Lipid Metabolic Defects and Lipid-Dependent Gating of Voltage-Gated Ion Channels

Eukaryotic cells contain phospholipids and nonphospholipids. The latter lack phosphodiester groups in their head group regions. Lipid-dependent gating of voltage-gated ion channels represents a steady-state energetic effect of nonphospholipids in favoring the resting state of voltage-sensor domains (VSDs) of the channels. It suggests adaptation of ion channels to lipid compositions in their native niche and significant roles of low-to-intermediate affinity lipid-binding sites at the channels. The nonphospholipids include glycoglycerolipids, glycosphingolipids, ceramides, cholesterol or cholesterol esters, diacylglycerol (DAG), fatty acids, cation lipids, etc. Change in relative ratios of phospholipids to nonphospholipids can shift the energetic levels of the VSDs and the gating of these channels, which in turn may alter excitability in certain cells. It is expected that reduced relative abundance of nonphospholipids / phospholipids in plasma membranes may change resting transmembrane potential or gating transitions of voltage-gated Na or K channels. The net results will be a change in action potential firing at least in certain areas of an excitable cell. Such changes in the central nervous system (CNS) are anticipated to affect brain functions and contribute to early-onset neurological phenotypes observed in patients carrying lipid metabolic defects. We will describe the basics of lipid-dependent gating and review its projected links to phenotypes of monogenic lipid metabolic defects and related changes of lipid composition in cell membranes as well as altered neuronal excitability in CNS. However, lack of high-resolution techniques to measure lipid composition around individual channels in cell membranes has been limiting the studies of direct connections between lipid redistribution caused by metabolic defects and altered ion channel activities. Potential solutions will be described for future studies

Chromogranin B (CHGB) is dimorphic and responsible for dominant anion channels delivered to cell surface via regulated secretion

Regulated secretion is conserved in all eukaryotes. In vertebrates granin family proteins function in all key steps of regulated secretion. Phase separation and amyloid-based storage of proteins and small molecules in secretory granules require ion homeostasis to maintain their steady states, and thus need ion conductances in granule membranes. But granular ion channels are still elusive. Here we show that granule exocytosis in neuroendocrine cells delivers to cell surface dominant anion channels, to which chromogranin B (CHGB) is critical. Biochemical fractionation shows that native CHGB distributes nearly equally in soluble and membrane-bound forms, and both reconstitute highly selective anion channels in membrane. Confocal imaging resolves granular membrane components including proton pumps and CHGB in puncta on the cell surface after stimulated exocytosis. High pressure freezing immuno-EM reveals a major fraction of CHGB at granule membranes in rat pancreatic β-cells. A cryo-EM structure of bCHGB dimer of a nominal 3.5 Å resolution delineates a central pore with end openings, physically sufficient for membrane-spanning and large single channel conductance. Together our data support that CHGB-containing (CHGB+) channels are characteristic of regulated secretion, and function in granule ion homeostasis near the plasma membrane or possibly in other intracellular processes

A bony-crested Jurassic dinosaur with evidence of iridescent plumage highlights complexity in early paravian evolution

The Jurassic Yanliao theropods have offered rare glimpses of the early paravian evolution and particularly of bird origins, but, with the exception of the bizarre scansoriopterygids, they have shown similar skeletal and integumentary morphologies. Here we report a distinctive new Yanliao theropod species bearing prominent lacrimal crests, bony ornaments previously known from more basal theropods. It shows longer arm and leg feathers than Anchiornis and tail feathers with asymmetrical vanes forming a tail surface area even larger than that in Archaeopteryx. Nanostructures, interpreted as melanosomes, are morphologically similar to organized, platelet-shaped organelles that produce bright iridescent colours in extant birds. The new species indicates the presence of bony ornaments, feather colour and flight- related features consistent with proposed rapid character evolution and significant diversity in signalling and locomotor strategies near bird origins

Quality assurance in the HIV/AIDS laboratory network of China

Background In 2009, there were 8273 local screening laboratories, 254 confirmatory laboratories, 35 provincial confirmatory central laboratories and 1 National AIDS Reference Laboratory (NARL) in China. These laboratories were located in Center for Disease Control and Prevention (CDC) facilities, hospitals, blood donation clinics, maternal and child health (MCH) hospitals and border health quarantine health-care facilities

