1-Indanone retards cyst development in ADPKD mouse model by stabilizing tubulin and down-regulating anterograde transport of cilia.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. Cyst development in ADPKD involves abnormal epithelial cell proliferation, which is affected by the primary cilia-mediated signal transduction in the epithelial cells. Thus, primary cilium has been considered as a therapeutic target for ADPKD. Since ADPKD exhibits many pathological features similar to solid tumors, we investigated whether targeting primary cilia using anti-tumor agents could alleviate the development of ADPKD. Twenty-four natural compounds with anti-tumor activity were screened in MDCK cyst model, and 1-Indanone displayed notable inhibition on renal cyst growth without cytotoxicity. This compound also inhibited cyst development in embryonic kidney cyst model. In neonatal kidney-specific Pkd1 knockout mice, 1-Indanone remarkably slowed down kidney enlargement and cyst expansion. Furthermore, we demonstrated that 1-Indanone inhibited the abnormal elongation of cystic epithelial cilia by promoting tubulin polymerization and significantly down-regulating expression of anterograde transport motor protein KIF3A and IFT88. Moreover, we found that 1-Indanone significantly down-regulated ciliary coordinated Wnt/ß-catenin, Hedgehog signaling pathways. These results demonstrate that 1-Indanone inhibits cystic cell proliferation by reducing abnormally prolonged cilia length in cystic epithelial cells, suggesting that 1-Indanone may hold therapeutic potential to retard cyst development in ADPKD.

Description of Limnobaculum eriocheiris sp. nov., an intestinal bacterium of Eriocheir sinensis, and reclassification of the genera Jinshanibacter and Insectihabitans as Limnobaculum.

A Gram-stain-negative, aerobic, non-motile and rod-shaped strain, designated LJY008T, was isolated from the intestinal of Eriocheir sinensis in Pukou base of Jiangsu Institute of Freshwater Fisheries. Strain LJY008T could grow at 4-37 â„ƒ (optimum, 30 â„ƒ), pH 6.0-8.0 (optimum, pH 7.0), and with 1.0-6.0% NaCl (w/v; optimum, 1.0%). Strain LJY008T shared highest 16S rRNA gene sequence similarity with Jinshanibacter zhutongyuii CF-458T (99.3%), followed by J. allomyrinae BWR-B9T (99.2%), Insectihabitans xujianqingii CF-1111T (97.3%), and Limnobaculum parvum HYN0051T (96.7%). The major polar lipids include phosphatidylethanolamine, phosphatidylglycerol, and diphosphatidylglycerol. The only respiratory quinone was Q8, and the main fatty acids (> 10%) were C16:0, summed feature 3 (C16:1ω7c/C16:1ω6c), summed feature 8 (C18:1ω7c), and C14:0. The genome-based phylogenies showed that strain LJY008T was closely associated with members of the genus Jinshanibacter, Insectihabitans, and Limnobaculum. The average nucleotide identities and average amino acid identities (AAI) among strain LJY008T and closely related neighbours were all below 95%, and the digital DNA-DNA hybridization values among them were all below 36%. The genomic DNA G + C content of strain LJY008T was 46.1%. Based on the phenotypic, phylogenetic, biochemical and chemotaxonomic analysis, strain LJY008T represents a novel species of the genus Limnobaculum, for which the name Limnobaculum eriocheiris sp. nov. is proposed. The type strain is LJY008T (= JCM 34675T = GDMCC 1.2436T = MCCC 1K06016T). In addition, the genera Jinshanibacter and Insectihabitans were reclassified as Limnobaculum, because there was no significant genome-scale divergence or diagnosable difference on phenotypic and chemotaxonomic traits, such as strains of Jinshanibacter and Insectihabitans sharing AAI values of 93.88-94.96%.

Color curved hologram calculation method based on angle multiplexing.

