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Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer’s disease. Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases, including Parkinson’s and Huntington’s diseases, however, the effect of Citri Reticulatae Semen on Alzheimer’s disease remains unelucidated. In the current study, the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated. Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy. In addition, Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro, and suppress amyloid-beta-induced pathology such as paralysis, in a transgenic Caenorhabditis elegans in vivo model. Moreover, genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent. Most importantly, Citri Reticulatae Semen extract was confirmed to improve cognitive impairment, neuronal injury and amyloid-beta burden in 3×Tg Alzheimer’s disease mice. As revealed by both in vitro and in vivo models, these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer’s disease via its neuroprotective autophagic effects.

BackgroundPrevious research has indicated a vital association between hypertension, intraocular pressure (IOP), and diabetic retinopathy (DR); however, the relationship has not been elucidated. In this study, we aim to investigate the causal association of hypertension, IOP, and DR.MethodsThe genome-wide association study (GWAS) IDs for DR, hypertension, and IOP were identified from the Integrative Epidemiology Unit (IEU) Open GWAS database. There were 33,519,037 single-nucleotide polymorphisms (SNPs) and a sample size of 1,030,836 for DR. There were 16,380,466 SNPs and 218,754 participants in the hypertension experiment. There were 9,851,867 SNPs and a sample size of 97,465 for IOP. Univariable, multivariable, and bidirectional Mendelian randomization (MR) studies were conducted to estimate the risk of hypertension and IOP in DR. Moreover, causality was examined using the inverse variance weighted method, and MR results were verified by numerous sensitivity analyses.ResultsA total of 62 SNPs at the genome-wide significance level were selected as instrumental variables (IVs) for hypertension-DR. The results of univariable MR analysis suggested a causal relationship between hypertension and DR and regarded hypertension as a risk factor for DR [p = 0.006, odds ratio (OR) = 1.080]. A total of 95 SNPs at the genome-wide significance level were selected as IVs for IOP-DR. Similarly, IOP was causally associated with DR and was a risk factor for DR (p = 0.029, OR = 1.090). The results of reverse MR analysis showed that DR was a risk factor for hypertension (p = 1.27×10-10, OR = 1.119), but there was no causal relationship between DR and IOP (p > 0.05). The results of multivariate MR analysis revealed that hypertension and IOP were risk factors for DR, which exhibited higher risk scores (p = 0.001, OR = 1.121 and p = 0.030, OR = 1.124, respectively) than those in univariable MR analysis. Therefore, hypertension remained a risk factor for DR after excluding the interference of IOP, and IOP was still a risk factor for DR after excluding the interference of hypertension.ConclusionThis study validated the potential causal relationship between hypertension, IOP, and DR using MR analysis, providing a reference for the targeted prevention of DR.

Background: Disease progression during neoadjuvant systemic therapy for breast cancer indicates poor prognosis, while predictors of the clinical outcomes of these patients remain unclear. By comparing the clinical outcomes of patients with different patterns of salvage treatment strategies, we try to evaluate the factors predicting distant failure and explore the favourable treatment for them. Methods: Patients with disease progression during neoadjuvant systemic therapy for stage I–III breast cancer diagnosed between January 1, 2008 and July 31, 2021 in Fudan University Shanghai Cancer Center were enrolled. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions or the appearance of new breast or nodal lesions. Kaplan-Meier, univariate and multivariate Cox proportional hazard regressions were utilized to compare survival outcomes between different salvage treatment strategies. Results: Among 3775 patients treated with NST, 60 (1.6%) patients encountered disease progression. A significant difference between the outcomes of patients receiving direct surgery and other salvage modalities was found (p = 0.007). Triple-negative breast cancer (p = 0.010) and not receiving direct surgery (p = 0.016) were independently associated with distant disease-free survival on multivariate analysis. Conclusions: Predictors of distant failure in patients with disease progression include triple-negative breast cancer and not receiving direct surgery. Direct surgery seems to be more favourable than other treatments for patients with disease progression. For inoperable patients, neoadjuvant radiation can increase their operability but not improve their prognosis.

Blood retinal barrier (BRB) damage is an important pathogenesis of diabetic retinopathy, and alleviating BRB damage has become a key target for DR treatment. We previously found that Lycopene seed polyphenols (LSP) maintained BRB integrity by inhibiting NLRP3 inflammasome-mediated inflammation. However, it is still unknown whether LSP inhibits retinal neovascularization with abnormal capillaries and its mechanism of action. Here, we employed db/db mice and hRECs to find that LSP increases the level of glycolipid metabolism, maintains the morphology of retinal endothelial cells and inhibits acellular capillary neogenesis. Mechanistic studies revealed that LSP inhibits the NLRP3 inflammasome, reduces cell apoptosis in retinal tissue, increases tight junction protein (TJ) expression, and reduces vascular endothelial growth factor (VEGF) and Ve-Cadherin in vivo and in vitro. Collectively, this study finds that LSP inhibits inflammation and angiogenesis to improve BRB function to ameliorate DR.

