The P2X3 receptor, a trimeric ionotropic purinergic receptor, has emerged as a potential therapeutic target for refractory chronic cough (RCC). Nevertheless, gefapixant/AF-219, the only marketed P2X3 ...receptor antagonist, might lead taste disorders by modulating the human P2X2/3 (hP2X2/3) heterotrimer. Hence, in RCC drug development, compounds exhibiting strong affinity for the hP2X3 homotrimer and a weak affinity for the hP2X2/3 heterotrimer hold promise. An example of such a molecule is sivopixant/S-600918, a clinical Phase II RCC candidate with a reduced incidence of taste disturbance compared to gefapixant. Sivopixant and its analogue, (3-(4-(3-chloro-4-isopropoxyphenylamino)-3-(4-methylbenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)propanoic acid (DDTPA), exhibit both high affinity and high selectivity for hP2X3 homotrimers, compared with hP2X2/3 heterotrimers. The mechanism underlying the druggable site and its high selectivity remains unclear.
To analyse mechanisms that distinguish this drug candidate from other inhibitors of the P2X3 receptors we used a combination of chimera construction, site covalent occupation, metadynamics, mutagenesis and whole-cell recording.
The high affinity and selectivity of sivopixant/DDTPA for hP2X3 receptors was determined by the tri-symmetric site located close to the upper vestibule. Substitution of only four amino acids inside the upper body domain of hP2X2 with those of hP2X3, enabled the hP2X2/3 heterotrimer to exhibit a similar level of apparent affinity for sivopixant/DDTPA as the hP2X3 homotrimer.
From the receptor-ligand recognition perspective, we have elucidated the molecular basis of novel RCC clinical candidates' cough-suppressing properties and reduced side effects, offering a promising approach to the discovery of novel drugs that specifically target P2X3 receptors.
Abstract
P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of ...refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.
Abstract BACKGROUND We retrospectively investigated incidence, morbidity, and mortality of neonatal necrotizing enterocolitis in China, with special emphasis on determining the predictors of ...necrotizing enterocolitisassociated mortality. METHODS We identified neonates as having necrotizing enterocolitis if they met the accepted diagnostic criterion. Data pertaining to antenatal period, labor and birth, and the postnatal course of illness were collected. Multivariate analysis and logistic regression were used to analyze the risk factors. RESULTS There were 1167 cases of necrotizing enterocolitis identified from the 95 participating NICUs in mainland China in 2011, with the incidence of 2.50% and 4.53% in LBW (birth weight <2500g) and VLBW (birth weight <1500g) infants, respectively. Stage 1, 2 and 3 diseases were noted in 51.1%, 30.3% and 18.6% of cases respectively. The mortality from stage 2 and 3 necrotizing enterocolitis in this cohort was 41.7%. In VLBW infants, the important risk factors for mortality were small for gestation age (OR: 5.02, 95%CI 1.73-14.6; P=0.003) and stage 3 NEC (OR: 8.09, 95%CI 2.80-23.3, P<0.001). In moderate LBW infants (birth weight 1500-2499g), the risk factors identified for mortality were sepsis during hospitalization (OR: 2.59, 95%CI 1.57-4.28, P<0.001) and stage 3 NEC (OR: 5.37, 95%CI 3.24-8.90; P<0.001). CONCLUSIONS Necrotizing enterocolitis remains an important cause of morbidity and mortality in prematurely born neonates in Chinese neonatal units. Awareness of the associated risk factors and appropriate
According to the survey of Bartolini et al,2 pediatric neurologists were more likely to repeat the first-line immunotherapy when compared with adult neurologists and pediatric rheumatologists. ...the ...commonest prescribed drugs were mycophenolate mofetil, and followed by azathioprine. In conjunction with two previous surveys, we suggest that the zones of the agreement to be used as a step toward the establishment of standardized treatment guidelines and research protocols should focus on clinical trials. Prof. Jing Peng, Department of Pediatrics, Xiangya Hospital, Central South University, Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan 410005, ChinaE-Mail: pengjing4346@163.com How to cite this article:
IIE, the interface between the Indian Summer Monsoon (ISM) and the East Asian Summer Monsoon (EASM), is defined using the equivalent potential temperature and summer long‐term mean reanalysis data ...provided by NOAA/OAR/ESRL PSD. The June–July–August reanalysis data for the period 1951–2008 and empirical orthogonal function analysis are further applied to obtain the IIE index at the near‐surface isobaric level. The index has a prominent interannual variation that is strongly correlated with the seesaw variation between the ISM and EASM. When a strong EASM and weak ISM occur, this interface index is higher than the normal, with the interface between the two summer monsoons shifting farther eastward than normal. When a weak EASM and strong ISM appear, the index is lower than normal, with the interface moving farther westward than normal. The western North Pacific subtropical high, a major factor in the EASM system, plays an important role in the year‐to‐year variation of the IIE. Compared with approaches taken in previous studies, this index objectively and quantitatively describes the IIE variation and better represents the two teleconnection patterns associated with the Asian summer monsoon, thus enhancing interpretations of the interaction between the ISM and EASM and its effects on regional droughts and floods in East Asia.
