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A time-economical and robust synthesis of selenofunctionalized heterocycles by an I2O5-promoted selenylative heterocyclization of olefins with easily accessible diselenides is reported herein.

Purpose This study aimed to investigate the mechanistic downregulation of mucin 6 (MUC6) and its influence on the progression of gastric cancer (GC). Materials and methods The expression of MUC6 was examined in 40 GC patients. The methylation status of the MUC6 promoter region was investigated using GC cell lines and GC tissue specimens by immunohistochemistry and/or quantitative polymerase chain reaction (qPCR). MUC6 was knocked down in the gastric epithelial cells (GES-1) cell and overexpressed in the SGC7901 cell. The effects of MUC6 knockdown and overexpression on cell migration and invasion were examined using Transwell assays. The effects of demethylation and methylation on MUC6 expression were examined by western blot, qPCR, or double luciferase reporter assays. Results The expression of MUC6 in GC with lymph node metastasis and poor pathological stage was significantly lower than that in GC without lymph node metastasis and good pathological stage, respectively. While cell migration and invasion were significantly decreased after overexpression of MUC6, these abilities significantly increased after the knockdown of MUC6. The methylation levels of MUC6 in GC tissues and GC cell lines were significantly higher than those in para-cancerous tissues and normal GES. Promoter methylation could significantly reduce the binding of related transcription factors to the MUC6 promoter. The expression of MUC6 increased with the concentration and time of action of demethylation drugs. Conclusion Expression of MUC6 was regulated by promotor methylation. This methylation of the MUC6 promoter may lead to significant downregulation of MUC6 in GC and promote the progression of GC.

This paper presents an experimental study on the emergence of the central recirculation zone (CRZ) in a V-shaped premixed swirling flame, using simultaneous measurement of particle image velocimetry (PIV) and CH* chemiluminescence. The results show that either increasing the Reynolds number (Re) or decreasing the equivalence ratio ({\Phi}) would facilitate the emergence of CRZ. Further analysis demonstrates that the CRZ characteristics and its emergence are strongly influenced by the inner shear layer (ISL) surrounding the CRZ, while the swirl intensity remains unchanged. Dimensional analysis is performed to understand the underlying mechanism, suggesting the CRZ emergence is controlled by a non-dimensional parameter, Re_s=|{\gamma}|_max D/{\nu}_s, defined based on the maximum ISL intensity (|{\gamma}|_max), the exit diameter (D), and the kinematic viscosity ({\nu}_s) of the burnt gas. By estimating the temperature and viscosity with a simple heat-loss model, we show in the |{\gamma}|_max D-{\nu}_s regime diagram that the cases with and without CRZ are separated by a single boundary line, corresponding to a critical Re_s of about 424. This verifies the applicability of the proposed Re_s criterion to lean-premixed V-shaped swirling flames under various conditions. Unlike most previous works that attribute the CRZ of swirling flames to vortex breakdown, the present work reveals the non-negligible effect of the ISL, especially the CRZ suppression when the ISL is weakened by flame heating.

Air pollution is the leading environmental risk factor for ill health, estimated to account for 4.9 million deaths and 147 million years of healthy life lost in 2017. As people spend the majority of their time indoors, there has been great concerns about the ubiquitous exposure to indoor air pollution, particularly fine particulate matter (PM2.5). Accumulating evidence suggests that both short- and long-term exposure to PM2.5 are associated excess risks of cardiovascular disease (CVD) and mortality. The use of air purifiers to reduce indoor air pollution exposure is increasingly recommended in air quality control strategies, but the cardiovascular impact of such intervention remain to be investigated in randomized controlled trials (RCTs). Therefore, we aimed to conduct a systematic review and meta-analyses to synthesize the results of all randomized controlled trials assessing the cardiovascular effects of indoor air purification interventions.

Multiple factors such as genes, environment, and age are involved in developing Parkinson’s disease (PD) pathology. However, how various factors interact to cause PD remains unclear. Here, 3-month and 9-month-old hα-syn+⁣/− mice were treated with low-dose rotenone for 2 months to explore the mechanisms that underline the environment–gene–age interaction in the occurrence of PD. We have examined the behavior of mice and the PD-like pathologies of the brain and gut. The present results showed that impairments of the motor function and olfactory function were more serious in old hα-syn+/– mice with rotenone than that in young mice. The dopaminergic neuron loss in the SNc is more in old hα-syn+/– mice with rotenone than in young mice. Expression of hα-syn+/– is increased in the SNc of hα-syn+/– mice following rotenone treatment for 2 months. Furthermore, the number of activated microglia cells increased in SNc and accompanied the high expression of inflammatory cytokines, namely, TNF-α and IL-18 in the midbrain of old hα-syn+/– mice treated with rotenone. Meanwhile, we found that after treatment with rotenone, hα-syn positive particles deposited in the intestinal wall, intestinal microflora, and T lymphocyte subtypes of Peyer’s patches changed, and intestinal mucosal permeability increased. Moreover, these phenomena were age-dependent. These findings suggested that rotenone aggravated the PD-like pathologies and affected the brain and gut of human α-syn+/– transgenic mice in an age-dependent manner.