Purpose: We aim to analyze the clinical and genetic features in a Chinese family with congenital retinoschisis by whole-exome sequencing and comprehensive clinical examination.Methods: Six members were recruited from a Chinese family. Three of them were diagnosed as congenital retinoschisis, including two twin siblings. All subjects received a full eye examination. Whole-exome sequencing (WES) and Sanger sequencing were performed on two twin probands and all participants, respectively.Results: A novel splice site mutation RS1.c.53-1G>A was identified in a Chinese congenital retinoschisis family. The mean onset age was 16.7 ± 2.4 years old. The average BCVA in patients was 0.37 ± 0.05. A typical spoke-wheel pattern was observed in all affected eyes. OCT examination results showed fovea schisis and schisis cavities were located in the inner nuclear layer in 100% eyes (6/6). ERG b/a ratio was decreased markedly, but was still more than 1 in the four eyes that were available.Conclusion: The present study discovered a new pathogenic splice cite variant of RS1 in congenital retinoschisis, which expands the mutational spectrum. In contrast to previous research, the phenotype of patients with the same mutation within one family was highly similar. Early molecular testing is crucial for early diagnosis, clinical management, and genetic counseling of patients with congenital retinoschisis.

Ubiquitination-mediated protein degradation plays important roles in ABA signal transduction and delivering responses to chloroplast stress signals in plants, but additional E3 ligases of protein ubiquitination remain to be identified to understand the complex signaling network. Here we reported that ZEITLUPE (ZTL), an F-box protein, negatively regulates abscisic acid (ABA) signaling during ABA-inhibited early seedling growth and ABA-induced stomatal closure in Arabidopsis thaliana. Using molecular biology and biochemistry approaches, we demonstrated that ZTL interacts with and ubiquitinates its substrate, CHLH/ABAR (Mg-chelatase H subunit/putative ABA receptor), to modulate CHLH stability via the 26S proteasome pathway. CHLH acts genetically downstream of ZTL in ABA and drought stress signaling. Interestingly, ABA conversely induces ZTL phosphorylation, and high levels of ABA also induce CHLH proteasomal degradation, implying that phosphorylated ZTL protein may enhance the affinity to CHLH, leading to the increased degradation of CHLH after ABA treatment. Taken together, our results revealed a possible mechanism of reciprocal regulation between ABA signaling and the circadian clock, which is thought to be essential for plant fitness and survival.

In this study, 0.6Ag3PO4/CoWO4 composites were synthesized by hydrothermal method. The prepared materials were systematically characterized by techniques of scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray diffractometer (XRD), X-ray photoelectron spectroscopy (XPS), N2 adsorption/desorption, and UV–vis diffuse reflectance spectrum (DRS). Furthermore, the sonocatalytic degradation performance of 0.6Ag3PO4/CoWO4 composites towards tetracycline (TC) was investigated under ultrasonic radiation. The results showed that, combined with potassium persulfate (K2S2O8), the 0.6Ag3PO4/CoWO4 composites achieved a high sonocatalytic degradation efficiency of 97.89 % within 10 min, which was much better than bare Ag3PO4 or CoWO4. By measuring the electrochemical properties, it was proposed that the degradation mechanism of 0.6Ag3PO4/CoWO4 is the formation of S-scheme heterojunction, which increases the separation efficiency of electron-hole pairs (e--h+) and generates more electrons and holes, thereby enhancing the degradation activity. The scavenger experiments confirmed that hole (h+) was the primary active substance in degrading TC, and free radicals (·OH) and superoxide anion radical (·O2–) were auxiliary active substances. The results indicated that 0.6Ag3PO4/CoWO4 nanocomposites could be used as an efficient and reliable sonocatalyst for wastewater treatment.

Abstract This study describes a sequence of microbialites and volcanics of the Lower Cretaceous Shipu Group, an example of microbialites influenced by volcanic activity. It is located at Shipu town in eastern Zhejiang Province on the coast of southeastern China. Based on macroscopic outcrop observations, microscopic examination of thin sections, electron probe microanalysis (EPMA), field emission scanning electron microscopy (FESEM) imaging analysis, and energy dispersive X-ray spectrometry (EDS) analysis, nine microbialite–tuffite assemblages have been recognized in the section. Their thickness increased gradually upwards as volcanism decreased. There are ooids, bioclastic grains, intraclasts and tuffaceous grains in the grain shoal with local dolomitization. Above the grain shoal, microbial reefs develop either individually or conjoining with adjacent ones, and consist of stromatolites and serpulid tubes with common recrystallization. Tubes of serpulids are calcified and the tube wall is micrite. The tube and intertube parts are filled by sparry calcite. Colonial serpulids are surrounded by microbes to form stromatolites. Black layers of stromatolites contain many calcite crystals with fan-shaped growth pattern and preserved organic matter. Microbes are so well preserved in crystal lattices that the original microstructure of the microbes can be clearly observed by FESEM imaging analysis. Microbial reefs develop at a local high point near or above fair-weather wave-base where waves removed fine volcanic ashes. Interreef deposits are coarse tuffite due to physical differentiation. Volcanic activity could provide rich nutrition for microbes, but too much fine volcanic ash inhibits microbial growth. As a result, a moderate supply of volcanic ash favors the development of microbialites.

