Search

It is well known that long non-coding RNAs (lncRNAs) play an important role in the regulation of tumor genesis and development. They can modulate gene expression of transcriptional regulation, epigenetic regulation of chromatin modification, and post-transcriptional regulation, thus influencing the biological behavior of tumors, such as cell proliferation, apoptosis, cell cycle, invasion, and migration. Tumor angiogenesis not only provides nutrients and helps excrete metabolites, but it also opens a pathway for tumor metastasis. Anti-angiogenic therapy has become one of the effective treatment methods for tumor. But its drug resistance leads to the limitation of clinical application. Recent studies have shown that lncRNAs are closely related to tumor angiogenesis and anti-angiogenic therapy resistance, which provides a new direction for tumor research. lncRNAs are expected to be new targets for tumor therapy. For the first time to our knowledge, this paper reviews advancement of lncRNAs in tumor angiogenesis and anti-angiogenic therapy resistance and further discusses their potential clinical application.

Recent studies indicate that CGG repeat expansions in LRP12, GIPC1, and NOTCH2NLC are associated with oculopharyngodistal myopathy (OPDM) types 1, 2, and 3, respectively. However, some clinicopathologically confirmed OPDM cases continue to have unknown genetic causes. Here, through a combination of long-read whole-genome sequencing (LRS), repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis PCR (AL-PCR), we found that a CGG repeat expansion in the 5' UTR of RILPL1 is associated with familial and simplex OPDM type 4 (OPDM4). The number of repeats ranged from 139 to 197. Methylation analysis indicates that the methylation levels in RILPL1 were unaltered in OPDM4 individuals. Analyses of muscle biopsies suggested that the expanded CGG repeat might be translated into a toxic poly-glycine protein that co-localizes with p62 in intranuclear inclusions. Moreover, analyses suggest that the toxic RNA gain-of-function effects also contributed to the pathogenesis of this disease. Intriguingly, all four types of OPDM have been found to be associated with the CGG repeat expansions located in 5' UTRs. This finding suggests that a common pathogenic mechanism, driven by the CGG repeat expansion, might underlie all cases of OPDM.

The basic leucine zipper (bZIP) family is one of the largest families of transcription factors (TFs) in plants and is responsible for various functions, including regulating development and responses to abiotic/biotic stresses. However, the roles of bZIPs in the regulation of responses to drought stress and salinity stress remain poorly understood in Jatropha curcas L., a biodiesel crop. In the present study, 50 JcbZIP genes were identified and classified into ten groups. Cis-element analysis indicated that JcbZIP genes are associated with abiotic stress. Gene expression patterns and quantitative real-time PCR (qRT-PCR) showed that four JcbZIP genes (JcbZIPs 34, 36, 49 and 50) are key resistance-related genes under both drought and salinity stress conditions. On the basis of the results of cis-element and phylogenetic analyses, JcbZIP49 and JcbZIP50 are likely involved in responses to drought and salinity stress; moreover, JcbZIP34 and JcbZIP36 might also play important roles in seed development and response to abiotic stress. These findings advance our understanding of the comprehensive characteristics of JcbZIP genes and provide new insights for functional validation in the further.

Modification of eukaryotic RNA by methylation of adenosine residues to generate N6-methyladenosine (m6A) is a highly prevalent process. m6A is dynamically regulated during cell metabolism and embryo development, and it is mainly involved in various aspects of RNA metabolism, including RNA splicing, processing, transport from the nucleus, translation, and degradation. Accumulating evidence shows that dynamic changes to m6A are closely related to the occurrence and development of cancer and that methyltransferases, as key elements in the dynamic regulation of m6A, play a crucial role in these processes. Therefore, in this review, we describe the role of methyltransferases as m6A writers in cancer and summarize their potential molecular mechanisms of action.

