KCNQ1 and KCNE1 in the IKs Channel Complex Make State-dependent Contacts in their Extracellular Domains

KCNQ1 and KCNE1 (Q1 and E1) associate to form the slow delayed rectifier IKs channels in the heart. A short stretch of eight amino acids at the extracellular end of S1 in Q1 (positions 140–147) harbors six arrhythmia-associated mutations. Some of these mutations affect the Q1 channel function only when coexpressed with E1, suggesting that this Q1 region may engage in the interaction with E1 critical for the IKs channel function. Identifying the Q1/E1 contact points here may provide new insights into how the IKs channel operates. We focus on Q1 position 145 and E1 positions 40–43. Replacing all native cysteine (Cys) in Q1 and introducing Cys into the above Q1 and E1 positions do not significantly perturb the Q1 channel function or Q1/E1 interactions. Immunoblot experiments on COS-7 cells reveal that Q1 145C can form disulfide bonds with E1 40C and 41C, but not E1 42C or 43C. Correspondingly, voltage clamp experiments in oocytes reveal that Q1 145C coexpressed with E1 40C or E1 41C manifests unique gating behavior and DTT sensitivity. Our data suggest that E1 40C and 41C come close to Q1 145C in the activated and resting states, respectively, to allow disulfide bond formation. These data and those in the literature lead us to propose a structural model for the Q1/E1 channel complex, in which E1 is located between S1, S4, and S6 of three separate Q1 subunits. We propose that E1 is not a passive partner of the Q1 channel, but instead can engage in molecular motions during IKs gating

Building KCNQ1/KCNE1 Channel Models and Probing their Interactions by Molecular-Dynamics Simulations

The slow delayed rectifier (IKs) channel is composed of KCNQ1 (pore-forming) and KCNE1 (auxiliary) subunits, and functions as a repolarization reserve in the human heart. Design of IKs-targeting anti-arrhythmic drugs requires detailed three-dimensional structures of the KCNQ1/KCNE1 complex, a task made possible by Kv channel crystal structures (templates for KCNQ1 homology-modeling) and KCNE1 NMR structures. Our goal was to build KCNQ1/KCNE1 models and extract mechanistic information about their interactions by molecular-dynamics simulations in an explicit lipid/solvent environment. We validated our models by confirming two sets of model-generated predictions that were independent from the spatial restraints used in model-building. Detailed analysis of the molecular-dynamics trajectories revealed previously unrecognized KCNQ1/KCNE1 interactions, whose relevance in IKs channel function was confirmed by voltage-clamp experiments. Our models and analyses suggest three mechanisms by which KCNE1 slows KCNQ1 activation: by promoting S6 bending at the Pro hinge that closes the activation gate; by promoting a downward movement of gating charge on S4; and by establishing a network of electrostatic interactions with KCNQ1 on the extracellular surface that stabilizes the channel in a pre-open activated state. Our data also suggest how KCNE1 may affect the KCNQ1 pore conductance

Long-Term Fish Oil Supplementation Induces Cardiac Electrical Remodeling by Changing Channel Protein Expression in the Rabbit Model

Clinical trials and epidemiological studies have suggested that dietary fish oil (FO) supplementation can provide an anti-arrhythmic benefit in some patient populations. The underlying mechanisms are not entirely clear. We wanted to understand how FO supplementation (for 4 weeks) affected the action potential configuration/duration of ventricular myocytes, and the ionic mechanism(s)/molecular basis for these effects. The experiments were conducted on adult rabbits, a widely used animal model for cardiac electrophysiology and pathophysiology. We used gas chromatography - mass spectroscopy to confirm that FO feeding produced a marked increase in the content of n-3 polyunsaturated fatty acids in the phospholipids of rabbit hearts. Left ventricular myocytes were used in current and voltage clamp experiments to monitor action potentials and ionic currents, respectively. Action potentials of myocytes from FO-fed rabbits exhibited much more positive plateau voltages and prolonged durations. These changes could be explained by an increase in the L-type Ca current (ICaL) and a decrease in the transient outward current (Ito) in these myocytes. FO feeding did not change the delayed rectifier or inward rectifier current. Immunoblot experiments showed that the FO-feeding induced changes in ICaL and Ito were associated with corresponding changes in the protein levels of major pore-forming subunits of these channels: increase in Cav1.2 and decrease in Kv4.2 and Kv1.4. There was no change in other channel subunits (Cav1.1, Kv4.3, KChIP2, and ERG1). We conclude that long-term fish oil supplementation can impact on cardiac electrical activity at least partially by changing channel subunit expression in cardiac myocytes

Strain-induced partially flat band, helical snake states, and interface superconductivity in topological crystalline insulators

Topological crystalline insulators in IV-VI compounds host novel topological surface states consisting of multi-valley massless Dirac fermions at low energy. Here we show that strain generically acts as an effective gauge field on these Dirac fermions and creates pseudo-Landau orbitals without breaking time-reversal symmetry. We predict the realization of this phenomenon in IV-VI semiconductor heterostructures, due to a naturally occurring misfit dislocation array at the interface that produces a periodically varying strain field. Remarkably, the zero-energy Landau orbitals form a flat band in the vicinity of the Dirac point, and coexist with a network of snake states at higher energy. We propose that the high density of states of this flat band gives rise to interface superconductivity observed in IV-VI semiconductor multilayers at unusually high temperatures, with non-BCS behavior. Our work demonstrates a new route to altering macroscopic electronic properties to achieve a partially flat band, and paves the way for realizing novel correlated states of matter.Comment: Accepted by Nature Physic

