High-Performance 2D Ambipolar MoTe2 Lateral Memristors by Mild Oxidation.

2D transition metal dichalcogenides (TMDCs) have been intensively explored in memristors for brain-inspired computing. Oxidation, which is usually unavoidable and harmful in 2D TMDCs, could also be used to enhance their memristive performances. However, it is still unclear how oxidation affects the resistive switching behaviors of 2D ambipolar TMDCs. In this work, a mild oxidation strategy is developed to greatly enhance the resistive switching ratio of ambipolar 2H-MoTe2 lateral memristors by more than 10 times. Such an enhancement results from the amplified doping due to O2 and H2O adsorption and the optimization of effective gate voltage distribution by mild oxidation. Moreover, the ambipolarity of 2H-MoTe2 also enables a change of resistive switching direction, which is uncommon in 2D memristors. Consequently, as an artificial synapse, the MoTe2 device exhibits a large dynamic range (≈200) and a good linearity (1.01) in long-term potentiation and depression, as well as a high-accuracy handwritten digit recognition (>96%). This work not only provides a feasible and effective way to enhance the memristive performance of 2D ambipolar materials, but also deepens the understanding of hidden mechanisms for RS behaviors in oxidized 2D materials.

Acteoside ameliorates learning and memory impairment in APP/PS1 transgenic mice by increasing Aß degradation and inhibiting tau hyperphosphorylation.

Alzheimer's disease (AD) is a neurodegenerative disease. Senile plaques and intracellular neurofibrillary tangles are pathological hallmarks of AD. Recent studies have described the improved cognitive and neuroprotective functions of acteoside (AS). This study aimed to investigate whether the improved cognition of AS was mediated by Aß degradation and tau phosphorylation in APP/PS1 mice. The open field, Y maze, and novel object recognition tests were used to assess cognitive behavioral changes. We evaluated the levels of Aß40 and Aß42 in serum, cortex, and hippocampus, and Aß-related scavenging enzymes, phosphorylated GSK3ß and hyperphosphorylated tau in the cortex and hippocampus of APP/PS1 mice by western blotting. Our results revealed that AS treatment ameliorated anxious behaviors, spatial learning, and memory impairment in APP/PS1 mice and significantly reduced Aß deposition in their serum, cortex, and hippocampus. AS significantly increased Aß degradation, inhibited the hyperphosphorylation of tau, and significantly decreased the activity of GSK3ß, which is involved in tau phosphorylation. Altogether, these findings indicated that the beneficial effects of AS on AD-associated anxious behaviors and cognitive impairments could be attributed to promoting Aß degradation and inhibiting tau hyperphosphorylation, which might be partly mediated by GSK3ß.

Multi-omics profiling of cholangiocytes reveals sex-specific chromatin state dynamics during hepatic cystogenesis in polycystic liver disease.

BACKGROUND & AIMS: Cholangiocytes transit from quiescence to hyperproliferation during cystogenesis in polycystic liver disease (PLD), the severity of which displays prominent sex differences. Epigenetic regulation plays important roles in cell state transition. We aimed to investigate the sex-specific epigenetic basis of hepatic cystogenesis and to develop therapeutic strategies targeting epigenetic modifications for PLD treatment. METHODS: Normal and cystic primary cholangiocytes were isolated from wild-type and PLD mice of both sexes. Chromatin states were characterized by analyzing chromatin accessibility (ATAC sequencing) and multiple histone modifications (chromatin immunoprecipitation sequencing). Differential gene expression was determined by transcriptomic analysis (RNA sequencing). Pharmacologic inhibition of epigenetic modifying enzymes was undertaken in PLD model mice. RESULTS: Through genome-wide profiling of chromatin dynamics, we revealed a profound increase of global chromatin accessibility during cystogenesis in both male and female PLD cholangiocytes. We identified a switch from H3K9me3 to H3K9ac on cis-regulatory DNA elements of cyst-associated genes and showed that inhibition of H3K9ac acetyltransferase or H3K9me3 demethylase slowed cyst growth in male, but not female, PLD mice. In contrast, we found that H3K27ac was specifically increased in female PLD mice and that genes associated with H3K27ac-gained regions were enriched for cyst-related pathways. In an integrated epigenomic and transcriptomic analysis, we identified an estrogen receptor alpha-centered transcription factor network associated with the H3K27ac-regulated cystogenic gene expression program in female PLD mice. CONCLUSIONS: Our findings highlight the multi-layered sex-specific epigenetic dynamics underlying cholangiocyte state transition and reveal a potential epigenetic therapeutic strategy for male PLD patients. IMPACT AND IMPLICATIONS: In the present study, we elucidate a sex-specific epigenetic mechanism underlying the cholangiocyte state transition during hepatic cystogenesis and identify epigenetic drugs that effectively slow cyst growth in male PLD mice. These findings underscore the importance of sex difference in the pathogenesis of PLD and may guide researchers and physicians to develop sex-specific personalized approaches for PLD treatment.

