ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling

Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form

Whole-transcriptome sequencing identifies key differentially expressed circRNAs/lncRNAs/miRNAs/mRNAs and linked ceRNA networks in adult degenerative scoliosis

BackgroundAdult degenerative scoliosis (ADS) is forecast to be a prevalent disabling condition in an aging society. Universally, its pathogenesis is perceived as intervertebral disc degeneration (IDD), however, a thought-provoking issue is why precisely a subset of patients with disc degeneration develop ADS. Exploring the diversities between common IDD and ADS would contribute to unraveling the etiological mechanisms of ADS. Therefore, we aimed to integrate the circRNA, lncRNA, miRNA, and mRNA expression profiles from normal adults (Normal), patients with lumbar disc herniation (LDH), and ADS by whole transcriptome sequencing, which identifies critical functional ncRNA and ceRNA networks and crosstalk between the various transcripts.MethodsThe fresh whole blood samples (n = 3/group) were collected from ADS patients, LDH patients, and healthy volunteers (Normal group), which were examined for mRNA, miRNA, lncRNA, and circRNA expression and screened for differentially expressed (DE) ncRNAs. Then, Gene Ontology (GO) and KEGG analyses were performed for gene annotation and enrichment pathways on the DE RNAs, which were constructed as a lncRNA-miRNA-mRNA network. Eventually, DE RNAs were validated by qRT-PCR targeting disc nucleus pulposus (NP) tissue in ADS and LDH group (n = 10/group).ResultsCompared to the LDH group, we identified 3322 DE mRNAs, 221 DE lncRNAs, 20 DE miRNAs, and 15 DE circRNAs in the ADS. In contrast to Normal, 21 miRNAs and 19 circRNAs were differentially expressed in the ADS. The expression of multiple differentially expressed ncRNAs was confirmed by qRT-PCR analysis to be consistent with the sequencing results. In addition, GO, and KEGG analysis demonstrated that most DE mRNAs and ncRNAs target genes are involved in various biological processes, including Endocytosis, Apoptosis, Rap1 signaling pathway, Notch signaling pathway, and others. The constructed lncRNA-miRNA-mRNA co-expression network was primarily related to angiogenesis and regulation.ConclusionBy focusing on comparing asymmetric and symmetric disc degeneration, whole-transcriptome sequencing and bioinformatics analysis systematically screened for key ncRNAs in the development of ADS, which provided an abundance of valuable candidates for the elucidation of regulatory mechanisms. The DE ncRNAs and the lncRNA-miRNA-mRNA network are intrinsically involved in the regulation of mediator and angiogenesis, which may contribute to the insight into the pathogenesis of ADS

Exploring the electrochromic properties of poly(thieno[3,2-b]thiophene)s decorated with electron-deficient side groups

Two novel thieno[ 3,2-b] thiophene (TT)/3,4-ethylenedioxythiophene (EDOT)-based compounds of 2,5( EDOT-TT-EDOT) type bearing electron-withdrawing side groups (4-cyanophenyl or 4-pyridyl) at 3,6-positions of the TT moiety have been synthesized. Their electropolymerization leads to electroactive conjugated polymers, P(CNPh-ETTE) and P(Py-ETTE), which possess electrochromic properties changing the color from purple to pale grey-blue or from sand brown to pale grey-green, respectively. Cyclic voltammetry and spectroelectrochemical experiments reveal that functionalization with electron-withdrawing side groups decreases the HOMO and LUMO energy levels and contracts the band gap of materials. Both new polymers demonstrated extremely short response times of 0.9-1.1 s for bleaching and 0.34-0.35 s for coloring. P(CNPh-ETTE) and P(Py-ETTE) polymers showed reasonably good contrast (16-23%) and coloration efficiency (120-190 cm(2) C-1) in the visible region (at the maxima of their pi-pi* transitions, 540/570 nm), and high contrast and coloration efficiency in the near-infrared region (50-62% and 324-440 cm(2) C-1 at 1500 nm, respectively). While the stability of the pyridine-functionalized polymer, P(Py-ETTE), was shown to be low (with unstable charge-discharge characteristics, presumably due to the protonation of the pyridine ring during the redox process), P(CNPh-ETTE) demonstrated superior electrochromic performance retaining 91-96% of its electroactivity after 2000 cycles between -0.5 and +1.0 V. DFT calculations on these and related EDOT-TT-EDOT polymers reported by us early have been presented and analyzed to understand the structure-property relationships in this class of electrochromic polymers.Shenzhen Key Laboratory of Organic Optoelectromagnetic FunctionalMaterials of Shenzhen Science and Technology Plan [ZDSYS20140509094114164]; Shenzhen Peacock Program [KQTD2014062714543296]; Shenzhen Science and Technology Research Grant [JCYJ20140509093817690, JCYJ20160331095335232]; Nanshan Innovation Agency Grant [KC2015ZDYF0016A]; Guangdong Key Research Project [2014B090914003, 2015B090914002]; Guangdong Talents Project; National Basic Research Program of China (973 Program) [2015CB856505]; Natural Science Foundation of Guangdong Province [2014A030313800]; Guangdong Academician Workstation [2013B090400016]SCI(E)ARTICLE4769-784