Selective laser melting (SLM) is an emerging layer-wise additive manufacturing technique that can generate complex components with high performance. Particulate-reinforced aluminum matrix composites (PAMCs) are important materials for various applications due to the combined properties of Al matrix and reinforcements. Considering the advantages of SLM technology and PAMCs, the novel SLM PAMCs have been developed and researched in recent years. Therefore, the current research progress about the SLM PAMCs is reviewed. Firstly, special attention is paid to the solidification behavior of SLM PAMCs. Secondly, the important issues about the design and fabrication of high-performance SLM PAMCs, including the selection of reinforcement, the influence of parameters on the processing and microstructure, the defect evolution and phase control, are highlighted and discussed comprehensively. Thirdly, the performance and strengthening mechanism of SLM PAMCs are systematically figured out. Finally, future directions are pointed out on the advancement of high-performance SLM PAMCs.

Stirling type pulse tube cryocoolers (SPTCs) usually require multi-stage configuration for working below liquid hydrogen temperatures but their cooling efficiency is still poor at present. One of the main reasons is that their high-temperature part regenerators consume large amount of input pV power as isothermal components with large temperature drop. Theoretically, when there is a surplus cold source such as LN2 or LNG for precooling, the high-temperature part regenerator can be replaced by an empty tube with little pV power drop, which will increase the efficiency of the SPTC while recovering cold energy. In this paper, the SPTC with a precooled transmission tube instead of high-temperature part regenerator is proposed and studied. The hot end of the transmission tube was linked to the room-temperature compressor at ~300 K, while its cold end was connecting to the low-temperature part regenerator precooled to ~ 80 K by LN2. The heat transfer and pV power losses in the precooled transmission tubes under different sizes were calculated and analyzed. Experiments were carried out to verify the feasibility of the precooled transmission tube in a SPTC. Results show that the SPTC can work well with the precooled transmission tube. A no-load refrigeration temperature of 17.7 K and cooling capacity of 1.74 W at 25 K are obtained with a total input pV power of about 52.9 W. The hot end heat exchanger of the precooled transmission tube is found to be necessary for quickly stabilizing the cold end cooling temperature.

Additional file 4: Fig. S4. Transcript accumulation measurements of colour-related genes involved in the flavonoid metabolic process. Note: BMJ, cultivar ‘Baihe’; FMJ, cultivar ‘Fenhe’; ZMJ, cultiv.

Additional file 3: Fig. S3. Transcription factor distribution between three R.pulchrum Sweet cultivars. Note: BMJ, cultivar ‘Baihe’; FMJ, cultivar ‘Fenhe’; ZMJ, cultivar ‘Zihe’. (a) Transcription factor distribution between cultivars ‘Baihe’ and ‘Fenhe’; (b) Transcription factor distribution between cultivars ‘Zihe’ and ‘Baihe’; (c) Transcription factor distribution between cultivars ‘Fenhe’ and ‘Zihe’.

Additional file 6: Table S2. The anthocyanin derivatives between three comparison groups of R.pulchrum Sweet.

Additional file 10: Table S6. The primers used for qRT-PCR analysis.

Additional file 7: Table S3. Transcriptome sequencing results from three R.pulchrum Sweet cultivars.

Additional file 2: Fig. S2. Hierarchical cluster analysis of differential flavonoid metabolites in R.pulchrum Sweet. Note: White, cultivar ‘Baihe’; Pink, cultivar ‘Fenhe’; Purple, cultivar ‘Zihe’. (a)Analysis of flavonoid metabolites between cultivars ‘Baihe’ and ‘Fenhe’;(b) Analysis of flavonoid metabolites between cultivars ‘Zihe’ and ‘Baihe’; (c) Analysis of flavonoid metabolites between cultivars ‘Fenhe’ and ‘Zihe’.

Additional file 1: Fig. S1. Volcano plot of differential metabolits in R.pulchrum Sweet.(a) volcano plot of differential metabolits between cultivars ‘Baihe’ and ‘Fenhe’.(b)volcano plot of differential metabolits between cultivars ‘Zihe’ and ‘Baihe’.(c)volcano plot of differential metabolits between cultivars ‘Fenhe’ and ‘Zihe’.

A time-economical and robust synthesis of various selenofunctionalized heterocycles was accomplished

Objective: To analyze the expression of sirtuin type 1 (SIRT1) signal pathway in intestinal tissues of neonatal necrotizing enterocolitis (NEC), and to preliminarily explore the role of SIRT1 in the occurrence of NEC. Methods: From January 2017 to June 2017, the ileal tissues of 35 neonates with NEC underwent one-stage fistula treatment were selected as NEC group, and the ileal tissues of these 35 neonates underwent two-stage fistula treatment were selected as control group. The expression levels of SIRT1, transcription factor-nuclear factor (NF-κB), and SUMO specific protease 1 (SENP1) were detected by qRT-PCR; the expressions of SIRT1, NF-κB, and SENP1 were detected by immunohistochemistry and Western blotting (WB). Results: SIRT1 mRNA, protein positive expression rate, average optical density, and relative protein expression in intestinal tissues of children in NEC group were significantly lower than those in control group (P