Abstract Background Mesenchymal stem cells (MSCs) are a population of pluripotent cells that might be used for treatment of liver disease. However, the efficacy of MSCs for mice with alcoholic hepatitis (AH) and its underlying mechanism remains unclear. Methods MSCs were isolated from the bone marrow (BM) of 4–6-week-old male C57BL/6 N mice. AH was induced in female mice by chronic-binge ethanol feeding for 10 days. The mice were given intraperitoneal injections of MSCs with or without transfection or AG490, recombinant mouse tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rmTSG-6), or saline at day 10. Blood samples and hepatic tissues were collected at day 11. Various assays such as biochemistry, histology, and flow cytometry were performed. Results MSCs reduced AH in mice, decreasing liver/body weight ratio, liver injury, blood and hepatic lipids, malondialdehyde, interleukin (IL)-6, and TNF-ɑ, but increasing glutathione, IL-10, and TSG-6, compared to control mice. Few MSCs engrafted into the inflamed liver. Knockdown of TSG-6 in MSCs significantly attenuated their effects, and injection of rmTSG-6 achieved similar effects to MSCs. The signal transducer and activator of transcription 3 (STAT3) was activated in mice with AH, and MSCs and rmTSG-6 inhibited the STAT3 activation. Injection of MSCs plus AG490 obtained more alleviation of liver injury than MSCs alone. Conclusions BM-MSCs injected into mice with AH do not engraft the liver, but they secrete TSG-6 to reduce liver injury and to inhibit STAT3 activation.

Objectives: Ventricular septal rupture (VSR) is a rare but lethal complication of acute myocardial infarction (AMI). We conducted a retrospective analysis of the clinical characteristics of VSR patients and explored the risk factors for long-term mortality.Methods: In this single-center cohort study, 127 patients diagnosed with post-AMI VSR between May 2012 and April 2019 were included. Demographic, clinical, operative, and outcome data were collected. The 30-day and long-term mortality were outcomes of interest. Cox proportional hazard regression analysis was used to explore the predictors of long-term mortality.Results: The mean age of the VSR cohort was 66.6 ± 8.7 years, 67 (52.8%) were males. Among the 127 patients, 78 patients (61.4%) were medically managed, 31 (24.4%) patients underwent percutaneous transcatheter closure (TCC), and 18 (14.2%) patients received surgical repair. The median follow-up time was 1129 days [interquartile range: 802–2019 days]. The 30-day mortality of the medically managed group, percutaneous TCC group, and surgical management group was 93.6, 22.6, and 11.1%, respectively; and the long-term mortality was 96.2, 25.8, and 22.2%, respectively. VSR repair treatment including surgical management (HR 0.01, 95% CI 0.001–0.09, p < 0.001) and percutaneous TCC (HR 0.09, 95% CI 0.03–0.26, p < 0.001) was associated with a better prognosis, and cardiogenic shock (CS) (HR 9.30, 95% CI 3.38–25.62, p < 0.001) was an independent risk factor of long-term mortality.Conclusions: The prognosis of VSR patients without operative management remains poor, especially in those complicated with CS. Timely and improved surgery treatment is needed for better outcomes in VSR patients.

Plant polysaccharides (PPS) composed of more than 10 monosaccharides show high safety and various pharmacological activities, including immunoregulatory, antitumor, antioxidative, antiaging, and other effects. In recent years, emerging evidence has indicated that many PPS are beneficial for metabolic diseases, such as cardiovascular disease (CVD), diabetes, obesity, and neurological diseases, which are usually caused by the metabolic disorder of fat, sugar, and protein. In this review, we introduce the common characteristics and functional activity of many representative PPS, emphasize the common risks and molecular mechanism of metabolic diseases, and discuss the pharmacological activity and mechanism of action of representative PPS obtained from plants including Aloe vera, Angelica sinensis, pumpkin, Lycium barbarum, Ginseng, Schisandra chinensis, Dioscorea pposite, Poria cocos, and tea in metabolic diseases. Finally, this review will provide directions and a reference for future research and for the development of PPS into potential drugs for the treatment of metabolic diseases.

The underlying mechanism of electroacupuncture (EA) in relieving obesity, anti-inflammation and the interaction with metabolic pathways in obese mice has not been elaborated. The aim of this study was to investigate the regulation of EA on macrophage polarization in obesity tissue of diet-induced obesity mice. Mice were divided in 6 groups: normal control group, model group, EA-7 group, EA-14 group, EA-21 group and EA-28 group. Low-frequency EA was applied at “Tianshu (ST 25)”, “Guanyuan (CV 4)”, “Zusanli (ST 36)” and “Sanyinjiao (SP 6)” for 10 min. Adipose tissue was assessed with hematoxylin and eosin staining. Adipocytokines and pro-inflammatory factors expression was measured by ELISA. The protein and mRNA levels of macrophage markers were examined by immumohistochemical staining and RT-PCR, respectively. EA treatment was associated with a decrease of adipose tissue and large adipocytes, and an increase of small adipocytes. After EA treatment, the levels of Leptin, Chemerin, TNF-α, F4/80, iNOS, and CD11c decreased obviously in adipose tissue, while IL-4, IL-10 and CD206 levels increased significantly. Besides, TNF-α in spleen tissue was also downregulated, but IL-4 and IL-10 were upregulated. EA prevents weight gain through modulation inflammatory response and macrophage polarization in obese adipose tissues.

