes found at the mammalian NMJ (Kv3.3 and Kv3.4). We identified a previously unreported high-Affinity (1-10 μM) partial antag onist effect of 3,4-DAP in addition to the well-known low-Af finity (0.1-1 mM) antagonist activity. We also showed that 1.5-μM DAP had no effects on Cav1.2 or Cav2.1 current. Next, we used voltage imaging to show that 1.5-or 100-μM 3,4-DAP broadened the AP waveform in a dose-dependent manner, in dependent of Cav1 calcium channels. Finally, we demonstrated that 1.5-or 100-μM 3,4-DAP augmented transmitter release in a dose-dependent manner and this effect was also independent of Cav1 channels. From these results, we conclude that low micromolar concentrations of 3,4-DAP act solely on Kv chan nels to mediate AP broadening and enhance transmitter release at the NMJ

Structural basis of nSH2 regulation and lipid binding in PI3Kα

We report two crystal structures of the wild-type phosphatidylinositol 3-kinase α (PI3Kα) heterodimer refined to 2.9 Å and 3.4 Å resolution: the first as the free enzyme, the second in complex with the lipid substrate, diC4-PIP2, respectively. The first structure shows key interactions of the N-terminal SH2 domain (nSH2) and iSH2 with the activation loop that suggest a mechanism by which the enzyme is inhibited in its basal state. In the second structure, the lipid substrate binds in a positively charged pocket adjacent to the ATP-binding site, bordered by the P-loop, the activation loop and the iSH2 domain. An additional lipid-binding site was identified at the interface of the ABD, iSH2 and kinase domains. The ability of PI3Kα to bind an additional PIP2 molecule was confirmed in vitro by fluorescence quenching experiments. The crystal structures reveal key differences in the way the nSH2 domain interacts with wild-type p110α and with the oncogenic mutant p110αH1047R. Increased buried surface area and two unique salt-bridges observed only in the wild-type structure suggest tighter inhibition in the wild-type PI3Kα than in the oncogenic mutant. These differences may be partially responsible for the increased basal lipid kinase activity and increased membrane binding of the oncogenic mutant