As one of the most common endocrine disorders affecting women, polycystic ovary syndrome (PCOS) is associated with serious conditions including anovulation, endometrial cancer, infertility, hyperandrogenemia, and an increased risk for obesity and metabolic derangements. One contributing etiology to the pathophysiology of hyperandrogenemia associated with PCOS is an intrinsic alteration in ovarian steroidogenesis, leading to enhanced synthesis of androgens including testosterone. Studies have suggested that the increased testosterone synthesis seen in PCOS is driven in part by increased activity of CYP17A1, the rate-limiting enzyme for the formation of androgens in the gonads and adrenal cortex, which represents a critical factor driving enhanced testosterone secretion in PCOS. In this work, we evaluated the hypothesis that dysregulation of the noncoding RNA H19 results in aberrant CYP17 and testosterone production. To achieve this, we measured Cyp17 in ovarian tissues of H19 knockout mice, and quantified serum testosterone levels, in comparison with wild-type controls. We also evaluated circulating and ovarian H19 expression and correlated results with the presence or absence of PCOS in a group of women undergoing evaluation and treatment for infertility. We found that the loss of H19 in a mouse model results in decreased ovarian Cyp17, along with decreased serum testosterone in female mice. Moreover, utilizing serum samples and cumulus cells from women with PCOS, we showed that circulating and ovarian levels of H19 are increased in women with PCOS compared to controls. Findings from our multimodal experimental strategy, involving both a mouse model of dysregulated H19 expression and clinical serum and ovarian cellular samples from women with PCOS, suggest that the loss of H19 may disrupt androgen production via a Cyp17-mediated mechanism. Conversely, excess H19 may play a role in the pathogenesis of PCOS-associated hyperandrogenemia.

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Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) have a common pathology. Both diseases are characterized by local deposition of amyloid proteins in the brain or islet organ, but their phenotypes and clinical manifestation vary widely. Although the sources of islet amyloid polypeptide (IAPP) and amyloid beta (Aβ) are independent, their fibrillar sequences are highly homologous. The prevalence of AD in T2DM populations is considerably higher than that in the normal population, but a mechanistic linkage remains elusive. Therefore, the present study aimed to explore the effects of Aβ42 deposition in the brain on the persistently expression of human IAPP (hIAPP). Additionally, cognitive ability, synaptic plasticity, the state of neural stem cells and mitochondrial function were evaluated at 2 or 6 months after stereotaxically injected the oligomer Aβ

Ya Li, Meng Gao, Kuo Zeng, Jia-xin Xing, Feng-ling Xu, Jin-feng Xuan, Xi Xia, Yong-ping Liu, Jun Yao, Bao-jie Wang School of Forensic Medicine, China Medical University, Shenyang 110122, People’s Republic of ChinaCorrespondence: Bao-jie Wang; Jun Yao Email wangbj77@163.com; yaojun198717@163.comBackground: Epidemiological studies have shown that genetic factors are among the causes of schizophrenia. Galanin receptor 1 is an inhibitory receptor of galanin that is widely distributed in the central nervous system. This study mainly explored the relationship between polymorphisms of the 5′ region of the GALR1 gene and schizophrenia in the northern Chinese Han population.Methods: A 1545 bp fragment of the 5′ regulatory region of the GALR1 gene was amplified and sequenced in 289 schizophrenia patients and 347 healthy controls.Results: Among the haplotypes composed of the 16 detected SNPs, the haplotype H3 was identified as conferring a risk of schizophrenia (p=0.011, OR=1.430, 95% CI=1.084– 1.886). In addition, the haplotypes H4 and H7 were both protective against schizophrenia (p=0.024, OR=0.526, 95% CI=0.298– 0.927; p=0.037, OR=0.197, 95% CI=0.044– 0.885, respectively). In the subgroup analysis by sex, it was found that seven SNP alleles (rs72978691, rs11662010, rs11151014, rs11151015, rs13306374, rs5373, rs13306375) conferred a risk of schizophrenia in females (p< 0.05), while allele G of rs7242919 (p=0.007) was protective against schizophrenia in females. Moreover, the rs72978691 AA+AC genotype (p=0.006, OR=1.874, 95% CI=1.196– 2.937, power=0.780), rs7242919 CC+CG genotype (p=0.002, OR=2.027, 95% CI=1.292– 3.180, power=0.861), rs11151014 GG+GT genotype (p=0.008, OR=1.834, 95% CI=1.168– 2.879, power=0.735), rs11151015 GG+AG genotype (p=0.002, OR=2.013, 95% CI =1.291– 3.137, power=0.843), rs13306374 CC+AC genotype (p=0.006, OR=1.881, 95% CI=1.198– 2.953, power=0.788), and rs13306375 GG+AG genotype (p=0.006, OR=1.868, 95% CI=1.194– 2.921, power=0.770) increased the risk of schizophrenia in females. The haplotype FH2 consisting of rs72978691, rs11662010, rs7242919, rs11151014, rs11151015, rs13306374, rs5373, and rs13306375 may also be associated with the risk of schizophrenia in females (p=0.024).Conclusion: This study identified an association between polymorphisms in the 5′ region of the GALR1 gene and schizophrenia, especially in females.Keywords: galanin receptor 1, schizophrenia, single-nucleotide variant, genetic polymorphism, northern Chinese Han population