KIAA1199 drives immune suppression to promote colorectal cancer liver metastasis by modulating neutrophil infiltration.

BACKGROUND AND AIMS: Metastasis is the primary cause of cancer mortality, and colorectal cancer (CRC) frequently metastasizes to the liver. Our previous studies demonstrated the critical role of KIAA1199 in tumor invasion and metastasis in CRC. In the present study, we described an immune regulatory effect of KIAA1199 that creates a permissive environment for metastasis. APPROACH AND RESULTS: Flow cytometry was used to examine the effects of KIAA1199 on the infiltration of tumor immune cells. Neutrophils and T cells were isolated, stimulated, and/or cultured for in vitro function assays. In the patients with CRC, high expression levels of KIAA1199 were associated with an increased neutrophil infiltration into the liver. This result was further validated in mouse metastasis models. The increased influx of neutrophils contributed to the KIAA1199-driven CRC liver metastasis. Mechanistically, KIAA1199 activated the TGFß signaling pathway by interacting with the TGFBR1/2 to stimulate CXCL1 and CXCL3 production, thereby driving the aggregation of immunosuppressive neutrophils. Genetic blockade or pharmacologic inhibition of KIAA1199 restored tumor immune infiltration, impeded tumor progression, and potentiated response to immune checkpoint blockade (ICB). CONCLUSIONS: These findings indicated that KIAA1199 could facilitate the liver infiltration of immunosuppressive neutrophils via the TGFß-chemokine (C-X-C motif) ligand (CXCL)3/1-CXCR2 axis, which might be clinically targeted for the treatment of hepatic metastasis.

Comprehensive transcriptomics and metabolomics analyses reveal that hyperhomocysteinemia is a high risk factor for coronary artery disease in a chinese obese population aged 40-65: a prospective cross-sectional study.

BACKGROUND: Clinical observations suggest a complex relationship between obesity and coronary artery disease (CAD). This study aimed to characterize the intermediate metabolism phenotypes among obese patients with CAD and without CAD. METHODS: Sixty-two participants who consecutively underwent coronary angiography were enrolled in the discovery cohort. Transcriptional and untargeted metabolomics analyses were carried out to screen for key molecular changes between obese patients with CAD (CAD obese), without CAD (Non-CAD obese), and Non-CAD leans. A targeted GC-MS metabolomics approach was used to further identify differentially expressed metabolites in the validation cohorts. Regression and receiver operator curve analysis were performed to validate the risk model. RESULTS: We found common aberrantly expressed pathways both at the transcriptional and metabolomics levels. These pathways included cysteine and methionine metabolism and arginine and proline metabolism. Untargeted metabolomics revealed that S-adenosylhomocysteine (SAH), 3-hydroxybenzoic acid, 2-hydroxyhippuric acid, nicotinuric acid, and 2-arachidonoyl glycerol were significantly elevated in the CAD obese group compared to the other two groups. In the validation study, targeted cysteine and methionine metabolomics analyses showed that homocysteine (Hcy), SAH, and choline were significantly increased in the CAD obese group compared with the Non-CAD obese group, while betaine, 5-methylpropanedioic acid, S-adenosylmethionine, 4-PA, and vitamin B2 (VB2) showed no significant differences. Multivariate analyses showed that Hcy was an independent predictor of obesity with CAD (hazard ratio 1.7; 95%CI 1.2-2.6). The area under the curve based on the Hcy metabolomic (HCY-Mtb) index was 0.819, and up to 0.877 for the HCY-Mtb.index plus clinical variables. CONCLUSION: This is the first study to propose that obesity with hyperhomocysteinemia is a useful intermediate metabolism phenotype that could be used to identify obese patients at high risk for developing CAD.

