KCNKØ: opening and closing the 2-P-domain potassium leak channel entails "C-type" gating of the outer pore.

Essential to nerve and muscle function, little is known about how potassium leak channels operate. KCNKØ opens and closes in a kinase-dependent fashion. Here, the transition is shown to correspond to changes in the outer aspect of the ion conduction pore. Voltage-gated potassium (VGK) channels open and close via an internal gate; however, they also have an outer pore gate that produces "C-type" inactivation. While KCNKØ does not inactivate, KCNKØ and VGK channels respond in like manner to outer pore blockers, potassium, mutations, and chemical modifiers. Structural relatedness is confirmed: VGK residues that come close during C-type gating predict KCNKØ sites that crosslink (after mutation to cysteine) to yield channels controlled by reduction and oxidization. We conclude that similar outer pore gates mediate KCNKØ opening and closing and VGK channel C-type inactivation despite their divergent structures and physiological roles

Block of Kcnk3 by protons. Evidence that 2-P-domain potassium channel subunits function as homodimers.

KCNK subunits have two pore-forming P domains and four predicted transmembrane segments. To assess the number of subunits in each pore, we studied external proton block of Kcnk3, a subunit prominent in rodent heart and brain. Consistent with a pore-blocking mechanism, inhibition was dependent on voltage, potassium concentration, and a histidine in the first P domain (P1H). Thus, at pH 6.8 with 20 mm potassium half the current passed by P1H channels was blocked (apparently via two sites approximately 10% into the electrical field) whereas channels with an asparagine substitution (P1N) were fully active. Furthermore, pore blockade by barium was sensitive to pH in P1H but not P1N channels. Although linking two Kcnk3 subunits in tandem to produce P1H-P1H and P1N-P1N channels bearing four P domains did not alter these attributes, the mixed tandems P1H-P1N and P1N-P1H were half-blocked at pH approximately 6.4, apparently via a single site. This implicates a dimeric structure for Kcnk3 channels with two (and only two) P1 domains in each pore and argues that P2 domains also contribute to pore formation

Standard and Null Weak Values

Weak value (WV) is a quantum mechanical measurement protocol, proposed by Aharonov, Albert, and Vaidman. It consists of a weak measurement, which is weighed in, conditional on the outcome of a later, strong measurement. Here we define another two-step measurement protocol, null weak value (NVW), and point out its advantages as compared to WV. We present two alternative derivations of NWVs and compare them to the corresponding derivations of WVs.Comment: 11 pages, 2 figures. To appear in Quantum Theory: A Two-Time Success Story: Yakir Aharonov Festschrif

Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and septic shock: A retrospective cohort study

INTRODUCTION: The impact of in vitro resistance on initially appropriate antibiotic therapy (IAAT) remains unclear. We elucidated the relationship between non-IAAT and mortality, and between IAAT and multi-drug resistance (MDR) in sepsis due to Gram-negative bacteremia (GNS). METHODS: We conducted a single-center retrospective cohort study of adult intensive care unit patients with bacteremia and severe sepsis/septic shock caused by a gram-negative (GN) organism. We identified the following MDR pathogens: MDR P. aeruginosa, extended spectrum beta-lactamase and carbapenemase-producing organisms. IAAT was defined as exposure within 24 hours of infection onset to antibiotics active against identified pathogens based on in vitro susceptibility testing. We derived logistic regression models to examine a) predictors of hospital mortality and b) impact of MDR on non-IAAT. Proportions are presented for categorical variables, and median values with interquartile ranges (IQR) for continuous. RESULTS: Out of 1,064 patients with GNS, 351 (29.2%) did not survive hospitalization. Non-survivors were older (66.5 (55, 73.5) versus 63 (53, 72) years, P = 0.036), sicker (Acute Physiology and Chronic Health Evaluation II (19 (15, 25) versus 16 (12, 19), P <0.001), and more likely to be on pressors (odds ratio (OR) 2.79, 95% confidence interval (CI) 2.12 to 3.68), mechanically ventilated (OR 3.06, 95% CI 2.29 to 4.10) have MDR (10.0% versus 4.0%, P <0.001) and receive non-IAAT (43.4% versus 14.6%, P <0.001). In a logistic regression model, non-IAAT was an independent predictor of hospital mortality (adjusted OR 3.87, 95% CI 2.77 to 5.41). In a separate model, MDR was strongly associated with the receipt of non-IAAT (adjusted OR 13.05, 95% CI 7.00 to 24.31). CONCLUSIONS: MDR, an important determinant of non-IAAT, is associated with a three-fold increase in the risk of hospital mortality. Given the paucity of therapies to cover GN MDRs, prevention and development of new agents are critical

Modern trends of scientific research and organizational methodological activities of Ural Scientific Research Institute of Dermatology, Venerology and Immunopathology

The paper presents main achivments of Ural Scientific Research Institute of Dermatology, Venerology an Immunopathology in scientific research and organizational methodological activities aimed at increasing of quality and accessibility of specialized medical care for patiens with chronical dermatoses, syphilis and other sexually transmitted diseases. Main trends of further development of Institute in current conditions of reorganization of National health care were defined.В статье представлены основные достижения Уральского научно-исследовательского института дерматовенерологии и иммунопатологии в научно-исследовательской и организационно-методической деятельности, направленной на повышение качество и доступности специализированной медицинской помощи больным хроническими дерматозами, сифилисом и другими инфекциями, передаваемыми половым путем. Определены основные направления дальнейшего развития института в современных условиях реорганизации отечественного здравоохранения

Exploring 4D Quantum Hall Physics with a 2D Topological Charge Pump

The discovery of topological states of matter has profoundly augmented our understanding of phase transitions in physical systems. Instead of local order parameters, topological phases are described by global topological invariants and are therefore robust against perturbations. A prominent example thereof is the two-dimensional integer quantum Hall effect. It is characterized by the first Chern number which manifests in the quantized Hall response induced by an external electric field. Generalizing the quantum Hall effect to four-dimensional systems leads to the appearance of a novel non-linear Hall response that is quantized as well, but described by a 4D topological invariant - the second Chern number. Here, we report on the first observation of a bulk response with intrinsic 4D topology and the measurement of the associated second Chern number. By implementing a 2D topological charge pump with ultracold bosonic atoms in an angled optical superlattice, we realize a dynamical version of the 4D integer quantum Hall effect. Using a small atom cloud as a local probe, we fully characterize the non-linear response of the system by in-situ imaging and site-resolved band mapping. Our findings pave the way to experimentally probe higher-dimensional quantum Hall systems, where new topological phases with exotic excitations are predicted

Experience in the treatment of psoriasis patients using Apremilast, a selective signalling pathway inhibitor

The article presents a brief description of Аpremilast — the target synthetic anti-inflammatory drug, which is representative of a new class of agents for the treatment of psoriasis and psoriatic arthritis. The efficiency and safety of the new drug in the treatment of patients with severe psoriasis are shown