PurposeThe aim of this study was to probe the global profile of the EYS-associated genotype-phenotype trait in the worldwide reported IRD cases and to build a model for predicting disease progression as a reference for clinical consultation.MethodsThis retrospective study of 420 well-documented IRD cases with mutations in the EYS gene included 39 patients from a genotype-phenotype study of inherited retinal dystrophy (IRD) conducted at the Beijing Institute of Ophthalmology and 381 cases retrieved from global reports. All patients underwent ophthalmic evaluation. Mutations were revealed using next-generation sequencing, followed by Sanger DNA sequencing and real-time quantitative PCR analysis. Multiple regression models and statistical analysis were used to assess the genotype and phenotype characteristics and traits in this large cohort.ResultsA total of 420 well-defined patients with 841 identified mutations in the EYS gene were successfully obtained. The most common pathogenic variant was a frameshift c.4957dupA (p.S1653Kfs∗2) in exon 26, with an allele frequency of 12.7% (107/841), followed by c.8805C > A (p.Y2935X) in exon 43, with an allele frequency of 5.9% (50/841). Two new hot spots were identified in the Chinese cohort, c.1750G > T (p.E584X) and c.7492G > C (p.A2498P). Several EYS mutation types were identified, with CNV being relatively common. The mean age of onset was 20.54 ± 11.33 (4–46) years. Clinical examinations revealed a typical progression of RPE atrophy from the peripheral area to the macula.ConclusionThis large global cohort of 420 IRD cases, with 262 distinct variants, identified genotype-phenotype correlations and mutation spectra with hotspots in the EYS gene.

In proton radiography, degeneracy of electric and magnetic fields in deflecting the probe protons can prevent full interpretation of proton flux perturbations in the detection plane. In this paper, theoretical analyses and numerical simulations suggest that the contributions of the electric and magnetic fields can be separately obtained by analyzing the difference between the flux distributions of two discriminated proton energies in a single shot of proton radiography. To eliminate the influence of field evolution on the separation, a strategy is proposed in which slow field evolution is assumed or an approximate estimate of field growth is made. This could help achieve a clearer understanding of the radiographic process and allow further quantitative analysis.

Abstract Background Nelson Bay orthoreovirus (NBV) was first isolated over 40 years ago from a fruit bat in Australia. Normally, NBV does not cause human diseases, but recently several NBV strains have been associated with human respiratory tract infections, thus attracting clinical attention. Autophagy, an evolutionarily conserved process in eukaryotic cells, degrades intracellular substrates, participates in multiple physiological processes, and maintains cellular homeostasis. In addition, autophagy is intimately involved in viral infection. Methods A new strain of NBV, isolated from a patient with a respiratory tract infection who returned to Japan from Bali, Indonesia, in 2007, was used in this study. NBV was rescued using a reverse genetics system involving cotransfection of BHK cells with 11 plasmids (pT7-L1 MB, pT7-L2 MB, pT7-L3 MB, pT7-M1 MB, pT7-M2 MB, pT7-M3 MB, pT7-S1 MB, pT7-S2 MB, pT7-S3 MB, pT7-S4 MB, and pcDNA3.1-T7), yielding NBV-MB. Recovered viruses were confirmed by immunofluorescence. The effect of NBV-MB on autophagy was evaluated by measuring the LC3-I/II proteins by immunoblot analysis after infection of BHK cells. Furthermore, after treatment with rapamycin (RAPA), 3-methyladenine (3-MA), chloroquine (CQ), or plasmid (GFP-LC3) transfection, the changes in expression of the LC3 gene and the amount of LC3-I/II protein were examined. In addition, variations in viral titer were assayed after treatment of BHK cells with drugs or after transfection with plasmids pCAGM3 and pCAGS3, which encode virus nonstructural proteins μNS and σNS, respectively. Results NBV-MB infection induced autophagy in host cells; however, the level of induction was dependent on viral replication. Induction of autophagy increased viral replication. By contrast, inhibiting autophagy suppressed NBV replication, albeit not significantly. The NBV-MB nonstructural protein μNS was involved in the induction of autophagy with viral infection. Conclusions NBV-MB infection triggered autophagy. Also, the NBV nonstructural protein μNS may contribute to augmentation of autophagy upon viral infection.

Abstract To improve the design speed and reduce the design cost for the previous blade design method, a modified inverse design method is presented. In the new method, after a series of physical and mathematical simplifications, a sail-like constrained area is proposed, which can be used to configure different runner blade shapes. Then, the new method is applied to redesign and optimize the runner blade of the scale core component of the 1400-MW canned nuclear coolant pump in an established multi-optimization system compromising the Computational Fluid Dynamics (CFD) analysis, the Response Surface Methodology (RSM) and the Non-dominated Sorting Genetic Algorithm-II (NSGA-II). After the execution of the optimization procedure, three optimal samples were ultimately obtained. Then, through comparative analysis using the target runner blade, it was found that the maximum efficiency improvement reached 1.6%, while the head improvement was about 10%. Overall, a promising runner blade inverse design method which will benefit the hydraulic design of the mixed-flow pump has been proposed.