In this paper, a method of color curved hologram calculation based on angle multiplexing is proposed. The relationship between the wavelength, center angle and sampling interval of the curved holograms is analyzed for the first time by analyzing the reconstruction process of the curved holograms with different wavelengths. Based on this relationship, the color curved holograms are calculated by compensating phase to the complex amplitude distribution of the planar holograms. To eliminate the chromatic aberration, the curved holograms of different objects with the same color channel are respectively used for angle multiplexing and phase compensation, and then the color composed curved hologram is generated. Different color objects without chromatic aberration can be reconstructed by bending the composed curved hologram into different central angles. The experimental results verify the feasibility of the proposed method. Besides, the application of the proposed method in augmented reality display is also shown.

Real scene acquisition and holographic near-eye display system based on a zoom industrial endoscope.

In this paper, we propose a real scene acquisition and holographic near-eye display system based on a zoom industrial endoscope. By controlling the driving current of the liquid lens, the working distance and focal length of the zoom industrial endoscope can be tuned accordingly. Thus, the object at different depths can be captured. Then, the sub-sampling algorithm is used to generate the hologram. By adjusting the hologram sampling rate of the objects with different depths, the holographic near-eye 3D display can be realized. Experimental results demonstrate that the working distance of the zoom industrial endoscope can be tuned from 20 mm to 200 mm with the driving current changing from 80 mA to 190 mA. With the proposed system, the human eye can intuitively see the depth relationships among the real objects. The proposed system is expected to be applied to 3D display and industrial inspection fields.

Holographic near-eye display system with large viewing area based on liquid crystal axicon.

In this paper, a liquid crystal axicon based holographic near-eye display system with large viewing area is proposed. The viewing area of the system is extended by implementing the liquid crystal axicon. The error diffusion algorithm is used to calculate the computer-generated hologram (CGH). When incident on the liquid crystal axicon placed at the back focal plane of Fourier lens, the reconstruction light modulated by the CGH is deflected into two directions resulting in a viewing area extension. Meanwhile, to illustrate the potential of the proposed system, two-dimensional viewing area extension is demonstrated. It combines the frequency spectrum shift with the proposed system and achieves a double expansion of the horizontal viewing area and three-times expansion of the vertical viewing area. Feasibility of the proposed system is verified by optical experiments. The proposed system has potential applications in holographic augmented reality (AR) display.

Revisiting the Mg/TMSCl/Dipolar Solvent System for Dearomatic Silylation of Aryl Carbonyl Compounds: Substrate Scope, Transformations, and Mechanistic Studies.

Dearomatic silylation of arene derivatives is an intriguing synthetic target, which represents an elegant extension of Birch reduction and produces silylated cyclohexene derivatives with great potential of further transformation. Herein, we report a systematic study on dearomatic silylation of aryl carbonyl compounds with Mg and the TMSCl/NMP adduct. The protocol displays a wide range of substrate scope, including alkyl aryl ketones, aromatic amides, benzonitriles, tert-butyl benzoates, and even 2,2'-bipyridines. Synthetic utility is demonstrated using the products as versatile substrate in various transformations. The detailed mechanism is presented with both control experimental analyses and theoretical calculations. An unusual five-coordinated silicon dianion intermediate is first proposed and described here. The selectivity is influenced by the relative rates of single electron reductions (the TMSCl/NMP adduct versus the substrate) and the steric effects.

Discovery of cinnamamide-barbiturate hybrids as a novel class of Nrf2 activator against myocardial ischemia/reperfusion injury.

Myocardial ischemia/reperfusion (MI/R) has been a challenge for global public health. Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling could attenuate MI/R injury by maintaining cell redox balance and reducing oxidative damage. Cinnamamide derivatives have been proven to be a class of potential Nrf2 activators and cardioprotective agents. The development of novel cinnamamide derivatives to combat oxidative stress in cardiomyocytes is highly desirable. In this study, twenty-three cinnamamide-barbiturate hybrids were studied. Cell-based assays showed that most of the compounds exhibited excellent protective activity against H2O2-induced oxidative injury in H9c2 cells. Notably, compound 7w, which had the highest activity and low cytotoxicity, was demonstrated to remarkably reduce intracellular ROS accumulation by activating the mRNA expression of Nrf2 and its downstream antioxidant gene HO-1, indicating a novel promising antioxidant and Nrf2 activator. The probable binding mode between protein Keap1 and compound 7w was also studied via molecule docking. Furthermore, we found that the administration of compound 7w could significantly reduce the cardiac infarct size and improve the cardiac function against MI/R injury in rats, as well as decrease cardiac oxidative stress. Taken together, we report, for the first time, that cinnamamide-barbiturate hybrids are a novel class of potential cardioprotective agents. The excellent cardioprotective action of such compounds rely on enhancing the endogenous antioxidative system by upregulating the Nrf2 signaling pathway in vitro and in vivo against MI/R damage. These findings provide a new perspective for designing cinnamamide-barbiturate hybrids as a novel class of Nrf2 activator against cardiovascular diseases.

