Identification, structural, and biophysical characterization of a positive modulator of human Kv3.1 channels.

Voltage-gated potassium channels (Kv) are tetrameric membrane proteins that provide a highly selective pathway for potassium ions (K+) to diffuse across a hydrophobic cell membrane. These unique voltage-gated cation channels detect changes in membrane potential and, upon activation, help to return the depolarized cell to a resting state during the repolarization stage of each action potential. The Kv3 family of potassium channels is characterized by a high activation potential and rapid kinetics, which play a crucial role for the fast-spiking neuronal phenotype. Mutations in the Kv3.1 channel have been shown to have implications in various neurological diseases like epilepsy and Alzheimer's disease. Moreover, disruptions in neuronal circuitry involving Kv3.1 have been correlated with negative symptoms of schizophrenia. Here, we report the discovery of a novel positive modulator of Kv3.1, investigate its biophysical properties, and determine the cryo-EM structure of the compound in complex with Kv3.1. Structural analysis reveals the molecular determinants of positive modulation in Kv3.1 channels by this class of compounds and provides additional opportunities for rational drug design for the treatment of associated neurological disorders.

Brain CT can predict low lean mass in the elderly with cognitive impairment: a community-dwelling study.

BACKGROUND: The coexistence of sarcopenia and dementia in aging populations is not uncommon, and they may share common risk factors and pathophysiological pathways. This study aimed to evaluate the relationship between brain atrophy and low lean mass in the elderly with impaired cognitive function. METHODS: This cross-sectional study included 168 elderly patients who visited the multi-disciplinary dementia outpatient clinic at Kaohsiung Chang Gung Memorial Hospital for memory issues, between 2017 and 2019. The body composition was assessed by dual energy X-ray absorptiometry (DEXA) and CT based skeletal muscle index including L3 skeletal muscle index (L3SMI) and masseter muscle mass index (MSMI). The brain atrophy assessment was measured by CT based visual rating scale. Possible predictors of low lean mass in the elderly with cognitive impairement were identified by binary logistic regression. ROC curves were generated from binary logistic regression. RESULTS: Among the 81 participants, 43 (53%) remained at a normal appendicular skeletal muscle index (ASMI), whereas 38 (47%) showed low ASMI. Compared with the normal ASMI group, subjects with low ASMI exhibited significantly lower BMI, L3SMI, and MSMI (all p < 0.05), and showed significant brain atrophy as assessed by visual rating scale (p < 0.001). The accuracy of predictive models for low ASMI in the elderly with cognitive impairment were 0.875, (Area under curve (AUC) = 0.926, 95% confidence interval [CI] 0.844-0.972) in model 1 (combination of BMI, GCA and L3SMI) and 0.885, (Area under curve (AUC) = 0.931, [CI] 0.857-0.979) in model 2 (combination of BMI, GCA and MSMI). CONCLUSIONS: Global cortical atrophy and body mass index combined with either L3 skeletal muscle index or masseter skeletal muscle index can predict low lean mass in the elderly with cognitive impairment.

A Wireless Monitoring System Using a Tunneling Sensor Array in a Smart Oral Appliance for Sleep Apnea Treatment.

Sleep apnea is a serious sleep disorder, and the most common type is obstructive sleep apnea (OSA). Untreated OSA will cause lots of potential health problems. Oral appliance therapy is an effective and popular approach for OSA treatment, but making a perfect fit for each patient is time-consuming and decreases its efficiency considerably. This paper proposes a System-on-a-Chip (SoC) enabled sleep monitoring system in a smart oral appliance, which is capable of intelligently collecting the physiological data about tongue movement through the whole therapy. A tunneling sensor array with an ultra-high sensitivity is incorporated to accurately detect the subtle pressure from the tongue. When the device is placed on the wireless platform, the temporary stored data will be retrieved and wirelessly transmitted to personal computers and cloud storages. The battery will be recharged by harvesting external RF power from the platform. A compact prototype module, whose size is 4.5 × 2.5 × 0.9 cm³, is implemented and embedded inside the oral appliance to demonstrate the tongue movement detection in continuous time frames. The functions of this design are verified by the presented measurement results. This design aims to increase efficiency and make it a total solution for OSA treatment.

Andrographolide inhibits adipogenesis of 3T3-L1 cells by suppressing C/EBPß expression and activation.