NRVC: Neural Representation for Video Compression with Implicit Multiscale Fusion Network.

Recently, end-to-end deep models for video compression have made steady advancements. However, this resulted in a lengthy and complex pipeline containing numerous redundant parameters. The video compression approaches based on implicit neural representation (INR) allow videos to be directly represented as a function approximated by a neural network, resulting in a more lightweight model, whereas the singularity of the feature extraction pipeline limits the network's ability to fit the mapping function for video frames. Hence, we propose a neural representation approach for video compression with an implicit multiscale fusion network (NRVC), utilizing normalized residual networks to improve the effectiveness of INR in fitting the target function. We propose the multiscale representations for video compression (MSRVC) network, which effectively extracts features from the input video sequence to enhance the degree of overfitting in the mapping function. Additionally, we propose the feature extraction channel attention (FECA) block to capture interaction information between different feature extraction channels, further improving the effectiveness of feature extraction. The results show that compared to the NeRV method with similar bits per pixel (BPP), NRVC has a 2.16% increase in the decoded peak signal-to-noise ratio (PSNR). Moreover, NRVC outperforms the conventional HEVC in terms of PSNR.

The prognostic factors in acute myeloid leukaemia with double-mutated CCAAT/enhancer-binding protein alpha (CEBPAdm).

The prognostic factors to stratify acute myeloid leukaemia (AML) with double-mutated CCAAT/enhancer-binding protein alpha (CEBPAdm) into different risk groups remains to be determined. In this retrospective study, we evaluated 171 consecutive patients with newly diagnosed AML with CEBPAdm by a Cox proportional hazards regression model. In univariate analyses, colony stimulating factor 3 receptor (CSF3R) and Wilms tumour 1 (WT1) mutations were associated with poor relapse-free survival (RFS). The induction regimens including homoharringtonine (omacetaxine mepesuccinate) or intermediate-dose cytarabine was associated with favourable RFS and overall survival (OS). The induction regimen including both homoharringtonine and intermediate-dose cytarabine was associated with the most favourable RFS (3-year RFS 84.7%) and OS (3-year OS 92.8%) compared to the conventional cytarabine and daunorubicin regimen (3-year RFS 27.7%, hazard ratio [HR] 0.126, 95% confidence interval [CI] 0.051-0.313, Wald p < 0.001; and 3-year OS 56.4%, HR 0.179, 95% CI 0.055-0.586, Wald p = 0.005). In multivariate analyses, the induction regimen including intermediate-dose cytarabine (HR 0.364, 95% CI 0.205-0.646, Wald p < 0.001) and CSF3R mutations (HR 2.667, 95% CI 1.276-5.572, Wald p = 0.009) were independently associated with RFS. Taken together, we found that induction regimen and CSF3R mutations were independent prognostic factors for AML with CEBPAdm.

Maternal vitamin D status in early pregnancy and its association with gestational diabetes mellitus in Shanghai: a retrospective cohort study.