Preserving Both Privacy and Utility in Network Trace Anonymization

As network security monitoring grows more sophisticated, there is an increasing need for outsourcing such tasks to third-party analysts. However, organizations are usually reluctant to share their network traces due to privacy concerns over sensitive information, e.g., network and system configuration, which may potentially be exploited for attacks. In cases where data owners are convinced to share their network traces, the data are typically subjected to certain anonymization techniques, e.g., CryptoPAn, which replaces real IP addresses with prefix-preserving pseudonyms. However, most such techniques either are vulnerable to adversaries with prior knowledge about some network flows in the traces, or require heavy data sanitization or perturbation, both of which may result in a significant loss of data utility. In this paper, we aim to preserve both privacy and utility through shifting the trade-off from between privacy and utility to between privacy and computational cost. The key idea is for the analysts to generate and analyze multiple anonymized views of the original network traces; those views are designed to be sufficiently indistinguishable even to adversaries armed with prior knowledge, which preserves the privacy, whereas one of the views will yield true analysis results privately retrieved by the data owner, which preserves the utility. We present the general approach and instantiate it based on CryptoPAn. We formally analyze the privacy of our solution and experimentally evaluate it using real network traces provided by a major ISP. The results show that our approach can significantly reduce the level of information leakage (e.g., less than 1\% of the information leaked by CryptoPAn) with comparable utility

Monotone and fast computation of Euler’s constant

Abstract We construct sequences of finite sums ( l ˜ n ) n ≥ 0 $(\tilde{l}_{n})_{n\geq 0}$ and ( u ˜ n ) n ≥ 0 $(\tilde{u}_{n})_{n\geq 0}$ converging increasingly and decreasingly, respectively, to the Euler-Mascheroni constant γ at the geometric rate 1/2. Such sequences are easy to compute and satisfy complete monotonicity-type properties. As a consequence, we obtain an infinite product representation for 2 γ $2^{\gamma }$ converging in a monotone and fast way at the same time. We use a probabilistic approach based on a differentiation formula for the gamma process

Circumcision to prevent HIV and other sexually transmitted infections in men who have sex with men: a systematic review and meta-analysis of global data

Background: Men who have sex with men (MSM) are disproportionately affected by HIV and other sexually transmitted infections (STIs) worldwide. Previous reviews investigating the role of circumcision in preventing HIV and other STIs among MSM were inconclusive. Many new studies have emerged in the past decade. To inform global prevention strategies for HIV and other STIs among MSM, we reviewed all available evidence on the associations between circumcision and HIV and other STIs among MSM. Methods: In this systematic review and meta-analysis, we searched PubMed, Web of Science, BioMed Central, Scopus, ResearchGate, Cochrane Library, Embase, PsycINFO, Google Scholar, and websites of international HIV and STI conferences for studies published before March 8, 2018. Interventional or observational studies containing original quantitative data describing associations between circumcision and incident or prevalent infection of HIV and other STIs among MSM were included. Studies were excluded if MSM could not be distinguished from men who have sex with women only. We calculated pooled odds ratios (ORs) and their 95% CIs using random-effect models. We assessed risk of bias using the Newcastle-Ottawa scale. Findings: We identified 62 observational studies including 119 248 MSM. Circumcision was associated with 23% reduced odds of HIV infection among MSM overall (OR 0·77, 95% CI 0·67–0·89; number of estimates [k]=45; heterogeneity I 2 =77%). Circumcision was protective against HIV infection among MSM in countries of low and middle income (0·58, 0·41–0·83; k=23; I 2 =77%) but not among MSM in high-income countries (0·99, 0·90–1·09; k=20; I 2 =40%). Circumcision was associated with reduced odds of herpes simplex virus (HSV) infection among MSM overall (0·84, 0·75–0·95; k=5; I 2 =0%) and penile human papillomavirus (HPV) infection among HIV-infected MSM (0·71, 0·51–0·99; k=3; I 2 =0%). Interpretation: We found evidence that circumcision is likely to protect MSM from HIV infection, particularly in countries of low and middle income. Circumcision might also protect MSM from HSV and penile HPV infection. MSM should be included in campaigns promoting circumcision among men in countries of low and middle income. In view of the substantial proportion of MSM in countries of low and middle income who also have sex with women, well designed longitudinal studies differentiating MSM only and bisexual men are needed to clarify the effect of circumcision on male-to-male transmission of HIV and other STIs. Funding: National Natural Science Foundation of China, National Science and Technology Major Project of China, Australian National Health and Medical Research Council Early Career Fellowship, Sanming Project of Medicine in Shenzhen, National Institutes of Health, Mega Projects of National Science Research for the 13th Five-Year Plan, Doris Duke Charitable Foundation

Disease-Associated Mutations Prevent GPR56-Collagen III Interaction

GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) family. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Using the N-terminal fragment of GPR56 (GPR56N) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56N, the ligand binding domain. This domain contains four disease-associated mutations and two N-glycosylation sites. Our study reveals that although glycosylation is not required for ligand binding, each of the four disease-associated mutations completely abolish the ligand binding ability of GPR56. Our data indicates that these four single missense mutations cause BFPP mostly by abolishing the ability of GPR56 to bind to its ligand, collagen III, in addition to affecting GPR56 protein surface expression as previously shown