Andrographolide, a diterpenoid, is the most abundant terpenoid in Andrographis paniculata, a popular Chinese herbal medicine. Andrographolide displays diverse biological activities including hypoglycemia, hypolipidemia, anti-inflammation, and anti-tumorigenesis. Recent evidence indicates that andrographolide displays anti-obesity property by inhibiting lipogenic gene expression, however, the underlying mechanisms remain to be elucidated. In this study, the effects of andrographolide on transcription factor cascade and mitotic clonal expansion in 3T3-L1 preadipocyte differentiation into adipocyte were determined. Andrographolide dose-dependently (0-15µM) inhibited CCAAT/enhancer-binding protein α (C/EBPα) and C/EBPß mRNA and protein expression as well as peroxisome proliferator-activated receptor γ (PPARγ) protein level during the adipogenesis of 3T3-L1 cells. Concomitantly, fatty acid synthase and stearoyl-CoA desaturase expression and lipid accumulation were attenuated by andrographolide. Oil-red O staining further showed that the first 48h after the initiation of differentiation was critical for andrographolide inhibition of adipocyte formation. Andrographolide inhibited the phosphorylation of PKA and the activation of cAMP response element-binding protein (CREB) in response to a differentiation cocktail, which led to attenuated C/EBPß expression. In addition, ERK and GSK3ß-dependent C/EBPß phosphorylation was attenuated by andrographolide. Moreover, andrographolide suppressed cyclin A, cyclin E, and CDK2 expression and impaired the progression of mitotic clonal expansion (MCE) by arresting the cell cycle at the Go/G1 phase. Taken together, these results indicate that andrographolide has a potent anti-obesity action by inhibiting PKA-CREB-mediated C/EBPß expression as well as C/EBPß transcriptional activity, which halts MCE progression and attenuates C/EBPα and PPARγ expression.

Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii.

Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial virulence and survival. Here we describe the cerastecins, inhibitors of the A. baumannii transporter MsbA, an LOS flippase. These molecules are potent and bactericidal against A. baumannii, including clinical carbapenem-resistant Acinetobacter baumannii isolates. Using cryo-electron microscopy and biochemical analysis, we show that the cerastecins adopt a serpentine configuration in the central vault of the MsbA dimer, stalling the enzyme and uncoupling ATP hydrolysis from substrate flipping. A derivative with optimized potency and pharmacokinetic properties showed efficacy in murine models of bloodstream or pulmonary A. baumannii infection. While resistance development is inevitable, targeting a clinically unexploited mechanism avoids existing antibiotic resistance mechanisms. Although clinical validation of LOS transport remains undetermined, the cerastecins may open a path to narrow-spectrum treatment modalities for important nosocomial infections.

Cerastecin Inhibition of the Lipooligosaccharide Transporter MsbA to Combat Acinetobacter baumannii: From Screening Impurity to In Vivo Efficacy.

Acinetobacter baumannii, a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat and constitutes a growing threat to human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms is essential for addressing this critical medical need. Herein, we describe our efforts to inhibit the essential A. baumannii lipooligosaccharide (LOS) ATP-binding cassette (ABC) transporter MsbA. An unexpected impurity from a phenotypic screening was optimized as a series of dimeric compounds, culminating with 1 (cerastecin D), which exhibited antibacterial activity in the presence of human serum and a pharmacokinetic profile sufficient to achieve efficacy against A. baumannii in murine septicemia and lung infection models.

Generation of high-order Hermite-Gaussian modes in end-pumped solid-state lasers for square vortex array laser beam generation.

This study reports the first systematic approach to the excitation of all high-order Hermite-Gaussian modes (HGMs) in end-pumped solid-state lasers. This study uses a metal-wire-inserted laser resonator accompanied with the "off axis pumping" approach. This study presents numerical analysis of the excitation of HGMs in end-pumped solid-state lasers and experimentally generated HGM patterns. This study also experimentally demonstrates the generation of an square vortex array laser beams by passing specific high-order HGMs (HGn,n + 1 or HGn + 1,n modes) through a Dove prism-embedded unbalanced Mach-Zehnder interferometer [Optics Express 16, 19934-19949]. The resulting square vortex array laser beams with embedded vortexes aligned in a square array can be applied to multi-spot dark optical traps in the future.

Chaotic oscillations associated with the breakup of polarization entangled coherent states in a microchip solid-state laser.

We demonstrate the breakup of spatial-polarization entangled lasing patterns, which possess vector phase singularities, and the resultant dynamic instabilities featuring chaotic oscillations. The frequency splitting between a pair of Ince-Gauss (IG) lasing modes, originally forming a coherent entanglement state, and a self-excited additional nonorthogonal IG mode through a new class of transverse effect of self-injection pattern seeding, is shown to result in modal-interference-induced modulation at the beat frequency, leading to chaotic oscillations.

Modeling transmission of hexavalent chromium concentration and its health cost with a water quality analysis simulation program.