Multi-depth hologram generation using stochastic gradient descent algorithm with complex loss function.

The stochastic gradient descent (SGD) method is useful in the phase-only hologram optimization process and can achieve a high-quality holographic display. However, for the current SGD solution in multi-depth hologram generation, the optimization time increases dramatically as the number of depth layers of object increases, leading to the SGD method nearly impractical in hologram generation of the complicated three-dimensional object. In this paper, the proposed method uses a complex loss function instead of an amplitude-only loss function in the SGD optimization process. This substitution ensures that the total loss function can be obtained through only one calculation, and the optimization time can be reduced hugely. Moreover, since both the amplitude and phase parts of the object are optimized, the proposed method can obtain a relatively accurate complex amplitude distribution. The defocus blur effect is therefore matched with the result from the complex amplitude reconstruction. Numerical simulations and optical experiments have validated the effectiveness of the proposed method.

Altered spontaneous brain activity in essential tremor with and without resting tremor: a resting-state fMRI study.

OBJECTIVES: Essential tremor with resting tremor (rET) often exhibits severer clinical features and more extensive functional impairment than essential tremor without resting tremor (ETwr). However, the pathophysiology of rET is still unclear. This study aims to use resting-state functional magnetic resonance imaging (rs-fMRI) to explore the alterations of brain activity between the drug-naïve patients of rET and ETwr. METHODS: We recruited 19 patients with rET, 31 patients with ETwr and 25 healthy controls (HCs) to undergo a 3.0-T rs-fMRI examination. The differences of regional brain spontaneous activity between the rET, ETwr and HCs, as well as between total ET (rET + ETwr) and HCs were measured by amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF). The relationships between the altered brain measurements and the clinical scores were analyzed. RESULTS: Compared with HCs, both ET subgroups showed significantly decreased ALFF or fALFF values in the basal ganglia, inferior orbitofrontal gyrus and insula. The rET group specifically showed decreased ALFF values in the hippocampus and motor cortices, while the ETwr group specifically evidenced increased ALFF and fALFF values in the cerebellum. DISCUSSION: Regional spontaneous activity in rET and ETwr share common changes and have differences, which may suggest that the functional activities in the limbic system and cerebellum are different between the two subtypes. Improved insights into rET and ETwr subtypes and the different brain spontaneous activity will be valuable for improving our understanding of the pathophysiology of the disease.

Fast hologram generation method based on the optimal segmentation of a sub-CGH.

In this paper, a fast hologram generation method is proposed based on the optimal segmentation of a sub-computer-generated-hologram (sub-CGH). The relationship between the pixels on the hologram and the corresponding reconstructed image is calculated firstly. Secondly, the sub-CGH corresponding to the object point from the recorded object is optimized and divided into the optimized diffraction area and the invalid diffraction area. Then, the optimized diffraction area of the sub-CGH for each object point is pre-calculated and saved. Finally, the final hologram can be generated by superimposing all the sub-CGHs. With the proposed method, the calculation time for the final hologram can be significantly reduced and the quality of the reconstructed image is not affected. Moreover, the proposed method has the advantages of perspective enlargement compared with the traditional method, and the experiment results verify its feasibility.

Method of curved composite hologram generation with suppressed speckle noise.

