The splice variants of TREK-1 act as dominant-negative suppressors of human uterine relaxation: Implications for preterm labor

Human myometrium plays a pivotal role during pregnancy remaining quiescent during fetal development while eventually producing the forceful contractions necessary for parturition. The complex mechanism of maintaining uterine quiescence and triggering contraction is unclear. Spontaneous or unexplained preterm labor (PTL) accounts for approximately 45% of preterm birth (PTB) which results in infant death every 30 seconds globally. Two-pore domain potassium channels (K2P) are an emerging family of ion channels; these K2P channels participate in the regulation of excitable cells through maintaining resting membrane potential by polarizing the plasma membrane. The aberrant regulation of K2P channels may switch the cells from a resting state to one of excitation. TREK-1, a member of the K2P channel family, has previously been shown to exhibit elevated expression in pregnant human myometrium during gestation. In this study, three splice variants of intact human TREK-1 were identified in myometrium. For the first time, five non-conducting splice variants of TREK-1 were identified in preterm laboring and non-laboring myometrium, and were named as SV-1 to SV-5 due to the number of deleted exons. The exon skipping contributes to heavily truncated proteins with defective TREK-1 channel properties. Quantitative real-time PCR provided evidence of elevated expression of SV-5 in preterm labor, while TREK-1 was down-regulated. The up-regulation of SV-1, SV-3 and SV-5 are seen in preterm non-laboring myometrium.Alternative splicing has been shown to generate variants that can interfere with TREK-1 channel activity. Each individual splice variant was determined to be dominant-negative suppressors of TREK-1. The cellular distribution of TREK-1 was altered by each splice variant, which caused reduced membrane TREK-1 expression. Electrophysiological experiments confirmed the direct interaction between TREK-1 and each splice variant in basic and intracellular acidic conditions. Individual splice variants inhibited TREK-1 channel activity by reducing current densities as well as membrane TREK-1 expression. While intracellular acidosis is associated with uterine relaxation as well as TREK-1 channel activation, the use of bicarbonate experimentally to activate TREK-1 could not rescue TREK-1 channels blocked by co-expression of variant channels. Hetero-dimerization of TREK-1 with splice variant subunits is the probable mechanistic basis for this inhibition. Our research has shown that individual splice variants have the ability to impair TREK-1 channel function, although only SV-5 was significantly up-regulated in patients that delivered due to preterm labor. The presence of all non-conducting splice variants and the reduced TREK-1 transcript in preterm patients may also correlate with preterm labor per se. The presence of splice variants may competitively inhibit normal TREK-1 monomers which puts the uterus at risk of not maintaining quiescence in the presence of contractile influence(s). New therapeutic targets and biomarkers for preterm labor are suggested by this research due to the finding of non-conductive splice variants as dominant-negative suppressors of TREK-1

General stationary charged black holes as charged particle accelerators

We study the possibility of getting infinite energy in the center of mass frame of colliding charged particles in a general stationary charged black hole. For black holes with two-fold degenerate horizon, it is found that arbitrary high center-of-mass energy can be attained, provided that one of the particle has critical angular momentum or critical charge, and the remained parameters of particles and black holes satisfy certain restriction. For black holes with multiple-fold degenerate event horizons, the restriction is released. For non-degenerate black holes, the ultra-high center-of-mass is possible to be reached by invoking the multiple scattering mechanism. We obtain a condition for the existence of innermost stable circular orbit with critical angular momentum or charge on any-fold degenerate horizons, which is essential to get ultra-high center-of-mass energy without fine-tuning problem. We also discuss the proper time spending by the particle to reach the horizon and the duality between frame dragging effect and electromagnetic interaction. Some of these general results are applied to braneworld small black holes.Comment: 23 pages, no figures, revised version accepted for publication in Phys. Rev.

SCOPE: Scalable Composite Optimization for Learning on Spark

Many machine learning models, such as logistic regression~(LR) and support vector machine~(SVM), can be formulated as composite optimization problems. Recently, many distributed stochastic optimization~(DSO) methods have been proposed to solve the large-scale composite optimization problems, which have shown better performance than traditional batch methods. However, most of these DSO methods are not scalable enough. In this paper, we propose a novel DSO method, called \underline{s}calable \underline{c}omposite \underline{op}timization for l\underline{e}arning~({SCOPE}), and implement it on the fault-tolerant distributed platform \mbox{Spark}. SCOPE is both computation-efficient and communication-efficient. Theoretical analysis shows that SCOPE is convergent with linear convergence rate when the objective function is convex. Furthermore, empirical results on real datasets show that SCOPE can outperform other state-of-the-art distributed learning methods on Spark, including both batch learning methods and DSO methods

An expectation-maximization algorithm for probabilistic reconstructions of full-length isoforms from splice graphs.

Reconstructing full-length transcript isoforms from sequence fragments (such as ESTs) is a major interest and challenge for bioinformatic analysis of pre-mRNA alternative splicing. This problem has been formulated as finding traversals across the splice graph, which is a directed acyclic graph (DAG) representation of gene structure and alternative splicing. In this manuscript we introduce a probabilistic formulation of the isoform reconstruction problem, and provide an expectation-maximization (EM) algorithm for its maximum likelihood solution. Using a series of simulated data and expressed sequences from real human genes, we demonstrate that our EM algorithm can correctly handle various situations of fragmentation and coupling in the input data. Our work establishes a general probabilistic framework for splice graph-based reconstructions of full-length isoforms

Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β.

Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation

Multi-objective Tool Sequence Optimization in 2.5D Pocket CNC Milling for Minimizing Energy Consumption and Machining Cost

Tool sequence selection is an important task for 2.5D pocket milling and has a significant influence on both the energy consumption and machining cost of the final product. In this paper, the influence of tool sequence on energy consumption is firstly analyzed. Then a multi-objective tool sequence optimization model is proposed with the objective of minimizing energy consumption and machining cost and solved by the graph algorithm. Finally, a case study is carried out to validate the proposed model and search for the trade-off solutions between energy consumption and machining cost

Controlled Morphological Structure of Ceria Nanoparticles Prepared by Spray Pyrolysis

AbstractCeria based materials have been widely used as catalyst supporters and electrolytes. Different applications require different morphologies, and the microstructural control during the synthesis is crucial. In the study, ceria particles were prepared from various precursors using a spray pyrolysis (SP). Comparing to the hollow and porous particles, the formation mechanism with solid spherical structure is not clarified readily. The ceria particles were characterized by transmission electron microscopy, thermogravimetry analysis and X-ray photoelectron spectroscopy. This experimental result suggests that the morphology is controlled by the precursors and could be related to their decomposed behavior during the heating process in SP