Feng-ling Xu, Jun Yao, Xue Wu, Xi Xia, Jia-xin Xing, Jin-feng Xuan, Yong-ping Liu, Bao-jie Wang School of Forensic Medicine, China Medical University, Shenyang 110122, People’s Republic of ChinaCorrespondence: Bao-jie WangSchool of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenbei New District, Shenyang 110122, People’s Republic of ChinaEmail wangbj77@163.comBackground: Abnormal RGS4 gene expression may cause neurotransmitter disorders, resulting in schizophrenia. The association between RGS4 and the risk of schizophrenia is controversial, and there has been little research on the SNPs in the promoter region of RGS4.Purpose: The present study was performed to detect theassociation between SNPs in the promoter region of the RGS4 gene and the risk of schizophrenia.Materials and Methods: In this study, the 1757-bp fragment (− 1119–+600, TSS+1) of RGS4 was amplified and sequenced in 198 schizophrenia patients and 264 healthy controls of the northern Chinese Han population. Allele, genotype and haplotype frequencies were analyzed by chi‐square test.Results: Four SNPs were detected in the region. LD analysis determined that rs7515900 was linked to rs10917671 (D’ = 1, r2 = 1). Therefore, the data for rs10917671 were eliminated from further analysis. Genotype TT of rs12041948 (P = 0.009, OR = 1.829, and 95% CI = 0.038– 0.766) was significantly different between the two groups in the northern Chinese Han population. In males, genotype GG of rs6678136 (P = 0.009, OR = 2.292, and 95% CI = 1.256– 4.18) and CC of rs7515900 (P = 0.003, OR = 2.523, and 95% CI = 1.332– 4.778) were significantly different.Conclusion: The results of this study suggested that genotype TT of rs12041948 in the pooled male and female samples and GG of rs6678136 and CC of rs7515900 in the male samples could be risk factors for schizophrenia. The present study is the first to detect an association between SNPs in the promoter region of the RGS4 gene and the risk of schizophrenia in the northern Chinese Han population. Functional studies are required to confirm these findings.Keywords: RGS4, schizophrenia, promoter region, SNPs

We report the effects of the growth temperature on the structural and electrical properties of the InAlGaN/GaN heterostructures grown on c-plane sapphire substrates. X-ray Photoelectron Spectroscopy and Atomic Force Microscopy measurements results indicate that the InAlGaN layer properties is strongly dependent on the growth temperature. It is observed that the Gallium incorporation increases with the increase of the growth temperature. Meanwhile, the surface roughness decreases from 0.49 nm to 0.34 nm with the increase of growth temperature. The variation of structural properties, composition and surface morphology influences the transport properties of the InAlGaN/GaN heterostructures. High 2DEG electron density, low sheet resistance and good C-V response with a steep slope for InAlGaN/GaN HEMT were achieved at an optimized growth temperature window between 900 °C and 950 °C.

To study the anatomical features and classification of the angle between the right gastroepiploic vein (RGEV) and superior mesenteric vein/portal vein (SMV/PV) and to guide the catheterization of intraportal infusion chemotherapy through RGEV and reduce surgical complications.A retrospective three-dimensional (3D) computed tomography study was undertaken on 200 consecutive subjects with or without hepatic malignant tumors with a dedicated workstation 3D-MIA (the improved MI-3DVS workstation) developed by ourselves to determine the prevalence of surgically significant angle between RGEV and SMV/PV anatomic variations and its classification.The mean value of the angles between the end of RGEV and SMV/PV (AERS/P) (200 cases) was 84.2° ± 23.8 (31.4°-151.5°): 40.6° ± 92.3 (-177.9° to 178.0°) (sagittal angle), 81.7° ± 29.8 (-79.3° to 160.7°) (coronal angle), and 10.5° ± 94.3 (-178.7° to 175.8°) (horizontal angle). The mean value of the angles between the right bend of RGEV and SMV/PV (ARRS/P) (168 cases) was 104.8° ± 26.1 (20.5°-159.7°):49.3° ± 117.8 (-175.3° to 179.5°) (sagittal angle), 103.5° ± 37.7 (-178.8° to 168.9°) (coronal angle), and 12.6° ± 102.8 (-179.9° to 179.2°) (horizontal angle). The AERS/P were classified into large angle group (32 cases, 16%), middle angle group (113 cases, 56.5%), and small angle group (55 cases, 27.5%) based on angle variations and risks of catheterization.Precognition of the variations of AERS/P and ARRS/P before surgery is useful during chemotherapy pump catheterizing through RGEV in reduction of surgical complications by modulating the angle and direction of RGEV running into SMV/PV properly.