Key Points
The IIE is quantitatively identified
The index for IIE is built
The relationship between IIE, ISM and EASM is obtained
Biodiesel-derived glycerol is a promising substrate for mixotrophic cultivation of oleaginous microalgae, which can also reduce the cost of microalgal biodiesel. The objective of this study is to ...investigate the potential of using glycerol and glucose as a complex carbon substrate to produce microalgal biomass and biochemical components, such as photosynthetic pigments, lipids, soluble carbohydrates and proteins by Chlorella vulgaris. The results show that C. vulgaris can utilize glycerol as a sole carbon substrate, but its effect is inferior to that of the mixture of glycerol and glucose. The effect of glycerol and glucose could enhance the algal cell growth rate, biomass content and volumetric productivity, and overcome the lower biomass production on glycerol as the sole organic carbon source in mixotrophic culture medium. The utilization of complex organic carbon substrate can stimulate the biosynthesis of lipids and soluble carbohydrates as the raw materials for biodiesel and bioethanol production, and reduce the anabolism of photosynthetic pigments and proteins. This study provides a promising niche for reducing the overall cost of biodiesel and bioethanol production from microalgae as it investigates the by-products of algal biodiesel production and algal cell hydrolysis as possible raw materials (lipids and carbohydrates) and organic carbon substrates (soluble carbohydrates and glycerol) for mixotrophic cultivation of microalgae.
The hitherto unknown hexakis(halomethyl)-functionalized tribenzotriquinacenes (TBTQs) 9 and 10 were synthesized from the key 4b,8b,12b-tribromo-TBTQ derivative 6 by an improved route in 67% overall ...yield. Extension of the bowl-shaped framework of 9 or 10 by threefold condensation with propargylamine or 2-azidoethylamine afforded the corresponding TBTQ-trialkyne 11 and TBTQ-triazide 12, respectively. While attempts to construct bis-TBTQ cages, including homodimerization of 11 and heterocoupling of 11 with 12, were unsuccessful, triazide 12 was found to undergo threefold 3 + 2-cycloaddition with 3-ethynylaniline and phloroglucinol tripropargyl ether under click chemistry conditions. The latter reaction enabled facile capping of the TBTQ bowl to give the novel cage compound 5 in 22% yield.
In physically based-based animation, pure particle methods are popular due to their simple data structure, easy implementation, and convenient parallelization. As a pure particle-based method and ...using Galerkin discretization, the Moving Least Square Reproducing Kernel Method (MLSRK) was developed in engineering computation as a general numerical tool for solving PDEs. The basic idea of Moving Least Square (MLS) has also been used in computer graphics to estimate deformation gradient for deformable solids. Based on these previous studies, we propose a multiphase MLSRK framework that animates complex and coupled fluids and solids in a unified manner. Specifically, we use the Cauchy momentum equation and phase field model to uniformly capture the momentum balance and phase evolution/interaction in a multiphase system, and systematically formulate the MLSRK discretization to support general multiphase constitutive models. A series of animation examples are presented to demonstrate the performance of our new multiphase MLSRK framework, including hyperelastic, elastoplastic, viscous, fracturing and multiphase coupling behaviours etc.
Background: Escitalopram is one of the most commonly used SSRIs at present, which has the characteristics of quick onset, less interactions with other drugs, and relative safety. Objective: This ...study aims to investigate the effects of escitalopram on neural functional prognoses and endothelial dysfunction after acute ischemic stroke. Methods: One hundred eligible patients afflicted with acute ischemic stroke were randomized into two groups: control and treatment groups. Patients in the treatment group received escitalopram in addition to the basic therapies in the control group over a period of 90 days. Neurological deficits were quantified using the National Institutes of Health Stroke Scale (NIHSS) score and Barthel index (BI) score, cognitive impairment was determined using the Mini-Mental State Examination (MMSE) score, depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale (HAMD). Furthermore, post-stroke depression (PSD) was defined based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), with a HAMD score ≥17. Flow-mediated vascular dilatation (FMD) of the brachial artery was use as a surrogate indicator for endothelial dysfunction assessment with ultrasound. Results: The mean NIHSS and HAMD scores on day 90 after treatment were significantly lower in the treatment group than in the control group (2.17±0.36 vs. 4.24±0.85; 5.81±1.35 vs. 10.43±4.91; P < 0.01), while the mean BI score and FMD were significantly higher in the treatment group (93.08±6.23 vs. 79.64±7.56, P < 0.01; 8.71±2.35 vs. 5.83±1.21, P < 0.05) than in the control group. The improvement in MMSE score was not significantly different between the two groups. Conclusions: Treatment with escitalopram early after ischemic stroke can improve neural functional prognoses and endothelial dysfunction. Escitalopram had less side effects, which is worthy of clinical prophylactic application.
Two novel anthracene-triphenylamine emitters, TPA-tBuANT and TPA-PyrANT, were synthesized efficiently by the coupling reactions of anthracene and triphenylamine derivatives. They emit blue-green ...light in the diluted solutions, having emission peaks at 488 and 510 nm, and exhibit high photoluminescence fluorescence quantum efficiency (PLQY) of 53% and 80%, respectively. Their PLQY were 19% and 49% in solid states at 470 and 487 nm, respectively. Employing TPA-tBuANT as an emitter, the maximum external quantum efficiencies (EQEs) were up to 4.1% in the non-doped devices of organic light-emitting diodes (OLEDs) and 5.2% in the doped devices. The maximum EQEs of the devices based on TPA-PyrANT were 4.5% for non-doped devices and 5.6% for the doped devices. The devices all exhibit negligible efficiency roll-off.
TPA-tBuANT and TPA-PyrANT exhibit good luminous efficiency in both diluted solutions and solid states. Both non-doped and doped OLED devices show high EQEs and negligible efficiency roll-off. Display omitted
•TPA-tBuANT and TPA-PyrANT exhibit high luminous efficiency both in diluted solutions and solid states.•Both non-doped and doped OLED devices show high EQEs and negligible efficiency roll-off.•Two fluorophores were synthesized by coupling reactions of triphenylamine and anthracene derivatives with high yields.
PDF