BACKGROUND: There is growing interest regarding vitamin D and its potential role in gestational diabetes mellitus (GDM). We aimed to assess maternal vitamin D status in early pregnancy and its relationships with the risk of GDM in a Chinese population in Shanghai. METHODS: The retrospective cohort study included a total of 7816 pregnant women who underwent a 75-g oral glucose tolerance test (OGTT) during 24-28 weeks of gestation. Participants' demographic information including maternal age, prepregnancy body mass index (BMI), gestational age, parity, season of blood collection, serum 25-hydroxy vitamin D [25(OH)D] data and other blood biomarker data at 6 to 14 weeks of gestation were retrospectivly extracted from the medical records in the hospital information system. RESULTS: In the cohort, the prevalence of GDM was 8.6% and the prevalence of vitamin D deficiency and insufficiency in early pregnancy was 53.1 and 38.5%, respectively. The mean value of the serum 25(OH)D concentration was 19.6±7.5 ng/mL. The restricted cubic splines model showed an inverted J-shaped relationship in which the risk of GDM decreased when the 25(OH)D concentrations were ≥ 20 ng/mL. Logistic model analysis showed that 25(OH)D concentrations ≥ 30 ng/mL significantly decreased the risk of GDM (odds ratio = 0.63, 95% confidence interval: 0.45-0.89; P = 0.010) compared with 25(OH)D concentrations < 20 ng/ml. CONCLUSIONS: In early pregnancy, vitamin D deficiency and insufficiency were very common, and a high level of vitamin D showed protective effects against the incidence risk of GDM.

Immediate risk of non-cancer deaths after a cancer diagnosis.

BACKGROUND: Receiving a cancer diagnosis may trigger immediate fatal non-cancer health outcomes in addition to dying of cancer itself. We aim to investigate the full pattern of non-cancer deaths in patients within a year of a cancer diagnosis. METHODS: Patients diagnosed with cancer between 1990 and 2016 were identified from the SEER program. Standardized mortality ratios (SMRs) were calculated to characterize the relative risks of non-cancer deaths compared with the general population. RESULTS: Among 7,366,229 patients, 241,575 non-cancer deaths (15.9%) were recorded in the first year following a cancer diagnosis. The relative risk of non-cancer deaths was 2.34-fold (95% confidence interval (CI): 2.33-2.35) that of the general population. The majority of non-cancer deaths were caused by cardiovascular diseases (21.8%), followed by infectious diseases (7.2%). Significant elevations in mortality risks were observed for nearly all non-cancer causes, particularly in infectious diseases (SMR: 5.08; 95% CI: 5.03-5.13). Patients with liver cancer (SMR: 12.29; 95% CI: 12.06-12.53) were at the highest risk of early non-cancer deaths. The risks of non-cancer deaths were highest within the first month after diagnosis, and decreased rapidly thereafter. CONCLUSIONS: Risks of non-cancer deaths vary by the types of causes and anatomic sites of cancer. Our data underscore the importance of close observation and early multidisciplinary care for noncancer conditions in patients who have recently received a cancer diagnosis.

Meta-analysis and indirect treatment comparison of modified FOLFIRINOX and gemcitabine plus nab-paclitaxel as first-line chemotherapy in advanced pancreatic cancer.

BACKGROUND: Modified FOLFIRINOX and gemcitabine plus nab-paclitaxel (GEM-NAB) have been recommended as first-line therapies for advanced pancreatic cancer (PC). Due to the lack of evidence to directly compare them, we conducted this network meta-analysis to indirectly compare the effectiveness and toxicity of modified FOLFIRINOX and GEM-NAB. METHODS: The eligible retrospective studies on treatments related to modified FOLFIRINOX and GEM-NAB up to 4 April 2020 were searched and assessed. We used the frequentist model to analyze the survival and toxicity data between different treatments. Pooled analysis for overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and events of toxicity were analyzed in this study. RESULTS: Twenty-two studies were involved in this network meta-analysis. The comparisons on OS and PFS showed that modified FOLFIRINOX and GEM-NAB had similar treatment efficacy (OS: 1.13; 95% CI: 0.78-1.63; PFS: HR: 1.19; 95% CI: 0.85-1.67). GEM-NAB was more effective than modified FOLFIRINOX based on the result of ORR (RR: 1.43; 95% CI: 1.04-1.96). Moreover, our analysis showed a similar toxicity profile between modified FOLFIRINOX and GEM-NAB. CONCLUSIONS: The current evidence showed that modified FOLFIRINOX and GEM-NAB were similar in survival and toxicity. Many factors should be considered for in the formulation of optimal treatment, and our meta-analysis could provide some guidance to treatment selection in the first-line setting for advanced PC.