In this paper, a curved composite hologram (CCH) generation method with suppressed speckle noise is proposed. The recorded 3D object is considered as many layers with different depths and the planar hologram (PH) for each layer is generated accordingly. Then the PH is transformed to curved hologram (CH). The CH of the recorded 3D object can be generated by superposing the CHs for all the layers. Also, the linear phase factor is superposed to the CH of the object. For different objects, the bending angle and linear phase factor of the hologram are different. The CCH is generated by superimposing the CHs of different objects. Finally, the CCH is encoded by using the error diffusion method and optimized by superposing of the digital lens. When the CCH is reproduced from different angles, the reconstructed images with suppressed speckle noise can be displayed. The experimental results verify the feasibility of the proposed method.

Cryptochrome-mediated hypocotyl phototropism was regulated antagonistically by gibberellic acid and sucrose in Arabidopsis.

Both phototropins (phot1 and phot2) and cryptochromes (cry1 and cry2) were proven as the Arabidopsis thaliana blue light receptors. Phototropins predominately function in photomovement, and cryptochromes play a role in photomorphogenesis. Although cryptochromes have been proposed to serve as positive modulators of phototropic responses, the underlying mechanism remains unknown. Here, we report that depleting sucrose from the medium or adding gibberellic acids (GAs) can partially restore the defects in phototropic curvature of the phot1 phot2 double mutants under high-intensity blue light; this restoration does not occur in phot1 phot2 cry1 cry2 quadruple mutants and nph3 (nonphototropic hypocotyl 3) mutants which were impaired phototropic response in sucrose-containing medium. These results indicate that GAs and sucrose antagonistically regulate hypocotyl phototropism in a cryptochromes dependent manner, but it showed a crosstalk with phototropin signaling on NPH3. Furthermore, cryptochromes activation by blue light inhibit GAs synthesis, thus stabilizing DELLAs to block hypocotyl growth, which result in the higher GAs content in the shade side than the lit side of hypocotyl to support the asymmetric growth of hypocotyl. Through modulation of the abundance of DELLAs by sucrose depletion or added GAs, it revealed that cryptochromes have a function in mediating phototropic curvature.

[Analysis of outcomes of randomized controlled trial on compound Chinese herbal medicine formulas in treatment of vascular cognitive impairment caused by cerebral small vessel].

The purpose of the study is to analyze the outcomes of randomized controlled trial(RCT) of Chinese herbal medicine formula(CHMF) in the treatment of vascular cognitive impairment caused by cerebral small vessel disease(CSVD-VCI), and provide suggestions for future studies in this field. Three English databases, four Chinese databases, and two online registration websites of clinical trials were searched with use of the search strategy established in advance. Relevant RCTs published in recent ten years were screened, and necessary information was extracted to assess the risk of bias and analyze the outcomes of these RCTs. As a result, a total of 10 461 articles were retrieved, of which 8 681 were kept after de-duplication, and 41 RCTs were included after screening, with a generally higher risk of bias. The outcomes of included RCTs were classified into 9 categories, namely, clinical symptom outcomes, neuroimaging outcomes, neuroelectrophysiological outcomes, blood biochemical outcomes, hemorheology outcomes, physical signs, syndrome scores of traditional Chinese medicine(TCM), clinical effective rate, and safety outcomes. Among them, the most frequently reported outcomes of included RCTs were blood biochemical outcomes, and clinical symptom outcomes showed the highest reporting rate. Besides, 9 RCTs reported syndrome scores of TCM as the outcomes and illustrated corresponding evaluation criteria. The analysis showed that the application of RCT outcomes in this field had clinical rationality and limitations, and there were also some deficiencies in the trial design level, namely, no distinction between primary and secondary outcomes, insufficient blind methods, not detailed description of outcomes, disunity of evaluation tools, and despised endpoint outcomes. These limitations and deficiencies were negatively affecting the quality of RCTs of CHMF in the treatment of CSVD-VCI. Therefore, we suggest that future researchers should be well prepared in the top-level design stage, and actively construct the core outcome set of this field, so as to improve the quality of clinical trials.

Holographic display method to suppress speckle noise based on effective utilization of two spatial light modulators.

