Rational prediction of pharmacological treatment options for a novel KCNH2-linked variant of the Short QT Syndrome

Congenital disorders of cardiac repolarization are associated with risk of serious arrhythmias and sudden death. The Long QT Syndrome (LQTS) is well-established to predispose towards torsades de pointes [1]. The Short QT Syndrome (SQTS) is a more recently discovered condition involving abbreviated repolarization that predisposes to atrial and ventricular arrhythmias and sudden death [2]. It is characterized by short QT intervals on the electrocardiogram, frequently with tall upright T waves and by a poor rate adaptation of the QT interval: short QT intervals persist even at slow heart rates [2-4]. Due to the risk of sudden death, SQTS patients are often treated with implantable cardioverter defi brillators (ICDs). Mutations to genes that encode critical components of cardiac potassium channels have been implicated in the syndrome: KCNH2 in SQT1, KCNQ1 in SQT2 and KCNJ2 in SQT3 [2-4]. Of successfully genotyped cases, the most prevalent mutations affect KCNH2 [3]. KCNH2 (alternative nomenclature hERG: human-Etherà- go-go-Related Gene) is responsible for encoding the pore-forming protein of channels that mediate the cardiac rapid delayed rectifi er current, IKr [5]. IKr is vital for normal ventricular repolarization, evidenced by the fact that lossof- function mutations in hERG-mediated subunits underpin the LQT2 form of congenital Long QT Syndrome [1,5]. Gainof- function mutations in hERG-mediated subunits underpin variant 1 (SQT1) of the SQTS [2,3]....</p

The use of Lapita pottery : results from the first analysis of lipid residues

Biomolecular and isotopic characterisation of absorbed organic residues have been performed on eight dentate-stamped and two plain Lapita potsherds from the site of Teouma, in Vanuatu. Lipid profiles associated with decorated pots are homogenous, suggesting that similar food types or mixtures of food types were placed in these vessels. This suggests a high degree of consistency in the use of Lapita decorated pots, irrespective of the morphological and stylistic variation of these vessels. Data obtained from single-compound isotope analysis are also not consistent with marine resources as potential food sources for Lapita vessels. The absence of such commonly consumed, ubiquitous and easily accessible resources in Lapita vessels suggests that these pots were not manufactured to be used for ordinary occasions and day-to-day food consumption. This is the first time tangible data related to the use of these vessels are provided to support this claim in addition to contextual inferences

Iterative precision measurement of branching ratios applied to 5P States in 88Sr+

We report and demonstrate a method for measuring the branching ratios of dipole transitions of trapped atomic ions by performing nested sequences of population inversions. This scheme is broadly applicable to species with metastable lambda systems and can be generalized to find the branching of any state to lowest states. It does not use ultrafast pulsed or narrow linewidth lasers and is insensitive to experimental variables such as laser and magnetic field noise as well as ion heating. To demonstrate its effectiveness, we make the most accurate measurements thus far of the branching ratios of both 5P[subscript 1/2] and 5P[subscript 3/2] states in [superscript 88]Sr[superscript +] with sub-1% uncertainties. We measure 17.175(27) for the 5P[subscript 1/2]–5S[subscript 1/2] branching ratio, 15.845(71) for 5P[subscript 3/2]–5S[subscript 1/2], and 0.056 09(21) for 5P[subscript 3/2]–4D[subscript 5/2]. These values represent the first precision measurement for 5P[subscript 3/2]–4D[subscript 5/2], as well as ten- and thirty-fold improvements in precision respectively for 5P[subscript 1/2]–5S[subscript 1/2] and 5P[subscript 3/2]–5S[subscript 1/2] over the best previous experimental values.National Science Foundation (U.S.). Center for Ultracold AtomsUnited States. Intelligence Advanced Research Projects Activity. Multi-Qubit Coherent Operation

Evidence for multiple mechanisms underlying surface electric-field noise in ion traps

Electric-field noise from ion-trap electrode surfaces can limit the fidelity of multiqubit entangling operations in trapped-ion quantum information processors and can give rise to systematic errors in trapped-ion optical clocks. The underlying mechanism for this noise is unknown, but it has been shown that the noise amplitude can be reduced by energetic ion bombardment, or “ion milling,” of the trap electrode surfaces. Using a single trapped ⁸⁸Sr⁺ ion as a sensor, we investigate the temperature dependence of this noise both before and after ex situ ion milling of the trap electrodes. Making measurements over a trap electrode temperature range of 4 K to 295 K in both sputtered niobium and electroplated gold traps, we see a marked change in the temperature scaling of the electric-field noise after ion milling: power-law behavior in untreated surfaces is transformed to Arrhenius behavior after treatment. The temperature scaling becomes material-dependent after treatment as well, strongly suggesting that different noise mechanisms are at work before and after ion milling. To constrain potential noise mechanisms, we measure the frequency dependence of the electric-field noise, as well as its dependence on ion-electrode distance, for niobium traps at room temperature both before and after ion milling. These scalings are unchanged by ion milling.National Science Foundation (U.S.) (Award DMR-14-19807)United States. Air Force Office of Scientific Research (Contract FA8721-05-C-0002