Purpose: Congenital nystagmus (CN) is a genetically and clinically heterogeneous ocular disorder that manifests as involuntary, periodic oscillations of the eyes. To date, only FRMD7 and GPR143 have been reported to be responsible for causing CN. Here, we aimed to identify the disease-causing mutations and describe the clinical features in the affected members in our study.Methods: All the subjects underwent a detailed ophthalmic examination. Direct sequencing of all coding exons and splice site regions in FRMD7 and GPR143 and a mutation assessment were performed in each patient.Results: We found 14 mutations in 14/37 (37.8%) probands, including nine mutations in the FRMD7 gene and five mutations in the GPR143 gene, seven of which are novel, including c.284G>A(R95K), c.964C>T(P322S), c.284+10T>G, c.901T>C (Y301H), and c.2014_2023delTCACCCATGG(S672Pfs*12) in FRMD7, and c.250+1G>C, and c.485G>A (W162*) in GPR143. The mutation detection rate was 87.5% (7/8) of familial vs. 24.1% (7/29) of sporadic cases. Ten mutations in 24 (41.7%) non-syndromic subjects and 4 mutations in 13(30.8%) syndromic subjects were detected. A total of 77.8% (7/9) of mutations in FRMD7 were concentrated within the FERM and FA domains, while all mutations in GPR143 were located in exons 1, 2, 4 and 6. We observed that visual acuity tended to be worse in the GPR143 group than in the FRMD7 group, and no obvious difference in other clinical manifestations was found through comparisons in different groups of patients.Conclusions: This study identified 14 mutations (seven novel and seven known) in eight familial and 29 sporadic patients with congenital nystagmus, expanding the mutational spectrum and validating FRMD7 and GPR143 as mutation hotspots. These findings also revealed a significant difference in the screening rate between different groups of participants, providing new insights for the strategy of genetic screening and early clinical diagnosis of CN.

Background: Pulmonary stenosis is common in children with complex congenital heart diseases. Proper management of this problem, especially postoperatively, is still controversial. This study was designed to assess the rate and determinants of success or failure of balloon angioplasty for such lesions. Methods: Clinical and hemodynamic data from 40 pediatric patients (24 boys and 16 girls) with complex congenital heart diseases who underwent balloon angioplasty were reviewed retrospectively from January 2012 to December 2016. Patients were divided into four groups according to the site of stenosis, which included pulmonary valve stenosis (PVS), valved conduit stenosis, pulmonary artery stenosis (PAS), and supravalvular pulmonary stenosis (SVPS). Success rates were calculated according to defined criteria for initial success and favorable clinical impacts, and comparison between the successful subgroup and the unsuccessful subgroups was analyzed. Results: Grouped by the site of stenosis, initial success rates varied from 40.0% to 52.4% with the greatest success being seen in the PVS group, followed by the PAS group and SVPS group. In the PVS group and the PAS group, there was no statistical difference among age at dilation, postoperative interval, balloon/stenosis ratio, or pressure gradient predilation between the successful and the unsuccessful subgroups. Favorable clinical impacts included success rates of balloon angioplasty in the SVPS group, which was best (100%), followed by the PVS group (90.9%) and the PAS group (85.7%). There were a total of two transient complications (5.0%). Conclusions: Balloon angioplasty was proven to be a safe and useful modality in children with complex congenital heart diseases and postoperative pulmonary stenosis, which should be the initial therapeutic modality in selected patients.

Background: Restrictive cardiomyopathy (RCM) is the least common cardiomyopathy in which the walls are rigid and the heart is restricted from stretching and filling properly. Cardiac troponin I (cTnI) mutation-caused myofibril Ca2+ hypersensitivity has been shown to be associated with impaired diastolic function. This study aimed to investigate the linkage between the genotype and clinical therapy of RCM. Methods: Five sporadic pediatric RCM patients confirmed by echocardiography were enrolled in this study. Whole-exome sequencing (WES) was performed for the cohort to find out candidate causative gene variants. Sanger sequencing confirmed the WES-identified variants. Results: TNNI3 variants were found in all of the five patients. R192H mutation was shared in four patients while R204H mutation was found only in one patient. Structure investigation showed that the C terminus of TNNI3 was flexible and mutation on the C terminus was possible to cause the RCM. Catechins were prescribed for the five patients once genotype was confirmed. Ventricular diastolic function was improved in three patients during the follow-up. Conclusions: Our data demonstrated that TNNI3 mutation-induced RCM1 is the most common type of pediatric RCM in this study. In addition, WES is a reliable approach to identify likely pathogenic genes of RCM and might be useful for the guidance of clinical treatment scheme.

The sheath electric field is localized with a thickness of only several Debye lengths. It widely exists at plasma boundaries and in some cases can be very intense. Previous diagnoses of an intense, localized sheath electric field could only deliver the spatially averaged amplitude of the field. The sheath’s spatial structures remain unresolved. In this paper, we numerically demonstrate the three-dimensional reconstruction of a cylindrically symmetric sheath electric field by means of the Abel inversion in combination with a correction of the spatial dislocation in the inversion process. By employing a divergent or/and relativistic proton beam for radiography of the sheath region, it is found that the crossings of the proton trajectories can be prevented and the linearity requirement for the Abel inversion can be satisfied. A sheath electric field with an amplitude of about 1×1011 V/m and a thickness of sub-μm level is well reconstructed with a 120 MeV proton beam. The inter dependences of the reconstruction on the proton beam energy, energy spread, beam divergence, and the amplitude of the sheath are discussed.

Mutations in LRRK2 are linked to Parkinson’s Disease. Here, the authors identify WSB1 as a LRRK2 interacting protein and find that it promotes LRRK2 aggregation in primary neurons and drosophila models via ubiquitin K27 and K29 linkages.