The reachability of the maximal number of critical periods bifurcated from a weak center is judged with independence of period quantities. Since the independence is a sufficient condition, in this paper we give a method to judge the reachability without the independence. Our main idea is to consider how the number of zeros for derivative of the period function changes as a curve in the parameter space scans near a specific point and choose an appropriate curve to find the largest number of zeros. We apply this method to two polynomial differential systems, having zero-dimensional isochronicity variety and nonzero-dimensional one separately, to show that the maximal number is reached and obtain greater numbers than those obtained by classical independence separately. With our method, the two examples give the possibility that more critical periods arise from an isochronous center than a finite order weak center, an opposite fact to many known results.

OBJECTIVE: To determine the relationship between various parameters of high-frequency biphasic stimulation (HFBS) and the recovery period of post-HFBS block of the pudendal nerve in cats. MATERIALS AND METHODS: A tripolar cuff electrode was implanted on the pudendal nerve to deliver HFBS in ten cats. Two hook electrodes were placed central or distal to the cuff electrode to stimulate the pudendal nerve and induce contractions of external urethral sphincter (EUS). A catheter was inserted toward the distal urethra to slowly perfuse the urethra and record the back-up pressure generated by EUS contractions. After determining the block threshold (T), HFBS (6 or 10 kHz) of different durations (1, 5, 10, 20, 30 min) and intensities (1T or 2T) was used to produce the post-HFBS block. RESULTS: HFBS at 10 kHz and 1T intensity must be applied for at least 30 min to induce post-HFBS block. However, 10 kHz HFBS at a higher intensity (2T) elicited post-HFBS block after stimulation of only 10 min; and 10 kHz HFBS at 2T for 30 min induced a longer-lasting (1–3 h) post-HFBS block that fully recovered with time. HFBS of 5-min duration at 6 kHz produced a longer period (20.4 ± 2.1 min, p < 0.05, N = 5 cats) of post-HFBS block than HFBS at 10 kHz (9.5 ± 2.1 min). CONCLUSION: HFBS of longer duration, higher intensity, and lower frequency can produce longer-lasting reversible post-HFBS block. This study is important for developing new methods to block nerve conduction by HFBS.

The discovery of long noncoding RNAs (lncRNAs) has increased our understanding of the development and progression of many cancers, but their contributions to non-small cell lung cancer (NSCLC) remain poorly understood. Here, we profiled lncRNA expression in NSCLC and investigated in detail the molecular function of one upregulated lncRNA, LINC01234. LINC01234 was overexpressed in NSCLC compared with normal lung tissue and correlated positively with poor prognosis. Downregulation of LINC01234 impaired cell proliferation in vitro and tumor growth in vivo. RNA pull-down/mass spectrometry experiments showed that LINC01234 interacted with the RNA-binding protein heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), which, in turn, led to the recruitment of DiGeorge syndrome critical region gene 8 (DGCR8), a subunit of the microRNA (miRNA) microprocessor complex. Accordingly, depletion of either LINC01234 or HNRNPA2B1 reduced the processing of several miRNA precursors, including primary microRNA (pri-miR)-106b. miR-106b-5p enhanced NSCLC cell growth by downregulating cryptochrome 2 (CRY2), thereby increasing c-Myc expression. Finally, we found that activated c-Myc binds to the LINC01234 promoter to increase its transcription, creating a c-Myc-LINC01234-HNRNPA2B1-miR-106b-5p-CRY2-c-Myc positive-feedback loop. We identified numerous lncRNAs with dysregulated expression in NSCLC and demonstrated a novel oncogenic axis involving LINC01234, HNRNPA2B1, miR-106b-5p, CRY2, and c-Myc. Components of this axis may be potential novel targets for NSCLC.

Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative autosomal-dominant or autosomal-recessive pattern. Here, using a comprehensive strategy combining whole-genome sequencing (WGS), long-read whole-genome sequencing (LRS), linkage analysis, repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR), we identified an abnormal GGC repeat expansion in the 5′ UTR of GIPC1 in one out of four families and three sporadic case subjects from a Chinese OPDM cohort. Expanded GGC repeats were further confirmed as the cause of OPDM in an additional 2 out of 4 families and 6 out of 13 sporadic Chinese individuals with OPDM, as well as 7 out of 194 unrelated Japanese individuals with OPDM. Methylation, qRT-PCR, and western blot analysis indicated that GIPC1 mRNA levels were increased while protein levels were unaltered in OPDM-affected individuals. RNA sequencing indicated p53 signaling, vascular smooth muscle contraction, ubiquitin-mediated proteolysis, and ribosome pathways were involved in the pathogenic mechanisms of OPDM-affected individuals with GGC repeat expansion in GIPC1. This study provides further evidence that OPDM is associated with GGC repeat expansions in distinct genes and highly suggests that expanded GGC repeat units are essential in the pathogenesis of OPDM, regardless of the genes in which the expanded repeats are located.

Lung cancer is the leading cause of cancer-related death worldwide. Owing to the difficulty in early diagnosis and the lack of effective treatment strategies, the 5-year survival rates for lung cancer remain very low. With the development of whole genome and transcriptome sequencing technology, long non-coding RNA (lncRNA) has attracted increasing attention. LncRNAs regulate gene expression at the epigenetic, transcriptional and post-transcriptional levels and are widely involved in a variety of diseases, including tumorigenesis. In lung cancer studies, multiple differentially expressed lncRNAs have been identified; several lncRNAs were identified as oncogenic lncRNAs with tumor-driving effects, while other lncRNAs play a role in tumor inhibition and are called tumor-suppressive lncRNAs. These tumor-suppressive lncRNAs are involved in multiple physiological processes such as cell proliferation, apoptosis, and metastasis and thus participate in tumor progression. In this review, we discussed the oncogenic and tumor-suppressive lncRNAs in lung cancer, as well as their biological functions and regulatory mechanisms. Furthermore, we found the potential significance of lncRNAs in clinical diagnosis and treatment.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib, have been established as first-line treatments for non-small cell lung cancer (NSCLC) patients and have exhibited notable clinical efficacy. However, resistance to TKIs has become one of the major obstacles in improving the therapeutic efficacy of patients with NSCLC. This study aims to investigate the role of the long non-coding RNA (lncRNA) LINC01116 in gefitinib resistance of NSCLC and explore its underlying mechanism. In this study, we found that LINC01116 is upregulated in the gefitinib-resistant NSCLC cells and tissues. Loss- and gain-of-function assays uncovered that LINC01116 downregulation sensitized gefitinib resistance, whereas the overexpression of LINC01116 conferred PC9/R cells to gefitinib resistance. Moreover, LINC01116 silencing increased IFI44 expression. Overexpression of IFI44 reversed the resistance to gefitinib in PC9/R cells, and rescue experiments confirmed that LINC01116 affects the gefitinib resistance of PC9/R cells partly dependent on regulating IFI44 expression. Moreover, downregulation of LINC01116 increased the sensitivity of PC9/R cells to gefitinib in vivo. Our study demonstrates that LINC01116 plays a critical role in gefitinib resistance of NSCLC cells by affecting IFI44 expression, providing a novel therapeutic target to overcome TKI resistance in NSCLC.

Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a common subtype of mitochondrial disease with high disability and mortality rate. The molecular mechanisms of MELAS are largely unknown and whether autophagy is activated in this disease remains controversial. In this work, we reported whole transcriptome profiling of skeletal muscle of MELAS patients and age-matched controls. Analyses revealed that MELAS patients had 224 differentially expressed genes (174 down-regulated, 50 up-regulated) compared to age-matched controls. Most of these genes relevant to MELAS are involved in signal transduction, metabolic process and immune system process. However, the RNA-seq data indicated that autophagy was not altered in MELAS. Functional assays showed that increased reactive oxygen species (ROS), decreased ATP production and decreased lysosome content in fibroblasts derived from MELAS patients, suggesting that mitochondrial dysfunction and degradation deficiency in MELAS. Furthermore, Western-blot analyses using skeletal muscle and fibroblasts derived from MELAS patients showed that autophagy was impaired in MEALS since two important autophagic genes: Beclin-1 and LC3-II, were significantly down-regulated. In conclusion, our study identified molecules and pathways involved in the mechanisms of MELAS, and the impairment of autophagy in this disease, which may serve as the potential therapeutic target for MELAS.