The direct current gas flow (DC flow), normally treated as a loss in the pulse tube cryocoolers (PTCs) in the past, has been found may be beneficial to the cooling performance of the PTC working at low temperatures recently. However, the reason why it can improve the cooling performance is still not clear enough. In order to reveal the working mechanism of the DC flow independently, simulation analysis and experiment verification are carried out on a two-stage Stirling type PTC without the double-inlet valve. Results indicate that in the second stage PTC working around 20 K, by introducing the DC flow with a positive direction from regenerator side to pulse tube side, the cooling performance will be improved due to the remarkable increase of the AC enthalpy flow in the pulse tube and the decrease of AC enthalpy flow in the regenerator. This is because with the help of positive DC flow, the temperature gradients in the pulse tube and the regenerator of the 20 K PTC are improved, i.e. the DC flow causes smaller heat losses in them. Nevertheless, the DC flow has no help on improving the cooling performance of the PTC working around 80 K. Simulation and experiment show consistency that with an optimized DC flow, the no-load refrigeration temperature of the second stage Stirling PTC drops 6–7 K, and the cooling capacity at 22 K increases about 1 W.

We investigate the dependence of material and electrical properties on the growth temperature of in situ SiN x on InAlGaN/GaN heterostructures grown by metal-organic chemical vapor deposition. Degradation of the interface between SiN x and InAlGaN layer was observed when growth temperature is below 900 °C or above 1100 °C. With the optimized SiN x growth temperature, the high-quality SiN x and low interface trap density can be realized. Thus, the double-sweep capacitance–voltage measurement showed a sharp transition from charge accumulation to depletion with low hysteresis of 0.09 V. A small threshold-voltage shift after gate bias stress (1001 s) was also characterized by I–V measurement.

Additional file 2: Supplementary Figures. Figure S1. Paired organoids derived from primary and metastatic CRC recapitulate the histopathological structure of parental tumor. A and B, Organoids architecture resembles parental tumor epithelium. Representative bright-field images of organoids together with H&E staining of parental tumors and patient-derived organoids. The scale bar represents 100 μm. C and D, Representative IHC sections for the intestinal epithelial marker CDX2. The scale bar represents 100 μm. Figure S2. Organoids derived from liver metastatic lesions exhibited the most aggressive phenotypes with significant high tumorigenic and metastatic potential. A, Representative micrographs of organoids in 3D invasion assay. Tumor organoids showed the smooth and protrusive leading fronts, respectively. B, Micrographs of the paired organoids stained with phalloidin–F-actin (right). The scale bar represents 100 μm. C, qRT-PCR analysis of MMP-2 in paired organoid lines. Error bars indicate SEMs. *P=0.0207, **P =0.0083, ***P=0.0008 (one-way ANOVA; left), ***P=0.0006 (Unpaired t test; right). D, Western blot analysis of the MMP-2 protein expression in paired organoid lines. α-tubulin was used as a loading control. E, Representative IHC sections for Ki67 in human colorectal tumor tissues and paired organoid lines. The scale bar represents 100 μm. F, Representative IHC sections for Ki67 in organoid xenografts and organoids derived from xenografts. The scale bar represents 100 μm. G, Representative gross image, histopathology and Ki67 staining of whole liver from primary organoid xenografts. The scale bar of the whole liver represents 1cm. The black scale bar represents 100 μm. Figure S3. A, Representation of the up-regulated genes in 13L organoids. Error bars indicate SEMs. *P = 0.0283, ***P = 0.0004, ****P < 0.0001 (one-way ANOVA). B, qRT-PCR analysis of the up-regulated genes in 13L organoids. Values were normalized to mean levels in 13a organoids. Error bars indicate SEMs. *P=0.02, ***P=0.0008 ****P < 0.0001 (one-way ANOVA). C, RNA sequencing analysis of SOX2 in human colorectal cancer tissues and normal colon tissues. D, qRT-PCR analysis of SOX2 in tumor tissues and paired normal colon tissues. Values were normalized to mean levels in normal colon tissues. Error bars indicate SEMs. **P = 0.0018, ****P < 0.0001 (one-way ANOVA). E, Western blot analysis of the SOX2 protein expression in tumor tissues and paired normal colon tissues. α-tubulin was used as a loading control. F, Representative IHC sections for SOX2 in human colorectal tumor tissues and paired normal colon tissues. The scale bar represents 100 μm. Figure S4. Silencing SOX2 in metastatic organoids attenuated cell invasion and proliferation and suppressed liver metastasis in vivo. A, qRT-PCR analysis of SOX2 in paired organoid lines (left). Values were normalized to mean levels in 21a organoids. Error bars indicate SEMs. ****P < 0.0001(Unpaired t test). Western blot analysis of the SOX2 protein expression in paired organoid lines. α-tubulin was used as a loading control (right). B, Representative IHC sections for SOX2 in human colorectal tumor tissues and organoids. The scale bar represents 100 μm. C, qRT-PCR analysis of SOX2 in the 13L-shRNA-1/2 (left) and 21L-shRNA-1/2 (right) organoids after 3 days of Dox-induction. The level of SOX2 was compared to that in the untreated sample. Error bars indicate SEMs. ***P=0.0001, ****P < 0.0001 (two-way ANOVA). D, Western blot analysis of the expression of SOX2 in the 13L-shRNA-1/2 and 21L-shRNA-1/2 organoids after 3 days of Dox-induction. α-tubulin was used as a loading control. E, Representative micrographs of Dox-transduced the 21L-shRNA-1/2 organoids after 5 days and stained with phalloidin–F-actin. The scale bar represents 100 μm. F, Proliferation of the 21L-shRNA-1/2 organoids were examined by CTG cell viability assays following 3- or 5-days growth in the presence or absence of Dox. Error bars indicate SEMs. **p=0.0019, ****P < 0.0001 (two-way ANOVA). G, Representative micrographs of colonies arising from the 21L-shRNA-1/2 organoids (top), with magnified insets showing colonies (bottom). The scale bar represents 200 μm. Colony forming efficiency in G was calculated and compared (right). Error bars indicate SEMs. **P=0.0015 (two-way ANOVA). H, Representative Ki67 immunostaining of liver metastases of the 13L-shRNA-1/2 organoids (left) and ratio of Ki67-positive tumor cells in liver metastases (right). Scale bars, 200 μm (top) and 100 μm (bottom). Each dot indicates individual mice. Error bars indicate SEMs. *p=0.0197, **P=0.0044 (two-way ANOVA). Figure S5. SOX2 is overexpressed in primary organoids. A, qRT-PCR analysis of SOX2 in primary organoid lines. Values were normalized to mean levels in control organoids. Error bars indicate SEMs. ****P < 0.0001 (one-way ANOVA). B, Western blot analysis of the SOX2 protein expression in primary organoid lines. α-tubulin was used as a loading control. C, Representative micrographs of colonies arising from the control, LV-Vector and LV-SOX2 primary organoid lines. The scale bar represents 200 μm. D-F, Colony forming efficiency in C was calculated and compared. Error bars indicate SEMs. ***P=0.0008, ****P < 0.0001 (one-way ANOVA). G, Proliferation of the control, LV-Vector and LV-SOX2 primary organoid lines were examined by CTG cell viability assays. Error bars indicate SEMs. ***P=0.0008, ****P < 0.0001 (one-way ANOVA). H, Representative micrographs of organoids in 3D invasion assay. Arrowheads, protrusive leading fronts. Micrographs of the paired organoids stained with phalloidin–F-actin. The scale bar represents 100 μm.