The unsteady phenomenon abounds in centrifugal compressors and significantly affects the compressor performance. In this paper, unsteady simulations are carried out to investigate the aerodynamic performance of a process-unshrouded centrifugal compressor and the unsteady mechanism in the vaned diffuser. The predicted stage performance and pressure fluctuations at some locations are in good agreement with experimental data. The predicted main pressure fluctuation frequency spectrums at the diffuser inlet and outlet are consistent with the measured results. The results indicate that at the inlet of the diffuser there are two pressure peaks in a passage cycle. The higher pressure peak relates to the impeller wake and the lower peak is connected with the vortex generated at the diffuser’s leading edge. With a decrease in the mass flow coefficient, the vortex core region becomes larger and the lower pressure peak becomes more pronounced. The change in circumferential flow angle at the diffuser inlet is mainly responsible for the unsteadiness in the diffuser flow field, which in turn affects the inlet incidence of the diffuser vane and the vane loading distributions.

Background:. Patent ductus arteriosus (PDA) is one of the most common congenital heart diseases and began to get treated by transcatheter occlusion since 1997 in China. Since then, several devices have been invented for occluding PDA. This study aimed to evaluate the technical feasibility, safety, and efficacy of transcatheter occlusion of PDA with different devices. Methods:. One thousand five hundred and twenty-six patients (537 boys, 989 girls) with PDA from January 1997 to September 2014 underwent descending aortogram and transcatheter occlusion procedure. We retrospectively analyzed data of these patients, including gender, age, weight, size and morphology of PDA, and devices used in transcatheter occlusion, outcomes, and postoperational complications. Results:. Median age and median weight were 4.0 years (range: 0.3-52.0 years old) and 15.3 kg (range: 4.5-91.0 kg), respectively. Mean ductal diameter, aortic ductal diameter, ductal length, and pulmonary artery pressure were 3.50 ± 2.15 mm, 10.08 ± 2.46 mm, 7.49 ± 3.02 mm, and 30.21 ± 17.28 mmHg, respectively. Morphology of PDA assessed by descending aortogram was of type A in 1428 patients, type B in 6 patients, type C in 79 patients, type D in 4 patients, and type E in 9 patients according to the classification of Krichenko. Of all the 1526 patients, 1497 patients underwent transcatheter PDA closure, among which 1492 were successful. Devices used were Amplatzer duct occluder I (ADO I, 1280, 85.8%), Cook detachable coils (116, 7.8%), ADO II (ADO II, 68, 4.6%), muscular VSD occluder (12, 0.8%), and Amplatzer vascular plug (16, 1.0%). Conclusions:. Excellent occlusion rates with low complication rates were achieved with all devices regardless of PDA types. With transcatheter occlusion technique and devices developing, more patients with PDA can be treated with transcatheter closure both safely and efficiently.

Background: Hand-foot-mouth disease (HFMD) is a widespread communicable disease and has caused large epidemics in many countries. This meta-analysis aimed to analyze and evaluate the epidemiological features of HFMD outbreaks in Chinese preschools. Methods: Literature review was based on PubMed, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases from 2008 to 2015. The temporal, spatial and demographic parameters were summarized and analyzed. Results: Overall, 19 studies with a total of 11269 HFMD cases were selected for data synthesis and analysis. April, May, June and July were detected as the peak months of HFMD outbreaks, with the pooled rate of 21% (95% CI: 12%-34%), 23% (95% CI: 19%-27%), 20% (95% CI: 17%-24%) and 11% (95% CI: 7%-15%). Urban areas were at a higher risk of suffering from HFMD outbreaks than rural areas, with the pooled rate of 65% (95% CI: 48%-78%) and 35% (95% CI: 22%-52%) respectively. The constituent ratio of children aged 37-48 months is the highest, accounting for 46% (95% CI: 39%-53%) of the total cases during HFMD outbreaks. The pooled rate of male cases (60%) was higher than that of female cases (40%). Conclusion: Month, residence, age, and gender may be early risk factors for potential HFMD outbreaks. Before the advent of peak months from Apr to Jul each year, measures should be taken to prevent the HFMD outbreaks among preschool children in China. Preschools located in urban areas should take priority over special prevention. HFMD surveillance should preferentially focus on children aged 37-48 months, especially boys in preschools.

Background:. Transcatheter occlusion has been applied to treat ostium secundum atrial septal defect (OS ASD) since 1997. During the clinical practice, several postoperative complications including arrhythmia have been reported. This study aimed to evaluate the value of the ratio of atrial septal occluder (ASO) versus atrial septal length (ASL) for predicting arrhythmia occurrence after transcatheter closure in children with OS ASD. Methods:. Six hundred and fifty-one children diagnosed with OS ASD underwent occlusion procedures after completing routine examinations. The onsets and types of arrhythmia both during and after the occlusion procedures were monitored. Treatments were given based on the individual types of arrhythmia. The binary logistic regression analysis and receiver-operating characteristic (ROC) curve were used in the analysis of value of the ratio of ASO/ASL for predicting postoperative arrhythmia occurrence. Results:. Transcather occlusions were conducted in 651 children, among whom 7 children had different types and degrees of arrhythmia, with an incidence of 1.1%. The types of arrhythmia included sinus bradycardia, atrial premature beats, bundle branch block, and different degrees of atrioventricular block. Normal electrocardiograph findings were resumed in these 7 patients following active therapies such as corticoids, nutrition, and surgeries. The binary logistic regression and ROC analysis suggested that the ratio of ASO/ASL exhibited an intermediate predictive value for predicting arrhythmia occurrence after occlusion procedures. A cut-off value of 0.576 in the ratio provided a sensitivity of 87.5% and a specificity of 76.2% with an area under the ROC curve of 0.791 (95% confidence intervals, 0.655-0.926; P < 0.05) in predicting arrhythmia occurrence after the closure procedures. Conclusions:. The ratio of ASO/ASL might be a useful index for predicting arrhythmia occurrence after closure procedures in children with OS ASD.