Off-diagonal Bethe Ansatz for the D3(1)D^{(1)}_3 model

The exact solutions of the $D^{(1)}_3$ model (or the $so(6)$ quantum spin chain) with either periodic or general integrable open boundary conditions are obtained by using the off-diagonal Bethe Ansatz. From the fusion, the complete operator product identities are obtained, which are sufficient to enable us to determine spectrum of the system. Eigenvalues of the fused transfer matrices are constructed by the $T-Q$ relations for the periodic case and by the inhomogeneous $T-Q$ one for the non-diagonal boundary reflection case. The present method can be generalized to deal with the $D^{(1)}_{n}$ model directly.Comment: 28 pages, no figure, published version. arXiv admin note: text overlap with arXiv:1902.0889

Engineering Colloidal Lithography and Nanoskiving to Fabricate Rows of Opposing Crescent Nanogaps

A scalable fabrication route combining colloidal lithography and nanoskiving is reported for generating free-standing asymmetric metal nanostructures of crescent-shaped gold nanowires and rows of opposing crescents with and without nanogaps. Strong localized surface plasmon resonances and propagating surface plasmon polaritons are excited at the sharp tips of the crescent and in the sub-10 nm nanogaps. High-order resonance modes are excited due to the coupling between the resonances in the tips and gaps. The Raman signals are greatly enhanced due to the strong electric fields. In addition, the optical responses and electric field distributions can be controlled by the polarization of the incident light. The strong electric field enhancement coupled with facile, scalable fabrication make crescent-shaped nanostructures promising in nonlinear optics, optical trapping, and surface-enhanced spectroscopy

Mechanistic evaluation of the inhibitory effect of four SGLT-2 inhibitors on SGLT 1 and SGLT 2 using physiologically based pharmacokinetic (PBPK) modeling approaches

Sodium-glucose co-transporter type 2 (SGLT 2, gliflozins) inhibitors are potent orally active drugs approved for managing type 2 diabetes. SGLT 2 inhibitors exert a glucose-lowering effect by suppressing sodium-glucose co-transporters 1 and 2 in the intestinal and kidney proximal tubules. In this study, we developed a physiologically based pharmacokinetic (PBPK) model and simulated the concentrations of ertugliflozin, empagliflozin, henagliflozin, and sotagliflozin in target tissues. We used the perfusion-limited model to illustrate the disposition of SGLT 2 inhibitors in vivo. The modeling parameters were obtained from the references. Simulated steady-state plasma concentration-time curves of the ertugliflozin, empagliflozin, henagliflozin, and sotagliflozin are similar to the clinically observed curves. The 90% prediction interval of simulated excretion of drugs in urine captured the observed data well. Furthermore, all corresponding model-predicted pharmacokinetic parameters fell within a 2-fold prediction error. At the approved doses, we estimated the effective concentrations in intestinal and kidney proximal tubules and calculated the inhibition ratio of SGLT transporters to differentiate the relative inhibition capacities of SGLT1 and 2 in each gliflozin. According to simulation results, four SGLT 2 inhibitors can nearly completely inhibit SGLT 2 transporter at the approved dosages. Sotagliflozin exhibited the highest inhibition activity on SGLT1, followed by ertugliflozin, empagliflozin, and henagliflozin, which showed a lower SGLT 1 inhibitory effect. The PBPK model successfully simulates the specific target tissue concentration that cannot be measured directly and quantifies the relative contribution toward SGLT 1 and 2 for each gliflozin