Additional file 3. Supplementary Materials and Methods.

Additional file 1 Supplementary Table 1. Factors associated with high LDL-C/HDL-C ratio in Logistic regression analysis. Supplementary Table 2. Univariate Cox proportional-hazards analysis showing predictors of CVD and all-cause mortalities in the study cohort. Supplementary Table 3. The Association between LDL-C/HDL-C ratio and mortality risk by different levels of hsCRP in diabetic patients.

Additional file 1 : Figure S1. Characterization of CRXp-tdTomato. a Polymerase chain reaction of CRXp-tdTomato clones with primers spanning the integration site to assess whether the cassette had integrated at the correct site. b Karyotype analysis of CRXp-tdTomato. c Immunohistochemical analysis of alkaline phosphatase. Scale bar, 400 μm. d Immunocytochemistry of marker proteins for α-fetoprotein [AFP] (marker of endoderm), α-smooth muscle actin [α-SMA] (marker of mesoderm) and GFAP (marker of ectoderm). Scale bar, 100 μm. Figure S2. 3D retinal organoids formed by COCO supplement schemes. a Morphology of retinal organoids after COCO with or without IWR1e and IGF1. Scale bar, 2000 μm. b Comparison of COCO inducing efficiency between 12-day-supplement and 30-day-supplement versus control group on D30 organoids. c Quantification of survival rate of organoids in panel B. e Fold change of CTNNB1 expression. *P

Additional file 1: Table S1. Significant influencing factors for plasma fibrinogen levels in a simple linear regression.

Background Long non-coding RNA (LncRNA) TUG1 plays critical roles in the development of human cancers. Its inhibition has been proved to participate in ankylosing spondylitis, which is an inverse pathological procedure of osteoporosis. In the present study, we aim to investigate the role of lncRNA TUG1 in ankylosing spondylitis. Materials and methods Expressions of lncRNA TUG1 in plasma of 98 patients with osteoporosis and 60 healthy participants were detected by real-time quantitative PCR (RT-qPCR). Diagnostic values of lncRNA CASC11 for osteoclasts were performed by the ROC curve with osteoporosis patients as positive and healthy participants as negative. All experiments were repeated 3 times. Mean ± standard deviation was calculated. Results We found that plasma lncRNA TUG1 was upregulated in osteoporosis patients than in healthy participants. Upregulation of plasma lncRNA TUG1 distinguished osteoporosis patients from healthy participants. LncRNA TUG1 level increased with the advances of clinical stages. Over-expression of lncRNA TUG1 promoted the proliferation and inhibited the apoptosis of mice osteoclasts, while lncRNA TUG1 siRNA silencing played an opposite role. In addition, lncRNA TUG1 over-expression led to downregulated PTEN, while lncRNA TUG1 siRNA silencing played an opposite role. Conclusion Therefore, lncRNA TUG1 is upregulated in osteoporosis and regulates the proliferation and apoptosis of osteoclasts. lncRNA TUG1 knockdown may serve as a promising therapeutic target for osteoporosis by inhibiting the proliferation and promoting the apoptosis of osteoclasts through PTEN.