Epidemiological studies have demonstrated that women with a history of preeclampsia have a two-fold increased risk of developing cardiovascular diseases in later life. It is not known whether or not this risk is associated with angiotensin II receptor type 1 autoantibody (AT1-AA), an agonist acting via activation of AT1 receptor (AT1R), which is believed to be involved in the pathogenesis of preeclampsia. The objective of the present study was to confirm the hypothesis that AT1-AA exposure during pregnancy may change the maternal cardiac structure and increase the susceptibility of the postpartum heart to ischemia/reperfusion injury (IRI). In the present study, we first established a preeclampsia rat model by intravenous injection of AT1-AA extracted from the plasma of rats immunized with AT1R, observed the susceptibility of the postpartum maternal heart to IRI at 16 weeks postpartum using the Langendorff preparation, and examined the cardiac structure using light and transmission electron microscopy. The modeled animals presented with symptoms very similar to the clinical symptoms of human preeclampsia during pregnancy, including hypertension and proteinuria. The left ventricular weight (LVW) and left ventricular mass index (LVMI) in AT1-AA treatment group were significantly increased as compared with those of the control group (p < 0.01), although there was no significant difference in final weight between the two groups. AT1-AA acting on AT1R not only induced myocardial cell hypertrophy, mitochondrial swelling, cristae disorganization and collagen accumulation in the interstitium but affected the left ventricular (LV) function and delayed recovery from IRI. In contrast, co-treatment with AT1-AA + losartan completely blocked AT1-AA-induced changes in cardiac structure and function. These data indicate that the presence of AT1-AA during pregnancy was strongly associated with the markers of LV geometry changes and remodeling, and increased the cardiac susceptibility to IRI in later life of postpartum maternal rats.

ABSTRACT Bacterial communities associated with plant roots play an important role in the suppression of soil-borne pathogens, and multispecies probiotic consortia may enhance disease suppression efficacy. Here we introduced defined Pseudomonas species consortia into naturally complex microbial communities and measured the importance of Pseudomonas community diversity for their survival and the suppression of the bacterial plant pathogen Ralstonia solanacearum in the tomato rhizosphere microbiome. The survival of introduced Pseudomonas consortia increased with increasing diversity. Further, high Pseudomonas diversity reduced pathogen density in the rhizosphere and decreased the disease incidence due to both intensified resource competition and interference with the pathogen. These results provide novel mechanistic insights into elevated pathogen suppression by diverse probiotic consortia in naturally diverse plant rhizospheres. Ecologically based community assembly rules could thus play a key role in engineering functionally reliable microbiome applications. IMPORTANCE The increasing demand for food supply requires more-efficient control of plant diseases. The use of probiotics, i.e., naturally occurring bacterial antagonists and competitors that suppress pathogens, has recently reemerged as a promising alternative to agrochemical use. It is, however, still unclear how many and which strains we should choose for constructing effective probiotic consortia. Here we present a general ecological framework for assembling effective probiotic communities based on in vitro characterization of community functioning. Specifically, we show that increasing the diversity of probiotic consortia enhances community survival in the naturally diverse rhizosphere microbiome, leading to increased pathogen suppression via intensified resource competition and interference with the pathogen. We propose that these ecological guidelines can be put to the test in microbiome engineering more widely in the future.

A canned nuclear coolant pump is used in an advanced third-generation pressurized water reactor. Impeller is a key component of a canned nuclear coolant pump. Usually, the blade is installed between the hub and the shroud as an entire part. The blade is divided into two parts and is staggered in the circumferential direction is an approach of blade design. To understand the effects of staggered blades on a canned nuclear coolant pump, this article numerically investigated different types of staggering. The validity of the numerical simulation was confirmed by comparing the numerical and experimental results. The performance change of a canned nuclear coolant pump with staggered blades was acquired. Hydraulic performance curves, axial force curves, static pressure distributions at the impeller outlet, and static pressure pulsations were performed to investigate the performance changes caused by the staggered blades. The results show that the staggered blade has an important influence on the performance of canned nuclear coolant pumps. A staggered blade does not improve hydraulic performance but does improve the axial force and pressure pulsation. Specifically, the staggered blades can significantly reduce the pressure pulsation amplitude on the impeller pass frequency.

X-linked hyper-IgM syndrome (XHIGM) is one type of primary immunodeficiency diseases, resulting from defects in the CD40 ligand/CD40 signaling pathways. We retrospectively analyzed the clinical and molecular features of 20 Chinese patients diagnosed and followed up in hospitals affiliated to Shanghai Jiao Tong University School of Medicine from 1999 to 2013. The median onset age of these patients was 8.5 months (range: 20 days–21 months). Half of them had positive family histories, with a shorter diagnosis lag. The most common symptoms were recurrent sinopulmonary infections (18 patients, 90%), neutropenia (14 patients, 70%), oral ulcer (13 patients, 65%), and protracted diarrhea (13 patients, 65%). Six patients had BCGitis. Six patients received hematopoietic stem cell transplantations and four of them had immune reconstructions and clinical remissions. Eighteen unique mutations in CD40L gene were identified in these 20 patients from 19 unrelated families, with 12 novel mutations. We compared with reported mutation results and used bioinformatics software to predict the effects of mutations on the target protein. These mutations reflected the heterogeneity of CD40L gene and expanded our understanding of XHIGM.