In this paper, a holographic display method to suppress the speckle noise is proposed. Firstly, the effective viewing area (EVA) of the reconstructed image is calculated. The object points are separated into groups by pixel separation. Then, the sub-computer-generated holograms (sub-CGHs) which can be reconstructed in the EVA are generated by calculating the principal fringe patterns. Finally, by loading the sub-CGHs on the two spatial light modulators respectively and using spatiotemporal multiplexing method, the reconstructed image can be displayed with lower speckle noise. Moreover, the calculation speed of the hologram is improved. Experimental results demonstrate the feasibility of the proposed method.

Upregulation of CBP by PLY can cause permeability of blood-brain barrier to increase meningitis.

BACKGROUND: Streptococcus pneumoniae causes many human diseases including bacterial meningitis. Previous study proposed that pneumolysin (PLY), a cytotoxin from pneumococcus, is related to the infection across blood-brain barrier (BBB). However, the mechanism of how PLY break through BBB remains elusive. The present study showed that PLY can increase the permeability of BBB both in vitro and in vivo in our experiments. RESULTS: Further we found out that PLY leads to the high expression of CERB-binding protein (CBP) which can lead to releasing of tumor necrosis factor α then enhance apoptosis of cells which is a significant factor leading to permeabilization of BBB. CONCLUSION: Our findings demonstrate that CBP plays an important role in the pneumococcus infection in the brain and could be a potential therapeutic target against pneumococcal meningitis.

Rational Design of Alginate Lyase from Microbulbifer sp. Q7 to Improve Thermal Stability.

Alginate lyase degrades alginate by the ß-elimination mechanism to produce oligosaccharides with special bioactivities. The low thermal stability of alginate lyase limits its industrial application. In this study, introducing the disulfide bonds while using the rational design methodology enhanced the thermal stability of alginate lyase cAlyM from Microbulbifer sp. Q7. Enzyme catalytic sites, secondary structure, spatial configuration, and molecular dynamic simulation were comprehensively analyzed. When compared with cAlyM, the mutants D102C-A300C and G103C-T113C showed an increase by 2.25 and 1.16 h, respectively, in half-life time at 45 °C, in addition to increases by 1.7 °C and 0.4 °C in the melting temperature, respectively. The enzyme-specific activity and kcat/Km values of D102C-A300C were 1.8- and 1.5-times higher than those of cAlyM, respectively. The rational design strategy that was used in this study provides a valuable method for improving the thermal stability of the alginate lyase.

Cardiac Ablation of SOCS3 Aggravates DOCA-Salt-Induced Hypertrophic Remodeling by Activation of Gp130-Dependent Signaling in Mice.

BACKGROUND/AIMS: Cardiac remodeling is a critical pathogenetic process leading to heart failure. Suppressor of cytokine signaling-3 (SOCS3) is demonstrated as a key negative regulator of the gp130 receptor to inhibit cardiac hypertrophy. However, the role of SOCS3 in deoxycorticosterone-acetate (DOCA)-salt-induced cardiac remodeling remains unclear. METHODS: Cardiac-specific SOCS3 knockout (SOCS3cKO) and wild-type (WT) C57BL/6J mice were subjected to uninephrectomy and DOCA-salt for 3 weeks. The effect of SOCS3 on cardiac remodeling and inflammation was evaluated by histological analysis. Gene and protein levels were measured by real-time PCR and immunoblotting analysis. RESULTS: After DOCA-salt treatment, the expression of SOCS3, activation of gp130/JAK/STAT3, cardiac dysfunction and fibrosis in DOCA-salt mice were significantly elevated, which were markedly attenuated by eplerenone, a specific mineralocorticoid receptor (MR) blocker. Moreover, DOCA-salt-induced cardiac dysfunction, hypertrophy, fibrosis and inflammation were aggravated in SOCS3cKO mice, but were significantly reduced in AAV9-SOCS3-injected mice. These effects were mostly associated with activation of gp130/STAT3/AKT/ERK1/2, TGF-ß/Smad2/3 and NF-κB signaling pathways. CONCLUSIONS: Our data demonstrate that loss of SOCS3 in cardiomyocytes promotes DOCA-salt-induced cardiac remodeling and inflammation, and it may be a novel potential therapeutic target for hypertensive heart disease.