The accumulation of human islet amyloid polypeptide (hIAPP) in pancreatic islets under induction by a high-fat diet plays a critical role in the development of type-2 diabetes mellitus (T2DM). T2DM is a risk factor of late-onset Alzheimer’s disease (AD). Nevertheless, whether hIAPP in combination with hyperlipidemia may lead to AD-like pathological changes in the brain remains unclear. hIAPP transgenic mice were fed with a high-fat diet for 6 or 12 months to establish the T2DM model. The accumulation of amylin, the numbers of Fluoro-Jade C (FJC)-positive and β-gal positive cells, and the deposition level of Aβ42 in the hippocampi of the transgenic mice were detected by using brain sections. Cytoplasmic and membrane proteins were extracted from the hippocampi of the transgenic mice, and the ratio of membrane GLUT4 expression to cytoplasmic GLUT4 expression was measured through Western blot analysis. Changes in the cognitive functions of hIAPP transgenic mice after 12 months of feeding with a high-fat diet were evaluated. hIAPP transgenic mice fed with a high-fat diet for 6 or 12 months showed elevated blood glucose levels and insulin resistance; increased amylin accumulation, number of FJC-positive and β-gal positive cells, and Aβ42 deposition in the hippocampi; and reduced membrane GLUT4 expression levels. hIAPP transgenic mice fed with a high-fat diet for 12 months showed reductions in social cognitive ability and passive learning ability. A high-fat diet increased amylin accumulation in the hippocampi of hIAPP transgenic mice, which presented AD-like pathology and behavior characterized by neural degeneration, brain aging, Aβ42 deposition, and impaired glucose utilization and cognition.

The decline of cell function caused by ageing directly impacts the therapeutic effects of autologous stem cell transplantation for heart repair. The aim of this study was to investigate whether overexpression of neuron‐derived neurotrophic factor (NDNF) can rejuvenate the adipose‐derived stem cells in the elderly and such rejuvenated stem cells can be used for cardiac repair. Human adipose‐derived stem cells (hADSCs) were obtained from donors age ranged from 17 to 92 years old. The effects of age on the biological characteristics of hADSCs and the expression of ageing‐related genes were investigated. The effects of transplantation of NDNF over‐expression stem cells on heart repair after myocardial infarction (MI) in adult mice were investigated. The proliferation, migration, adipogenic and osteogenic differentiation of hADSCs inversely correlated with age. The mRNA and protein levels of NDNF were significantly decreased in old (>60 years old) compared to young hADSCs (

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) have a common pathology. Both diseases are characterized by local deposition of amyloid proteins in the brain or islet organ, but their phenotypes and clinical manifestation vary widely. Although the sources of islet amyloid polypeptide (IAPP) and amyloid beta (Aβ) are independent, their fibrillar sequences are highly homologous. The prevalence of AD in T2DM populations is considerably higher than that in the normal population, but a mechanistic linkage remains elusive. Therefore, the present study aimed to explore the effects of Aβ42 deposition in the brain on the persistently expression of human IAPP (hIAPP). Additionally, cognitive ability, synaptic plasticity, the state of neural stem cells and mitochondrial function were evaluated at 2 or 6 months after stereotaxically injected the oligomer Aβ1-42 into the dentate gyrus of hIAPP (−/+) mice or the wild-type littermates. We found that Aβ42 and amylin were co-located in hippocampus and Aβ42 levels increased when Aβ1-42 was injected in hIAPP transgenic mice compared with that of the wild-type littermates. Furthermore, at 6 months after Aβ1-42 injection in hIAPP (−/+) mice, it exhibits exacerbated AD-related pathologies including Aβ42 deposition, cognitive impairment, synapse reduction, neural stem cells exhaustion and mitochondrial dysfunction. Our present study suggested that hIAPP directly implicated the Aβ42 production and deposition as an important linkage between T2DM and AD.

In this paper, we present the dependence of structural and electrical properties of AlN/GaN heterostructure on the growth temperature on sapphire substrates by metal organic chemical vapor deposition. The results revealed that higher Ga incorporation (~47%) and higher trench density on the surface of AlN barrier layer when grown at 1125 °C. However, further decreasing the AlN growth temperature to 500 °C results in the lower Ga incorporation (~5%), higher dislocation density, 3D island growth and larger tensile strain of AlN barrier layer. Degradation of structural properties and surface morphologies AlN barrier layer results in the higher resistivity of 2-dimensional electron gas transport properties. Low sheet resistance (255.45 Ω/sq), high free carrier electron density (2.86 × 1013 cm−2), simultaneously maintaining low surface roughness and high crystal quality of AlN barrier were achieved at optimized growth temperature around 800 °C.