Natural killer cells are the first line of host immune surveillance and play major roles in the defence against infection and tumours. Hepatic NK cells exhibit unique phenotypic and functional characteristics compared to circulating and spleen NK cells, such as higher levels of cytolytic activity and cytotoxicity mediators against tumour cells. However, the activities of NK cells may be reversed during tumour progression. Recent studies demonstrated that hepatic NK cells were exhausted in hepatocellular carcinoma (HCC) and exhibited impaired cytolytic activity and decreased production of effector cytokines. The present review discusses current knowledge on the role of exhausted NK cells in promoting HCC development and the mechanisms contributing to tumour immune escape, including an imbalance of activating and inhibitory receptors on NK cells, abnormal receptor-ligand interaction, and cross-talk with immune cells and other stromal cells in the tumour environment. We provide a fundamental basis for further study of innate immunity in tumour progression and serve the purpose of exploring new HCC treatment strategies.

Titin, encoded by the gene TTN, is one of the main sarcomere components. It is involved in not only maintaining the structure of cardiac and skeletal muscles, but also in their development, extensibility, elasticity, and signaling events. Congenital titinopathy increasingly appears an important and common form of axial predominant congenital myopathy. The pathophysiological role of TTN in congenital titinopathy and pediatric heart diseases is yet to be explored. Here, we delineate the phenotype of two female siblings who developed severe congenital multi-minicore disease without cardiac involvement. Genetic investigation by whole exome sequencing demonstrated compound heterozygous TTN mutations (c.15496+1G>A, p.5166_5258del; c.18597_18598insC, p.Thr6200Hisfs*15), corresponding to the Ig domain of the proximal I-band. Aberrant splicing causing exon skipping was verified by in vitro minigene analysis. Our results suggest that TTN mutations affecting the Ig domain of the proximal I-band may be a cause of severe congenital defect in skeletal muscles without severe cardiac involvement, thereby providing evidence for the hypothesis that congenital titinopathy patients carrying biallelic N2BA only mutations are at lower cardiac risk than those with other combinations of mutations. Meanwhile, this study confirm the hypothesis on recessive truncating variants of TTN experimentally and thus support earlier reported genotype-phenotype correlations.

Multiple studies have revealed that long non-coding RNAs (lncRNAs) extensively participate in human cancer malignant progression. The long intergenic non-protein coding RNA 707 (LINC00707), 3087 bp in length, was recently reported to be an essential oncogene in promoting lung adenocarcinoma cell proliferation and metastasis. However, its role in gastric cancer (GC) remains unclear. In this study, we identified that LINC00707 was excessively expressed in GC tissues and correlated with advanced stage, larger tumor size, lymph node metastasis and poorer prognosis in GC patients. In vitro and in vivo assays showed that LINC00707 promote GC cell proliferation and metastasis. Mechanistically, LINC00707 could abundantly interact with mRNA stabilizing protein HuR; "LINC00707-HuR" coalition ulteriorly combined with VAV3/F11R mRNAs and increased their stability. Taken together, our findings prove that LINC00707 may act as an oncogene in GC by regulating mRNA stability and serve as a potential target for GC diagnosis and prognosis.