Molecular engineering tuning optoelectronic properties of thieno[3,2-b]thiophenes-based electrochromic polymers

Thieno[3,2-b]thiophene (TT) monomers end-capped with 3,4-ethylenedioxythiophene (EDOT) moieties are electropolymerized to form pi-conjugated polymers with distinct electrochromic (EC) properties. Steric and electronic factors (electron donor and acceptor substituents) in the side groups of the TT core, as well as the structure of the polymer backbone strongly affect the electrochemical and optical properties of the polymers and their electrochromic characteristics. The studied polymers show low oxidation potentials, tunable from-0.78 to +0.30 V (vs. Fc/Fc(+)) and the band gaps from 1.46 to 1.92 eV and demonstrate wide variety of color palettes in polymer films in different states, finely tunable by structural variations in the polymer backbone and the side chains. EC materials of different colors in their doped/dedoped states have been developed (violet, deep blue, light blue, green, brown, purple-red, pinkish-red, orange-red, light gray, cyan and colorless transparent). High optical contrast (up to 79%), short response time (0.57-0.80 s), good cycling stability (up to 91% at 2000 cycles) and high coloration efficiency (up to 234.6 cm(2) C-1) have been demonstrated and the influence of different factors on the above parameters of EC polymers have been discussed.Shenzhen Key Laboratory of Organic Optoelectromagnetic Functional Materials of Shenzhen Science and Technology Plan [ZDSYS20140509094114164]; Shenzhen Peacock Program [KQTD2014062714543296]; Shenzhen Science and Technology Research Grant [JCYJ20140509093817690]; Nanshan Innovation Agency Grant [KC2015ZDYF0016A]; Guangdong Key Research Project [2014B090914003, 2015B090914002]; Guangdong Talents Project; National Basic Research Program of China [2015CB856505]; National Natural Science Foundation of China [51373075]; Guangdong Academician Workstation [2013B090400016]; Natural Science Foundation of Guangdong Province [2014A030313800]; Santander Universities Research Mobility AwardSCI(E)中国科学引文数据库(CSCD)ARTICLE163-766

Urinary dysfunction in patients with vascular cognitive impairment

Vascular cognitive impairment (VCI) is caused by vascular pathologies, with the spectrum of cognitive disorders ranging from subjective cognitive dysfunction to dementia. Particularly among older adults, cognitive impairment is often complicated with urinary dysfunction (UD); some patients may present with UD before cognitive impairment owing to stroke or even when there are white matter hyperintensities on imaging studies. Patients with cognitive impairment often have both language and movement dysfunction, and thus, UD in patients with VCI can often be underdiagnosed and remain untreated. UD has an impact on the quality of life of patients and caregivers, often leading to poor outcomes. Medical history is an important aspect and should be taken from both patients and their caregivers. Clinical assessment including urinalysis, voiding diary, scales on UD and cognitive impairment, post-void residual volume measurement, uroflowmetry, and (video-) urodynamics should be performed according to indication. Although studies on UD with VCI are few, most of them show that an overactive bladder (OAB) is the most common UD type, and urinary incontinence is the most common symptom. Normal urine storage and micturition in a specific environment are complex processes that require a sophisticated neural network. Although there are many studies on the brain–urinary circuit, the specific circuit involving VCI and UD remains unclear. Currently, there is no disease-modifying pharmacological treatment for cognitive impairment, and anti-acetylcholine drugs, which are commonly used to treat OAB, may cause cognitive impairment, leading to a vicious circle. Therefore, it is important to understand the complex interaction between UD and VCI and formulate individualized treatment plans. This review provides an overview of research advances in clinical features, imaging and pathological characteristics, and treatment options of UD in patients with VCI to increase subject awareness, facilitate research, and improve diagnosis and treatment rates