Circumferential grooved liquid seals are utilized inside turbomachinery to provide noncontacting control of internal incompressible fluid leakage. Accurate prediction of the flow field is fundamental in producing robust and efficient designs. To validate the capabilities of the computational fluid dynamics FLUENT for incompressible fluid seal flow, comparisons of velocity parameters are made to the published experimental results and other CFD code for a circumferential grooved liquid seal. This work employs a pressure-based CFD code FLUENT to calculate the flow field in the seal, using four different turbulence models respectively. The velocity contours are compared with experimental values. It shows good overall agreement of the axial, radial, and azimuthal velocities in the through-flow jet, shear layer, and recirculation zone. Quantitative comparisons of velocity profiles at the center of the groove are made to experiment. This study verifies the prediction accuracy of three turbulence models. Various structures were considered to obtain a better understanding of the circumferential grooved liquid flow characteristics. The best groove structure to control leakage was also found within the limited designed seal. This study will provide a useful reference for designing the circumferential grooved liquid seal.

BACKGROUNDMany published data on the association between single nucleotide polymorphisms (SNPs) in the ESR1 gene and prostate cancer susceptibility are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis is to derive a more precise estimation of this relationship.METHODSA literature search of PubMed, Embase, Web of Science and Chinese Biomedical (CBM) databases was conducted from their inception through July 1st, 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of association.RESULTSTwelve case-control studies were included with a total 2,165 prostate cancer cases and 3,361 healthy controls. When all the eligible studies were pooled into the meta-analysis, ESR1 PvuII (C>T) and XbaI (A>G) polymorphisms showed no association with the risk of prostate cancer. However, in the stratified analyses based on ethnicity and country, the results indicated that ESR1 PvuII (C>T) polymorphism was significantly associated with increased risk of prostate cancer among Asian populations, especially among Indian population; while ESR1 XbaI (A>G) polymorphism may significantly increase the risk of prostate cancer among American population. Furthermore, we also performed a pooled analysis for all eligible case-control studies to explore the role of codon 10 (T>C), codon 325 (C>G), codon 594 (G>A) and +261G>C polymorphisms in prostate cancer risk. Nevertheless, no significant associations between these polymorphisms and the risk of prostate cancer were observed.CONCLUSIONResults from the current meta-analysis indicate that ESR1 PvuII (C>T) polymorphism may be a risk factor for prostate cancer among Asian populations, especially among Indian population; while ESR1 XbaI (A>G) polymorphism may increase the risk of prostate cancer among American population.

Helical groove seal is designed in reactor coolant pump to control the leakage along the front surface of the impeller face due to its higher resistance than the circumferentially grooved seal. The flow and the friction factors in helical groove seals are predicted by employing a commercial CFD code, FLUENT. The friction factors of the helical groove seals with helix angles varying from 20 deg to 50 deg, at a range of rotational speed and axial Reynolds number, were, respectively, calculated. For the helically grooved stator with the helix angle greater than 20 deg, the leakage shows an upward trend with the helix angle. The circumferentially grooved stator has a lower resistance to leakage than the 20 deg and 30 deg stators. It can be predicated that, for a bigger helix angle, the friction factor increases slightly with an increase in high axial Reynolds number, which arises from the high-pressure operation condition, and the friction factor is generally sensitive to changes in the helix angle in this operation condition. The study lays the theoretical foundation for liquid seal design of reactor coolant pump and future experimental study to account for the high-pressure condition affecting the leakage characteristic.

In the laser wakefield acceleration, the generation of electron beam is very sensitive to the plasma density. Not only the laser-wakefield interaction, but also the electron trapping and acceleration would be effected by the plasma density. However, the plasma density could be changed in the experiment by different reasons, which will result in the mismatch of parameters arranged initially. Forward Raman scattering spectrum demonstrated that the interaction density was decreased obviously in the experiment, which was verified by the pre-pulse conditions and two-dimensional particle-in-cell simulations. It was demonstrated that the plasma density was very important on the self-evolutions and energy coupling of laser pulse and wakefield, and eventually the energy spectrum of electron beam.

In the title compound, [Cu3(C8H4O4)2(C8H5O4)2(C18H10N4)2]n, one CuII atom, located on an inversion center, is hexacoordinated and shows a distorted octahedral coordination geometry, while the other CuII atom is pentacoordinated and exhibits a distorted square-pyramidal geometry. The CuII atoms are bridged by isophthalate and 3-carboxybenzoate ligands, forming a chain structure along the b axis. Furthermore, the chains are linked by O—H...O hydrogen bonds, forming a layer parallel to the ab plane.

The title compound, C34H25Cl3O3S2·0.5CH3OH, was synthesized by the reaction of thiophene-2-carbaldehyde with acetophenone and NaOH under solvent-free conditions, using tetrabutylammonium bromide as a phase-transfer catalyst. The central six-membered ring adopts a chair conformation with the bulky thiophene, 4-chlorophenyl and 4-chlorobenzoyl substituents in equatorial positions. The hydroxyl group is in an axial position and forms an intramolecular O—H...O hydrogen bond to the carbonyl group of an adjacent 4-chlorobenzoyl substituent. The methanol solvent molecules are disordered equally over two positions within one-dimensional channels, with site occupancy factors of 0.25.