The effect of resolvin D1 on bone regeneration in a rat calvarial defect model

Resolvin D1 (RvD1) is a pro-resolving lipid mediator of inflammation, endogenously synthesized from omega-3 docosahexaenoic acid. The purpose of this study was to investigate the effect of RvD1 on bone regeneration using a rat calvarial defect model. Collagen 3D nanopore scaffold (COL) and Pluronic F127 hydrogel (F127) incorporated with RvD1 (RvD1-COL-F127 group) or COL and F127 (COL-F127 group) were implanted in symmetrical calvarial defects. After implantation, RvD1 was administrated subcutaneously every 7 days for 4 weeks. The rats were sacrificed at weeks 1 and 8 post-implantation. Tissue samples were analyzed by real-time reverse transcriptase-polymerase chain reaction and histology at week 1. Radiographical and histological analyses were done at week 8. At week 1, calvarial defects treated with RvD1 exhibited decreased numbers of inflammatory cells and tartrate-resistant acid phosphatase (TRAP) positive cells, greater numbers of newly formed blood vessels, upregulated gene expression of vascular endothelial growth factor and alkaline phosphatase, and downregulated gene expression of receptor activator of nuclear factor-κB ligand, interleukin-1β and tumor necrosis factor-α. At week 8, the radiographical results showed that osteoid area fraction of the RvD1-COL-F127 group was higher than that of the COL-F127 group, and histological examination exhibited enhanced osteoid formation and newly formed blood vessels in the RvD1-COL-F127 group. In conclusion, this study showed that RvD1 enhanced bone formation and vascularization in rat calvarial defects

Statistical properties of volatility return intervals of Chinese stocks

The statistical properties of the return intervals $\tau_q$ between successive 1-min volatilities of 30 liquid Chinese stocks exceeding a certain threshold $q$ are carefully studied. The Kolmogorov-Smirnov (KS) test shows that 12 stocks exhibit scaling behaviors in the distributions of $\tau_q$ for different thresholds $q$. Furthermore, the KS test and weighted KS test shows that the scaled return interval distributions of 6 stocks (out of the 12 stocks) can be nicely fitted by a stretched exponential function $f(\tau/\bar{\tau})\sim e^{- \alpha (\tau/\bar{\tau})^{\gamma}}$ with $\gamma\approx0.31$ under the significance level of 5%, where $\bar{\tau}$ is the mean return interval. The investigation of the conditional probability distribution $P_q(\tau | \tau_0)$ and the mean conditional return interval $$demonstrates the existence of short-term correlation between successive return interval intervals. We further study the mean return interval$$ after a cluster of $n$ intervals and the fluctuation $F(l)$ using detrended fluctuation analysis and find that long-term memory also exists in the volatility return intervals.Comment: 8 pages, 8 figure

DOMAIN: MilDly COnservative Model-BAsed OfflINe Reinforcement Learning

Model-based reinforcement learning (RL), which learns environment model from offline dataset and generates more out-of-distribution model data, has become an effective approach to the problem of distribution shift in offline RL. Due to the gap between the learned and actual environment, conservatism should be incorporated into the algorithm to balance accurate offline data and imprecise model data. The conservatism of current algorithms mostly relies on model uncertainty estimation. However, uncertainty estimation is unreliable and leads to poor performance in certain scenarios, and the previous methods ignore differences between the model data, which brings great conservatism. Therefore, this paper proposes a milDly cOnservative Model-bAsed offlINe RL algorithm (DOMAIN) without estimating model uncertainty to address the above issues. DOMAIN introduces adaptive sampling distribution of model samples, which can adaptively adjust the model data penalty. In this paper, we theoretically demonstrate that the Q value learned by the DOMAIN outside the region is a lower bound of the true Q value, the DOMAIN is less conservative than previous model-based offline RL algorithms and has the guarantee of security policy improvement. The results of extensive experiments show that DOMAIN outperforms prior RL algorithms on the D4RL dataset benchmark, and achieves better performance than other RL algorithms on tasks that require generalization.Comment: 13 pages, 6 figure