Image learning to accurately identify complex mixture components.

The study of complex mixtures is very important for exploring the evolution of natural phenomena, but the complexity of the mixtures greatly increases the difficulty of material information extraction. Image perception-based machine-learning techniques have the ability to cope with this problem in a data-driven way. Herein, we report a 2D-spectral imaging method to collect matter information from mixture components, and the obtained feature images can be easily provided to deep convolutional neural networks (CNNs) for establishing a spectral network. The results demonstrated that a single CNN trained end-to-end from the proposed images can directly accomplish synchronous measurement of multi-component samples using only raw pixels as inputs. Our strategy has some innate advantages, such as fast data acquisition, low cost, and simple chemical treatment, suggesting that it can be extensively applied in many fields, including environmental science, biology, medicine, and chemistry.

Acteoside-improved streptozotocin-induced learning and memory impairment by upregulating hippocampal insulin, glucose transport, and energy metabolism.

Alzheimer's disease (AD), a neurodegenerative disease, has been, by and large, correlated to insulin pathway, glucose level, and energy metabolism in the brain. Intracerebroventricular administration of streptozotocin (ICV-STZ) leads to glucose and energy metabolism dysfunction, cognitive impairment, and increased oxidative stress in the brain. Acteoside has a myriad of pharmacological effects on the brain, namely, neuroprotection and recuperation of cognitive functions. The primary focus of the current study was to examine the effect of acteoside on insulin, glucose transport, and energy metabolism in the hippocampal area of the brain. The behavioral experiments such as spatial memory, active learning, and passive memory suggested that acetoside ameliorated the ICV-STZ-induced learning and cognitive impairment. The acteoside induced increase in the protein expression of glucose transporters (Glu T1, Glu T3, and Glu T4), glucose, and insulin levels in the hippocampus for maintaining normal learning and memory function were demonstrated by Western blot. In addition, acteoside's long-term oral administration increased the the ratio of ATP content divided by ADP content (ATP/ADP) ratio, which, in turn, reduced the reactiveoxygen species (ROS) level and improved the cellular oxidative stress response. Compared with the model group, the above results show significant differences in different degrees (p < .05 or p < .01). This study suggests that acteoside can ameliorate the ICV-STZ-induced learning and memory impairment caused due to insulin receptor, insulin receptor substrate 1, Glu T1, Glu T3, and Glu T4 pathways by triggering intracerebral metabolism.

Full-length genome sequence of segmented RNA virus from ticks was obtained using small RNA sequencing data.

BACKGROUND: In 2014, a novel tick-borne virus of the Flaviviridae family was first reported in the Mogiana region of Brazil and named the Mogiana tick virus (MGTV). Thereafter, the Jingmen tick virus (JMTV), Kindia tick virus (KITV), and Guangxi tick virus (GXTV)-evolutionarily related to MGTV-were reported. RESULTS: In the present study, we used small RNA sequencing (sRNA-seq) to detect viruses in ticks and discovered a new MGTV strain in Amblyomma testudinarium ticks collected in China's Yunnan Province in 2016. We obtained the full-length genome sequence of this MGTV strain Yunnan2016 (GenBank: MT080097, MT080098, MT080099 and MT080100) and recommended it for its inclusion in the NCBI RefSeq database for future studies on MGTV, JMTV, KITV and GXTV. Phylogenetic analysis showed that MGTV, JMTV, KITV and GXTV are monophyletic and belong to a MGTV group. Furthermore, this MGTV group of viruses may be phylogenetically related to geographical regions that were formerly part of the supercontinents Gondwana and Laurasia. CONCLUSIONS: To the best of our knowledge, this is the first study in which 5' and 3' sRNAs were used to generate full-length genome sequences of, but not limited to, RNA viruses. We also demonstrated the feasibility of using the sRNA-seq based method for the detection of viruses in pooled two and even possible one small ticks. MGTV may preserve the characteristic of ancient RNA viruses, which can be used to study the origin and evolution of RNA viruses. In addition, MGTV can be used as novel species for studies in phylogeography.

