Cryo-EM Studies of TMEM16F Calcium-Activated Ion Channel Suggest Features Important for Lipid Scrambling.

As a Ca2+-activated lipid scramblase and ion channel that mediates Ca2+ influx, TMEM16F relies on both functions to facilitate extracellular vesicle generation, blood coagulation, and bone formation. How a bona fide ion channel scrambles lipids remains elusive. Our structural analyses revealed the coexistence of an intact channel pore and PIP2-dependent protein conformation changes leading to membrane distortion. Correlated to the extent of membrane distortion, many tightly bound lipids are slanted. Structure-based mutagenesis studies further reveal that neutralization of some lipid-binding residues or those near membrane distortion specifically alters the onset of lipid scrambling, but not Ca2+ influx, thus identifying features outside of channel pore that are important for lipid scrambling. Together, our studies demonstrate that membrane distortion does not require open hydrophilic grooves facing the membrane interior and provide further evidence to suggest separate pathways for lipid scrambling and ion permeation

Model-Free Adaptive Sensing and Control for a Piezoelectrically Actuated System

Since the piezoelectrically actuated system has nonlinear and time-varying behavior, it is difficult to establish an accurate dynamic model for a model-based sensing and control design. Here, a model-free adaptive sliding controller is proposed to improve the small travel and hysteresis defects of piezoelectrically actuated systems. This sensing and control strategy employs the functional approximation technique (FAT) to establish the unknown function for eliminating the model-based requirement of the sliding-mode control. The piezoelectrically actuated system’s nonlinear functions can be approximated by using the combination of a finite number of weighted Fourier series basis functions. The unknown weighted vector can be estimated by an updating rule. The important advantage of this approach is to achieve the sliding-mode controller design without the system dynamic model requirement. The update laws for the coefficients of the Fourier series functions are derived from a Lyapunov function to guarantee the control system stability. This proposed controller is implemented on a piezoelectrically actuated X-Y table. The dynamic experimental result of this proposed FAT controller is compared with that of a traditional model-based sliding-mode controller to show the performance improvement for the motion tracking performance

Ventricular divergence correlates with epicardial wavebreaks and predicts ventricular arrhythmia in isolated rabbit hearts during therapeutic hypothermia

INTRODUCTION: High beat-to-beat morphological variation (divergence) on the ventricular electrogram during programmed ventricular stimulation (PVS) is associated with increased risk of ventricular fibrillation (VF), with unclear mechanisms. We hypothesized that ventricular divergence is associated with epicardial wavebreaks during PVS, and that it predicts VF occurrence. METHOD AND RESULTS: Langendorff-perfused rabbit hearts (n = 10) underwent 30-min therapeutic hypothermia (TH, 30°C), followed by a 20-min treatment with rotigaptide (300 nM), a gap junction modifier. VF inducibility was tested using burst ventricular pacing at the shortest pacing cycle length achieving 1:1 ventricular capture. Pseudo-ECG (p-ECG) and epicardial activation maps were simultaneously recorded for divergence and wavebreaks analysis, respectively. A total of 112 optical and p-ECG recordings (62 at TH, 50 at TH treated with rotigaptide) were analyzed. Adding rotigaptide reduced ventricular divergence, from 0.13±0.10 at TH to 0.09±0.07 (p = 0.018). Similarly, rotigaptide reduced the number of epicardial wavebreaks, from 0.59±0.73 at TH to 0.30±0.49 (p = 0.036). VF inducibility decreased, from 48±31% at TH to 22±32% after rotigaptide infusion (p = 0.032). Linear regression models showed that ventricular divergence correlated with epicardial wavebreaks during TH (p<0.001). CONCLUSION: Ventricular divergence correlated with, and might be predictive of epicardial wavebreaks during PVS at TH. Rotigaptide decreased both the ventricular divergence and epicardial wavebreaks, and reduced the probability of pacing-induced VF during TH

Letter of Intent: Jinping Neutrino Experiment

Jinping Neutrino Experiment (Jinping) is proposed to significantly improve measurements on solar neutrinos and geoneutrinos in China Jinping Laboratory - a lab with a number of unparalleled features, thickest overburden, lowest reactor neutrino background, etc., which identify it as the world-best low-energy neutrino laboratory. The proposed experiment will have target mass of 4 kilotons of liquid scintillator or water-based liquid scintillator, with a fiducial mass of 2 kilotons for neutrino-electron scattering events and 3 kilotons for inverse-beta interaction events. A number of initial sensitivities studies have been carried out, including on the transition phase for the solar neutrinos oscillation from the vacuum to the matter effect, the discovery of solar neutrinos from the carbon-nitrogen-oxygen (CNO) cycle, the resolution of the high and low metallicity hypotheses, and the unambiguous separation on U and Th cascade decays from the dominant crustal anti-electron neutrinos in China.Comment: Proposal for the Jinping Neutrino Experimen

Microbiologic Characteristics, Serologic Responses, and Clinical Manifestations in Severe Acute Respiratory Syndrome, Taiwan1

The genome of one Taiwanese severe acute respiratory syndrome-associated coronavirus (SARS-CoV) strain (TW1) was 29,729 nt in length. Viral RNA may persist for some time in patients who seroconvert, and some patients may lack an antibody response (immunoglobulin G) to SARS-CoV >21 days after illness onset. An upsurge of antibody response was associated with the aggravation of respiratory failure

Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement

Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan-a precursor amino acid for serotonin biosynthesis in the brain-and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake

Infection with hepatitis B virus carrying novel pre-S/S gene mutations in female siblings vaccinated at birth: two case reports

<p>Abstract</p> <p>Introduction</p> <p>After the initiation of a mass hepatitis B vaccination program in Taiwan, the prevalence of hepatitis B virus infection has declined progressively. However, about 1 percent of the young generation, who received hepatitis B vaccination at birth, remain carriers. Infection with vaccine-escape hepatitis B virus mutants always occurs shortly after birth. Here, we report two female siblings in whom the infection occurred in their adolescence. This report raises the question of whether a booster for hepatitis B vaccination is needed.</p> <p>Case presentation</p> <p>Two 19 and 14-year-old Taiwanese female siblings were born to a mother infected with hepatitis B virus and received a complete course of hepatitis B vaccination at birth. They remained negative for serum hepatitis B surface antigen and positive for serum anti-hepatitis B surface antibody throughout their childhood. However, both were infected with the hepatitis B virus in their adolescence. Hepatitis B virus DNA was extracted from serum samples from the mother and two siblings. Hepatitis B virus pre-S/S sequence was amplified by polymerase chain reaction followed by nucleotide sequencing. When compared with the sequence obtained from the mother, multiple amino acid substitutions located near or in the major hydrophilic region of the surface antigen were identified in the elder sister. Four of these mutations (sL97S, sL98S, sG102R, and sA159P) were novel. A novel in-frame deletion (14 amino acids deleted, pre-S 127-140) was found in the hepatitis B virus pre-S2 region in the younger sister.</p> <p>Conclusions</p> <p>Despite having received hepatitis B vaccination at birth, hepatitis B virus infection can still occur in adolescence with the emergence of novel mutations in the pre-S/S gene. This is a rare event and, to the best of our knowledge, has not been previously reported.</p

Detection of the inferred interaction network in hepatocellular carcinoma from EHCO (Encyclopedia of Hepatocellular Carcinoma genes Online)

BACKGROUND: The significant advances in microarray and proteomics analyses have resulted in an exponential increase in potential new targets and have promised to shed light on the identification of disease markers and cellular pathways. We aim to collect and decipher the HCC-related genes at the systems level. RESULTS: Here, we build an integrative platform, the Encyclopedia of Hepatocellular Carcinoma genes Online, dubbed EHCO , to systematically collect, organize and compare the pileup of unsorted HCC-related studies by using natural language processing and softbots. Among the eight gene set collections, ranging across PubMed, SAGE, microarray, and proteomics data, there are 2,906 genes in total; however, more than 77% genes are only included once, suggesting that tremendous efforts need to be exerted to characterize the relationship between HCC and these genes. Of these HCC inventories, protein binding represents the largest proportion (~25%) from Gene Ontology analysis. In fact, many differentially expressed gene sets in EHCO could form interaction networks (e.g. HBV-associated HCC network) by using available human protein-protein interaction datasets. To further highlight the potential new targets in the inferred network from EHCO, we combine comparative genomics and interactomics approaches to analyze 120 evolutionary conserved and overexpressed genes in HCC. 47 out of 120 queries can form a highly interactive network with 18 queries serving as hubs. CONCLUSION: This architectural map may represent the first step toward the attempt to decipher the hepatocarcinogenesis at the systems level. Targeting hubs and/or disruption of the network formation might reveal novel strategy for HCC treatment

Second-Hand Smoke–Induced Cardiac Fibrosis Is Related to the Fas Death Receptor Apoptotic Pathway without Mitochondria-Dependent Pathway Involvement in Rats

Exposure to environmental tobacco smoke has been epidemiologically linked to heart disease among nonsmokers. However, the molecular mechanism behind the pathogenesis of cardiac disease is unknown. In this study, we found that Wistar rats, exposed to tobacco cigarette smoke at doses of 5, 10, or 15 cigarettes for 30 min twice a day for 1 month, had a dose-dependently reduced heart weight to body weight ratio and enhanced interstitial fibrosis as identified by histopathologic analysis. The mRNA and activity of matrix metalloprotease-2 (MMP-2), representing the progress of cardiac remodeling, were also elevated in the heart. In addition, we used reverse-transcriptase polymerase chain reaction and Western blotting to demonstrate significantly increased levels of the apoptotic effecter caspase-3 in treated animal hearts. Dose-dependently elevated mRNA and protein levels of Fas, and promoted apoptotic initiator caspase-8 (active form), a molecule of a death-receptor–dependent pathway, coupled with unaltered or decreased levels of cytosolic cytochrome c and the apoptotic initiator caspase-9 (active form), molecules of mitochondria-dependent pathways, may be indicative of cardiac apoptosis, which is Fas death-receptor apoptotic-signaling dependent, but not mitochondria pathway dependent in rats exposed to second-hand smoke (SHS). With regard to the regulation of survival pathway, using dot blotting, we found cardiac insulin-like growth factor-1 (IGF-1) and IGF-1 receptor mRNA levels to be significantly increased, indicating that compensative effects of IGF-1 survival signaling could occur. In conclusion, we found that the effects of SHS on cardiomyocyte are mediated by the Fas death-receptor–dependent apoptotic pathway and might be related to the epidemiologic incidence of cardiac disease of SHS-exposed non-smokers