In this study, the Water Quality Analysis Simulation Program (WASP7) was used to evaluate the transmission of hexavalent chromium (Cr(VI)) contamination in a water-sediment system and its flux into cultivated soils. The agricultural areas adjacent to the Wu River in Taiwan were taken as the study area, as these soils were heavily polluted with Cr(VI) concentrations of 2173-3271 µg/kg. The rates of accumulation of Cr(VI) are affected by the distance from the source of contamination and the size and type of cultivated areas. The highest concentrations of Cr(VI) (4.27 mg/kg) were detected in soil from Changhua city and correlated with the greater risk of gastric cancer in residents. Specifically, the risk of gastric cancer due to Cr(VI) contamination of agricultural soil was 3 × 10 - 7 - 15.2 × 10 - 6 in Taichung city (upstream) and 1.3 × 10 - 6 - 76.3 × 10 - 6 in Changhua county (downstream). The values of statistical life-years (VSLYs) were US$6.2-10 million for rice, US$42-60 million for corn, and US$360-580 million for other vegetables, respectively, each year. It is critical that techniques other than source reduction are used to reduce human exposure to Cr(VI), such as chemical oxidation or ion-exchange treatment to remove Cr(VI) from factory wastewaters, prior to their discharge into rivers. PRACTITIONER POINTS: This study evaluated the transmission of hexavalent chromium (Cr(VI)) contamination in a water-sediment-soil system. Maximum concentrations of Cr(VI) most rapidly accumulated in the smallest cultivated areas. The highest concentrations of Cr(VI) (3.3 mg/kg) were correlated with the greater risk of gastric cancer. Young children had a threefold greater risk of gastric cancer than adults. Techniques other than source reduction are prior to their discharge into rivers.

Atomic-Scale Chemical Conversion of Single-Layer Transition Metal Dichalcogenides.

Chemical conversion by atomic substitution offers a powerful route toward the creation of unusual structures and functionalities. Here, we demonstrate the progressive transformation of single-layer TiTe2 into TiSe2 by reaction with a Se flux in vacuum. Angle-resolved photoemission spectroscopy and scanning tunneling microscopy reveal intriguing reaction patterns involving TiSe2 island ingrowth starting from the TiTe2 island edges, while the band structure and core level signatures of TiSe2 grow in intensity at the expense of those corresponding to TiTe2. Lattice mismatch between TiTe2 and TiSe2 results in misfit holes and lattice distortions over a distance behind a seamless fingerlike reaction front. The regions of TiSe2 and TiTe2 are distinguished by a height difference and a charge density wave (CDW) at different transition temperatures. The method of in situ chemical conversion offers opportunities for atomic-scale engineering of layered transition metal dichalcogenides that host useful properties arising from CDW, Dirac, Weyl, superconducting, spin-valley, and magnetic structures.

Micromachined Planar Supercapacitor with Interdigital Buckypaper Electrodes.

In this work, a flexible micro-supercapacitor with interdigital planar buckypaper electrodes is presented. A simple fabrication process involving vacuum filtration method and SU-8 molding techniques is proposed to fabricate in-plane interdigital buckypaper electrodes on a membrane filter substrate. The proposed process exhibits excellent flexibility for future integration of the micro-supercapacitors (micro-SC) with other electronic components. The device's maximum specific capacitance measured using cyclic voltammetry was 107.27 mF/cm² at a scan rate of 20 mV/s. The electrochemical stability was investigated by measuring the performance of charge-discharge at different discharge rates. Devices with different buckypaper electrode thicknesses were also fabricated and measured. The specific capacitance of the proposed device increased linearly with the buckypaper electrode thickness. The measured leakage current was approximately 9.95 µA after 3600 s. The device exhibited high cycle stability, with 96.59% specific capacitance retention after 1000 cycles. A Nyquist plot of the micro-SC was also obtained by measuring the impedances with frequencies from 1 Hz to 50 kHz; it indicated that the equivalent series resistance value was approximately 18 Ω.

Tongue Pressure Sensing Array Integrated with a System-on-Chip Embedded in a Mandibular Advancement Splint.

Obstructive sleep apnea (OSA), which is caused by obstructions of the upper airway, is a syndrome with rising prevalence. Mandibular advancement splints (MAS) are oral appliances for potential treatment of OSA. This work proposes a highly-sensitive pressure sensing array integrated with a system-on-chip (SoC) embedded in a MAS. The device aims to measure tongue pressure distribution in order to determine the efficacy of the MAS for treating OSA. The flexible sensing array consists of an interdigital electrode pair array assembled with conductive polymer films and an SoC capable of retrieving/storing data during sleep, and transmitting data for analysis after sleep monitoring. The surfaces of the conductive polymer films were patterned with microdomed structures, which effectively increased the sensitivity and reduced the pressure sensing response time. The measured results also show that the crosstalk effect between the sensing elements of the array was negligible. The sensitivity of the sensing array changed minimally after the device was submerged in water for up to 100 h.