Coupling Nanostructured Microchips with Covalent Chemistry Enables Purification of Sarcoma-Derived Extracellular Vesicles for Downstream Functional Studies.

Tumor-derived extracellular vesicles (EVs) play essential roles in intercellular communication during tumor growth and metastatic evolution. Currently, little is known about the possible roles of tumor-derived EVs in sarcoma because the lack of specific surface markers makes it technically challenging to purify sarcoma-derived EVs. In this study, a specific purification system is developed for Ewing sarcoma (ES)-derived EVs by coupling covalent chemistry-mediated EV capture/ release within a nanostructure-embedded microchip. The purification platform-ES-EV Click Chip-takes advantage of specific anti-LINGO-1 recognition and sensitive click chemistry-mediated EV capture, followed by disulfide cleavage-driven EV release. Since the device is capable of specific and efficient purification of intact ES EVs with high purity, ES-EV Click Chip is ideal for conducting downstream functional studies of ES EVs. Absolute quantification of the molecular hallmark of ES (i.e., EWS rearrangements) using reverse transcription Droplet Digital PCR enables specific quantification of ES EVs. The purified ES EVs can be internalized by recipient cells and transfer their mRNA cargoes, exhibiting their biological intactness and potential role as biological shuttles in intercellular communication.

C-reactive protein derived from perivascular adipose tissue accelerates injury-induced neointimal hyperplasia.

AIM: Inflammation within the perivascular adipose tissue (PVAT) in obesity plays an important role in cardiovascular disorders. C-reactive protein (CRP) level in obesity patients is significantly increased and associated with the occurrence and progression of cardiovascular disease. We tested the hypothesis CRP derived from PVAT in obesity contributes to vascular remodeling after injury. METHODS: A high-fat diet (HFD) significantly increased CRP expression in PVAT. We transplanted thoracic aortic PVAT from wild-type (WT) or transgenic CRP-expressing (CRPTG) mice to the injured femoral artery in WT mice. RESULTS: At 4 weeks after femoral artery injury, the neointimal/media ratio was increased significantly in WT mice that received PVAT from CRPTG mice compared with that in WT mice that received WT PVAT. Transplanted CRPTG PVAT also significantly accelerated adventitial macrophage infiltration and vasa vasorum proliferation. It was revealed greater macrophage infiltration in CRPTG adipose tissue than in WT adipose tissue and CRP significantly increased the adhesion rate of monocytes through receptor Fcγ RI. Proteome profiling showed CRP over-expression promoted the expression of chemokine (C-X-C motif) ligand 7 (CXCL7) in adipose tissue, transwell assay showed CRP increased monocyte migration indirectly via the induction of CXCL7 expression in adipocytes. CONCLUSION: CRP derived from PVAT was significantly increased in HFD mice and promoted neointimal hyperplasia after vascular injury.

Machine learning for total organic carbon analysis of environmental water samples using high-throughput colorimetric sensors.

Due to the complexity of nonlinear reactions, the analysis of environmental samples often relies on expensive equipment as well as tedious and time-consuming experimental procedures. Currently, the efficient machine learning (ML) strategy based on big data offers some new insights for the analysis of complex components in the environmental field. In this study, ML was applied for the analysis of total organic carbon (TOC). We prepared a special colorimetric sensor (c-sensor) by inkjet printing. The sensor reacted with water samples in a high-throughput process, producing characteristic patterns to map TOC information in water samples. To quickly acquire TOC information on c-sensors, a ML model was proposed to describe the relationship between the c-sensor and TOC value. According to this study, the c-sensor and ML can be effectively applied to TOC information analysis of environmental water samples, which provides convenience for environmental research. It is foreseeable that ML has a broad prospect of application in environmental research.