Lycopene, a tetraterpenoid containing 13 double bonds, has important pharmaceutical and industrial application values. However, unstable supply of raw for extracted from natural host and residue of chemical reagents in chemically synthesized products have limited the quality of lycopene. Engineering microorganism is thus regarded as an alternative and attractive route for lycopene production. To improve the ability of engineered yeast to synthesize lycopene, here we have optimized the lycopene biosynthesis pathway and chassis metabolism. The results have verified that S. cerevisiae CEN.PK2-1C was more suitable for lycopene production because of its strong ability of synthesizing precursors of terpenoids. Compared to use inducible promoter, the use of constitutive promoter controlling pathway expression was more efficient for balancing lycopene synthesis and chassis metabolism. GGPP was identified the rate-controlling metabolite. Through expanding GGPP pool and MVA pathway, lycopene production was thus significantly increased. By citric acid fed-batch fermentation, the yield of lycopene finally reached 115.64 mg/L, 2689-folds of initial engineered yeast. These results indicated that co-optimization of heterologous pathway and chassis metabolism is a good strategy for enforcing microbial overproduction of natural products.

The analysis of exosomes, which shows an increasing potential as prognostic biomarkers for non-invasive cancer diagnosis, can reveal their biological functions and disease associations. Nevertheless, the development of a convenient and quantitative method for determination of exosomes is still challenging. Herein, a novel approach for exosome quantification using pH test paper is developed via HRP-mediated promotion of mussel-inspired surface engineering and reagent-free functionalization of urease molecules. Uerase can hydrolyse urea into ammonia and carbon dioxide, and simultaneously raise the pH value of the solution. By establishing the relationship between exosome recognition and the change of pH value of the sensing solution, we can directly employ the low-cost, widely used and commercially available pH test paper to quantitatively analyse exosomes. The pH-responsive bioassay enables sensitive detection of exosomes with a detection of limit down to 4.46 × 103 particles/µL and can be successfully applied for determination of exosomes in clinical specimens. The versatility and reliability of our sensing platform may open up opportunities towards paper-based diagnosis of cancer.

With the rapid development of cloud computing, artificial intelligence technologies and big data applications, data centers have become widely deployed. High density IT equipment in data centers consumes a lot of electrical power, and makes data center a hungry monster of energy consumption. To solve this problem, renewable energy is increasingly integrated into data center power provisioning systems. Compared to the traditional power supply methods, renewable energy has its unique characteristics, such as intermittency and randomness. When renewable energy supplies power to the data center industrial park, this kind of power supply not only has negative effects on the normal operation of precision equipment, such as CPU/GPU chips and hard disk, in data center, but it would also impact the stability of the utility power grids operation. To solve this problem, this paper presents a novel tie-line power fluctuation smoothing algorithm with consideration of data center’s holistic demand response. The contributions of this paper are: (1) overcoming the limitations of treating IT load as uncontrollable workload in the traditional demand response research, we design a data center resource scheduling model to realize IT load demand response controllability; (2) two novel mechanisms are proposed: (i) the server cluster workload scheduling method with time shift mechanism, and (ii) the data center UPS (Uninterruptible Power Supply) energy storage dynamic response mechanism. (3) Combining these two mechanisms as holistic demand response of data center, we present a tie-line power fluctuation smoothing algorithm to improve power supply reliability, which is beneficial to both the high density and precision IT equipment in the data center and the utility power grid. In the experiments, the results show that the new algorithm can effectively regulate the tie-line power fluctuations under different server cluster utilization ranges and scenarios of large-scale penetration of distributed renewable energy scenarios. The new algorithm is hence able to contribute beneficially to the reliability and stability of intelligent industrial park micro-grid and utility power grids.