Knockout of immunoproteasome subunit ß2i ameliorates cardiac fibrosis and inflammation in DOCA/Salt hypertensive mice.

The immunoproteasome is a multicatalytic protease complex in all eukaryotic cells, which plays a key role in regulating essential cellular processes. However, the role of immunoproteasome subunit ß2i in regulation of cardiac fibrosis and inflammation in deoxycorticosterone-acetate (DOCA)/salt mice remains unknown. Wild-type (WT) and ß2i knockout (KO) mice were subjected to uninephrectomy and DOCA/salt treatment for 21 days. Blood pressure was measured by the tail-cuff system. Cardiac function and remodeling were examined by echocardiography, hematoxylin-eosin (H&E) and Masson's trichrome staining. The gene and protein expressions were detected by quantitative real-time PCR, and Western blot analysis. After 21 days, DOCA/salt treatment significantly up-regulated the expression of ß2i mRNA and protein in the hearts. Moreover, systolic blood pressure and heart weight/body weight (HW/BW) ratio were significantly higher in DOCA/salt mice than in sham groups, and these effects were markedly reversed in ß2i knockout mice. Importantly, DOCA/salt-induced cardiac fibrosis, inflammation and the expression of collagen I, collagen III, α-SMA, IL-1ß, IL-6 and TNF-α in the wild-type hearts, which were markedly attenuated by ß2i knockout. These beneficial effects were due, at least in part, to the inhibition of IκBα/NF-κB and TGF-ß1/Smad2/3 signaling pathways. Collectively, these findings indicate that knockout of ß2i ameliorates DOCA/salt-induced cardiac fibrosis and inflammation, and may be a novel potential therapeutic target for hypertensive heart diseases.

Genetic analysis of FGF20 in Chinese patients with Parkinson's disease.

Sequence variants in fibroblast growth factor 20 (FGF20) have been reported to be associated with Parkinson's disease (PD). We genotyped the rs591323 variant in a total of 2220 Han Chinese subjects, including 1051 patients with sporadic PD and 1169 controls, to investigate the association between rs591323 and the risk of PD. In addition, we also conducted a stratified analysis according to age at onset of PD and compared the clinical characteristics of AA + AG subjects with GG subjects. In this study, we confirmed that the A allele of rs591323 in FGF20 reduces the risk of developing sporadic PD (P = 0.013). Additionally, subjects with the AA + AG genotype have a reduced risk compared to individuals with the GG genotype (P = 0.024). This association was significant among females (P = 0.036), but was not significant among males (P = 0.266). Furthermore, no significant association was observed among either the early-onset PD group (P = 0.051) or the late-onset PD group (P = 0.187). Moreover, we demonstrated that the AA + AG subjects could not be distinguished from the GG subjects based on their clinical features. Our study is the first to demonstrate that FGF20 (rs591323) is associated with a lower risk of PD in a Southern Han Chinese population from mainland China.

Genetic association study between RIT2 and Parkinson's disease in a Han Chinese population.

Recent several meta-analyses and certain case-control studies suggested that the Ras-like without CAAX 2 (RIT2) rs12456492 increased the risk of Parkinson's disease (PD) in Asian and Caucasian populations. However, as so far, the association between RIT2 rs12456492 and PD is still controversial. We investigated genetic association of RIT2 rs12456492 with PD susceptibility in a Han Chinese population of 1747 ethnic Han Chinese subjects comprising 884 PD patients and 863 healthy controls. The minor allele frequency (MAF) of G at the RIT2 rs12456492 was not significantly different between the cases and the controls. Furthermore, no significant differences were observed in genotype distribution between PD patients and healthy controls for the RIT2 rs12456492, even after being stratified by age at onset and gender. In addition, we found that no significant differences were detected in the clinical manifestations for gender, age at onset, and onset symptoms between PD patients with AG + GG genotypes and those with AA genotypes. Our study from the mainland China demonstrates that RIT2 rs12456492 do not increase the risk of developing PD. Therefore, more replication studies in additional Chinese population and other cohorts are warranted to further clarify the role of RIT2 rs12456492 in PD susceptibility.