Surgery for Hilar cholangiocarcinoma: the Newcastle-upon-Tyne Liver Unit experience

Background: Hilar cholangiocarcinoma (HCCA) arises from the confluence of the common hepatic duct and has a poor prognosis. If resectable, an extended left (eLH) or right hemihepatectomy (eRH) is usually required to provide oncological clearance. We reviewed outcomes for patients with HCCA managed at our centre. Methods: Electronic records of patients referred to our centre for HCCA were retrospectively reviewed. The Kaplan–Meier method was used to estimate overall survival (OS) with the log rank test used for significance (p &lt; 0.05). A Cox regression was performed to ascertain factors that may influence survival. Results: 156 HCCA patients were identified (44 resected versus 112 non-resected). Resected patients had longer OS compared to non-resected patients (50.3 versus 9.8 months, p &lt; 0.001). Patients who underwent an eLH (n = 15) had significantly longer OS at 3 years compared to eRH patients (67.7 vs. 42.1%, respectively; p = 0.007). An eLH was an independent predictor of survival (HR 0.43, p = 0.04). Lymph node positivity (n = 23, hazard ratio 1.72, p = 0.027) and the presence of microvascular invasion (n = 28, hazard ratio 1.78, p = 0.047) were independent predictors of mortality. The frequency of lymph node positivity and microvascular invasion did not differ between eLH and eRH patients (p &gt; 0.05). Conclusion: Patients undergoing an eLH for HCCA have significantly better long-term outcomes compared to those undergoing eRH, independent of other pathological variables. The functional liver remnant (FLR) is usually smaller following eRH, resulting in a higher risk of post-operative liver failure. Combining CT volumetry with PVE may result in better prediction and optimisation of the FLR in the context of eRH for HCCA. Novel findings: An extended left hemihepatectomy is an independent predictor of survival; investigation into the precise interaction between left- and right-sided resections and pre- and post-embolization liver volume is warranted

Functional and pharmacological characterization of an S5 domain hERG mutation associated with short QT syndrome

Congenital short QT syndrome (SQTS) is a repolarization disorder characterized by abbreviated QT intervals, atrial and ventricular arrhythmias and a risk of sudden death. This study characterized a missense mutation (I560T) in the S5 domain of the hERG K+ channel that has been associated with variant 1 of the SQTS. Whole cell patch clamp recordings of wild-type (WT) and I560T hERG current (IhERG) were made at 37 °C from hERG expressing HEK 293 cells, and the structural context of the mutation was investigated using a recently reported cryo-EM structure of hERG. Under conventional voltage clamp, the I560T mutation increased IhERG amplitude without altering the voltage-dependence of activation, although it accelerated activation time-course and also slowed deactivation time-course at some voltages. The voltage dependence of IhERG inactivation was positively shifted (by ∼24 mV) and the time-course of inactivation was slowed by the I560T mutation. There was also a modest decrease in K+ over Na+ ion selectivity with the I560T mutation. Under action potential (AP) voltage clamp, the net charge carried by hERG was significantly increased during ventricular, Purkinje fibre and atrial APs, with maximal IhERG also occurring earlier during the plateau phase of ventricular and Purkinje fibre APs. The I560T mutation exerted only a modest effect on quinidine sensitivity of IhERG: the IC50 for mutant IhERG was 2.3 fold that for WT IhERG under conventional voltage clamp. Under AP voltage clamp the inhibitory effect of 1 μM quinidine was largely retained for I560T hERG and the timing of peak I560T IhERG was altered towards that of the WT channel. In both the open channel structure and a closed hERG channel model based on the closely-related EAG structure, I560T side-chains were oriented towards membrane lipid and away from adjacent domains of the channel, contrasting with previous predictions based on homology modelling. In summary, the I560T mutation produces multiple effects on hERG channel operation that result in a gain-of-function that is expected to abbreviate ventricular, atrial and Purkinje fibre repolarization. Quinidine is likely to be of value in offsetting the increase in IhERG and altered IhERG timing during ventricular APs in SQTS with this mutation