Figure S2. Publication bias. Funnel plots and Eggerâ s test were performed to assess the potential publication bias. (DOCX 5726 kb)

Genotype and allele distribution of SNPs in the GRIN1 gene (significance threshold = 0.0083). a Frequency is shown in brackets (%); b P value shown in bold reaches a significant level (P

This letter presents a theory on the coalescence of two spherical liquid droplets that are initially stationary. The evolution of the radius of a liquid neck formed upon coalescence was formulated as an initial value problem and then solved to yield an exact solution without free parameters, with its two asymptotic approximations reproducing the well-known scaling relations in the viscous and inertial regimes. The viscous-to-inertial crossover observed by Paulsen et al. [Phys. Rev. Lett. 106, 114501 (2011)] is also recovered by the theory, rendering the collapse of data of different viscosities onto a single curve., Comment: 5 pages; 4 figures

Figure S1. Sensitivity analysis. Sensitivity analyses were performed to evaluate the influence of a signal study on the overall risk estimate by removing one study at a time. (DOCX 13200 kb)

Table S1. The reasons of excluded articles at the stage of eligibility. The list showed the reasons of excluded articles. (DOCX 86 kb)

BACKGROUND Increasing epidemiological studies have confirmed the association between maternal preeclampsia and elevated blood pressure in their offspring. Though case-control or cohort studies have demonstrated long-term outcomes for the offspring of preeclampsia, it is still a question that how these changes were caused by genetic reasons or by preeclampsia itself. OBJECTIVE In our study, we explored the potential epigenetic regulation of delta-like homolog 1-maternally expressed gene 3 (DLK1-MEG3) region in human umbilical vein endothelial cells (HUVECs), and its connection with endothelium-derived factors. STUDY DESIGN We recruited 58 singletons born with spontaneous conception (control group) and 67 singletons whose mother with preeclampsia (preeclampsia group), and detected the infants' blood pressure and growth development index. To explore the potential mechanism, we did real-time PCR to test DLK1-MEG3 imprinted genes and endothelium-derived factors. ELISA confirmed the protein secretion changes between two groups. In addition to confirm epigenetic alteration in preeclampsia HUVEC, we performed pyro-sequencing to detect methylation status of two different methylation regions: intergenic differential methylation region (IG-DMR) and MEG3 DMR which control the expression of DLK1 and MEG3. Furthermore, Person correlation was used to make sure the association of methylation alteration of IG-DMR and endothelium-derived factors. RESULTS In our study, we found that DBP was significantly lower in preeclampsia offspring who born over 34 weeks compared with normal offspring (53.59 ± 1.38 vs. 59.9 ± 1.40 mmHg, P

Numerous investigations on procalcitonin (PCT) have been carried out, although few with large sample size. To deal with the complexity of sepsis, an understanding of PCT in heterogeneous clinical conditions is required.Hospitalized patients aged 10-79 years were included in this retrospective and cross-sectional study. PCT tests were assayed within 2 days of blood culture.A total of 2952 cases (from 2538 patients) were enrolled in this study, including 440 cases in the 'positive BC' group, 123 cases in the 'positive body fluid culture' group, and 2389 cases in the 'negative all culture' group. Median PCT values were 4.53 ng/ml, 2.95 ng/ml, and 0.49 ng/ml, respectively. Median PCT values in the gram-negative BC group and gram-positive BC group, respectively, were 6.99 ng/ml and 2.96 ng/ml. Median PCT values in the 'positive hydrothorax culture' group, 'positive ascites culture' group, 'positive bile culture' group, and 'positive cerebrospinal fluid culture' group, respectively, were 1.39 ng/ml, 8.32 ng/ml, 5.98 ng/ml, and 0.46 ng/ml. In all, 357 cases were classified into the 'sepsis' group, 150 of them were classified into the 'severe sepsis' group. Median PCT values were 5.63 ng/ml and 11.06 ng/ml, respectively.PCT could be used in clinical algorithms to diagnose positive infections and sepsis. Different PCT levels could be related to different kinds of microbemia, different infection sites, and differing severity of sepsis.

Previous studies have found that the flickering of buoyant diffusion flames is associated with the periodic shedding of a toroidal vortex, which is formed under gravity-induced shearing at the flames. Moreover, numerous experimental investigations have reported the scaling relation, $f \propto D^{-1/2}$, where $f$ is the flickering frequency and $D$ is the diameter of the fuel inlet. However, the connection between the toroidal vortex mechanism and the scaling relation has not been clearly understood. The current study theoretically revisits this problem from the perspective of vortex dynamics. The theory incorporates a recent finding in the vortex dynamics community: the detachment of a continuously growing vortex ring is inevitable and can be dictated by a universal constant that is essentially a non-dimensional circulation of the vortex. By calculating the total circulation of the toroidal vortex and applying the vortex ring detachment criterion, we mathematically established the connection between the lifetime of a toroidal vortex and the flickering of a buoyant diffusion flame, resulting in a general flickering frequency formulation, which is validated by comparing with existing experimental data of pool and jet diffusion flames.

This letter presents a scaling theory of the coalescence of two viscous spherical droplets. An initial value problem was formulated and analytically solved for the evolution of the radius of a liquid neck formed upon droplet coalescence. Two asymptotic solutions of the initial value problem reproduce the well-known scaling relations in the viscous and inertial regimes. The viscous-to-inertial crossover experimentally observed by Paulsen et al. [Phys. Rev. Lett. 106, 114501 (2011)] manifests in the theory, and their fitting relation, which shows collapse of data of different viscosities onto a single curve, is an approximation to the general solution of the initial value problem.