LncRNA H19 gene rs2839698 polymorphism is associated with a decreased risk of colorectal cancer in a Chinese Han population: A case-control study.

BACKGROUND: Long non-coding RNA (lncRNA) H19 is involved in the carcinogenesis, progression, and metastasis of colorectal cancer (CRC). Recently, a few studies explored the relationship between lncRNA H19 gene rs2839698 polymorphism and CRC risk, but with conflicting findings. MATERIALS AND METHODS: A case-control study with 315 CRC cases and 441 controls was designed in a Chinese population. Genotyping was performed using PCR-RFLP. RESULTS: It was found rs2839698 polymorphism was associated with a decreased risk of CRC (AA vs GG: OR, 0.73; 95% CI, 0.54-0.98; P = .037; A vs G: OR, 0.78; 95% CI, 0.63-0.96; P = .021). Stratified analyses indicated this positive association was also significant in the non-smokers (AA vs GG: OR, 0.49; 95% CI, 0.25-0.93; P = .029), non-drinkers, those aged ≥ 60 years, and overweight individuals (BMI ≥ 24). In addition, rs2839698 polymorphism was also related to the lymph node metastasis (AA vs GG: OR, 0.43; 95% CI, 0.21-0.88; P = .019) and tumor size (AA vs GG: OR, 0.42; 95% CI, 0.20-0.88; P = .020) for patients with CRC. CONCLUSION: To sum up, the lncRNA H19 gene rs2839698 polymorphism decreases the risk of CRC in Chinese individuals, especially among the non-smokers, non-drinkers, individuals aged ≥ 60 years, and overweight individuals (BMI ≥ 24). Thus, the lncRNA H19 gene rs2839698 polymorphism might be an important biomarker and diagnostic marker for predicting the susceptibility to CRC in Chinese Han population.

Pericardial application as a new route for implanting stem-cell cardiospheres to treat myocardial infarction.

KEY POINTS: Cardiospheres (CSps) are a promising new form of cardiac stem cells with advantage over other stem cells for myocardial regeneration, but direct implantation of CSps by conventional routes has been limited due to potential embolism. We have implanted CSps into the pericardial cavity and systematically demonstrated its efficacy regarding myocardial infarction. Stem cell potency and cell viability can be optimized in vitro prior to implantation by pre-conditioning CSps with pericardial fluid and hydrogel packing. Transplantation of optimized CSps into the pericardial cavity improved cardiac function and alleviated myocardial fibrosis, increased myocardial cell survival and promoted angiogenesis. Mechanistically, CSps are able to directly differentiate into cardiomyocytes in vivo and promote regeneration of myocardial cells and blood vessels through a paracrine effect with released growth factors as potential paracrine mediators. These findings establish a new strategy for therapeutic myocardial regeneration to treat myocardial infarction. ABSTRACT: Cardiospheres (CSps) are a new form of cardiac stem cells with an advantage over other stem cells for myocardial regeneration. However, direct implantation of CSps by conventional routes to treat myocardial infarction has been limited due to potential embolism. We have implanted CSps into the pericardial cavity and systematically assessed its efficacy on myocardial infarction. Preconditioning with pericardial fluid enhanced the activity of CSps and matrix hydrogel prolonged their viability. This shows that pretransplant optimization of stem cell potency and maintenance of cell viability can be achieved with CSps. Transplantation of optimized CSps into the pericardial cavity improved cardiac function and alleviated myocardial fibrosis in the non-infarcted area, and increased myocardial cell survival and promoted angiogenesis in the infarcted area. Mechanistically, CSps were able to directly differentiate into cardiomyocytes in vivo and promoted regeneration of myocardial cells and blood vessels in the infarcted area through a paracrine effect with released growth factors in pericardial cavity serving as possible paracrine mediators. This is the first demonstration of direct pericardial administration of pre-optimized CSps, and its effectiveness on myocardial infarction by functional and morphological outcomes with distinct mechanisms. These findings establish a new strategy for therapeutic myocardial regeneration to treat myocardial infarction.

Endoplasmic reticulum stress in perivascular adipose tissue promotes destabilization of atherosclerotic plaque by regulating GM-CSF paracrine.

BACKGROUND: Perivascular adipose tissue (PVAT) accelerates plaque progression and increases cardiovascular risk. We tested the hypothesis that PVAT contributed to plaque vulnerability and investigated whether endoplasmic reticulum stress (ER stress) in PVAT played an important role in vulnerable plaque. METHODS: We transplanted thoracic aortic PVAT or subcutaneous adipose tissue as a control, from donor mice to carotid arteries of recipient apolipoprotein E deficient (apoE-/-) mice after removing carotid artery collar placed for 6 weeks. Two weeks after transplantation, ER stress inhibitor 4-phenyl butyric acid (4-PBA) was locally administrated to the transplanted PVAT and then animals were euthanized after 4 weeks. Immunohistochemistry was performed to quantify plaque composition and neovascularization. Mouse angiogenesis antibody array kit was used to test the angiogenic factors produced by transplanted adipose tissue. In vitro tube formation assay, scratch wound migration assay and mouse aortic ring assay were used to assess the angiogenic capacity of supernatant of transplanted PVAT. RESULTS: Ultrastructural detection by transmission electron microscopy showed transplanted PVAT was a mixed population of white and brown adipocytes with abundant mitochondria. Transplanted PVAT increased the intraplaque macrophage infiltration, lipid core, intimal and vasa vasorum neovascularization and MMP2/9 expression in plaque while decreased smooth muscle cells and collagen in atherosclerotic plaque, which were restored by local 4-PBA-treatment. Antibody array analysis showed that 4-PBA reduced several angiogenic factors [Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), MCP-1, IL-6] secreted by PVAT. Besides, conditioned medium from 4-PBA treated-PVAT inhibited tube formation and migration capacity of endothelial cells and ex vivo mouse aortic ring angiogenesis compared to conditioned medium from transplanted PVAT. mRNA expression and protein levels of GM-CSF were markedly elevated in adipocytes under ER stress which would be suppressed by 4-PBA. In addition, ER stress enhanced NF-κB binding to the promoter of the mouse GM-CSF gene in adipocytes confirmed by Chromatin immunoprecipitation analyses. CONCLUSIONS: Our findings demonstrate that ER stress in PVAT destabilizes atherosclerotic plaque, in part through increasing GM-CSF paracrine via transcription factor NF-κB.

General Synthesis of Transition-Metal Oxide Hollow Nanospheres/Nitrogen-Doped Graphene Hybrids by Metal-Ammine Complex Chemistry for High-Performance Lithium-Ion Batteries.

We present a general and facile synthesis strategy, on the basis of metal-ammine complex chemistry, for synthesizing hollow transition-metal oxides (Co3 O4 , NiO, CuO-Cu2 O, and ZnO)/nitrogen-doped graphene hybrids, potentially applied in high-performance lithium-ion batteries. The oxygen-containing functional groups of graphene oxide play a prerequisite role in the formation of hollow transition-metal oxides on graphene nanosheets, and a significant hollowing process occurs only when forming metal (Co2+ , Ni2+ , Cu2+ , or Zn2+ )-ammine complex ions. Moreover, the hollowing process is well correlated with the complexing capacity between metal ions and NH3 molecules. The significant hollowing process occurs for strong metal-ammine complex ions including Co2+ , Ni2+ , Cu2+ , and Zn2+ ions, and no hollow structures formed for weak and/or noncomplex Mn2+ and Fe3+ ions. Simultaneously, this novel strategy can also achieve the direct doping of nitrogen atoms into the graphene framework. The electrochemical performance of two typical hollow Co3 O4 or NiO/nitrogen-doped graphene hybrids was evaluated by their use as anodic materials. It was demonstrated that these unique nanostructured hybrids, in contrast with the bare counterparts, solid transition-metal oxides/nitrogen-doped graphene hybrids, perform with significantly improved specific capacity, superior rate capability, and excellent capacity retention.