Breast cancer is a severe threat to the health and lives of women due to its difficult early diagnosis and the unsatisfactory therapeutic efficacy of breast cancer treatments. The development of theranostic strategies to combat breast cancer with high accuracy and effectiveness is therefore urgently needed. In this study, we describe a near-infrared (NIR) light-controllable, targeted and biocompatible drug delivery nanoplatform (PFH-PTX@PLGA/SPIO-Her) for photoacoustic (PA)/ultrasound (US) bimodal imaging-guided photothermal (PTT)/chemo synergistic cancer therapy of breast cancer. Carboxyl-modified PEGylated poly (lactic-co-glycolic acid) (PLGA-PEG-COOH) constituted the skeleton of the nanoplatform. Especially, the antibody Herceptin was modified onto the surface of nanoplatform for active HER2-targing to facilitate the tumor accumulation of the nanoplatform. The encapsulated superparamagnetic iron oxide (SPIO) nanoparticles could be employed as an excellent PA imaging agent to guide tumor therapy. When exposed to NIR light, the SPIO also could transform NIR light into thermal energy for photothermal ablation of tumor. The NIR-induced thermal effect subsequently triggered the optical droplet vaporization (ODV) of perfluorohexane (PFH) to generate PFH gas bubbles, which not only achieved the US imaging enhancement, but also contributed to the release of loaded paclitaxel (PTX) from the nanoplatform for significantly improving PTT therapeutic efficacy. Our results demonstrated that the targeted tumor accumulation, accurate real-time bimodal imaging, and the abundant drug release at the tumor site were all closely associated with the PTT therapeutic efficacy. Therefore, the theranostic nanoplatform is a very promising strategy for targeted imaging-guided photothermal/chemo synergistic tumor therapy with high therapeutic efficacy and minimized side effects. STATEMENT OF SIGNIFICANCE: Breast cancer is the most frequent cancer in women. Herein, we successfully developed a light-controllable and HER2 targeted theranostic nanoparticels (PFH-PTX@PLGA/SPIO-Her) as a specific drug delivery nanoplatform to overcome the low accuracy of tumor detection and the low specificity of traditional chemo-therapeutic protocols. The study demonstrated that PFH-PTX@PLGA/SPIO-Her could actively target to breast cancer cells with positive HER2 expression. The biocompatible PFH-PTX@PLGA/SPIO-Her nanoparticles as both photoacoustic/ultrasound bimodal imaging agents, photothermal-conversion nanomaterials (photothermal hyperthermia) and controllable drug delivery nanoagents (optical droplet vaporization) have completely eradicated the tumor without severe side effects. The theranostic strategy not only integrates strengthens of traditional imaging or therapeutic modalities, but also paves a new way for the efficient cancer treatment by taking the advantage of quickly-developing nanomedicine.

Our previous studies showed that paternal nicotine exposure can lead to hyperactivity in the offspring. Nevertheless, the cross-generational effects of maternal and biparental nicotine exposure remain unclear. In this study, female and male mice were exposed respectively by nicotine before pregnancy. The maternal pre-pregnancy nicotine exposure led to depression-like behaviors in the F1 offspring. However, after biparental pre-pregnancy nicotine exposure, seventy percentage of the offspring exhibited a depressive phenotype while 20% were hyperactive, and the remaining exhibited no obvious abnormal behavior. The cross-generational effects appeared to be mediated via disruption of the balance between GSK3 and p-GKS3 by nicotine. These results suggested that pre-pregnancy nicotine exposure can induce alterations in the behavior of the offspring, and the cross-generational effects of maternal nicotine exposure were particularly serious.

Autosomal recessive axonal neuropathy with neuromyotonia (ARAN NM) is a rare disease caused by mutations of histidine triad nucleotide binding protein 1 (HINT1) gene. ARAN NM has been reported mainly in European countries but little reported so far in China. We describe novel mutations of HINT1 in three Chinese patients with ARAN NM from unrelated families. Patient 1 was a 14-year-old girl who presented with progressive distal weakness of upper limbs at two years of age. After that, she reported weakness of both feet, and difficulty in muscle relaxation after making a fist. Patient 2 was an 18-year-old boy, who presented with progressive distal weakness of all limbs with foot drop at the age of ten with loss of ambulation at age 15. Patient 3 was a 26-year-old man who had been afflicted with weakness and atrophy of distal lower limbs since the age of 16 complaining about muscle stiffness of the lower limbs when standing and walking, and contraction of finger flexion muscles when releasing a forced grip. Electrodiagnostic testing revealed an axonal motor or sensorimotor neuropathy with or without myokymic discharges. Sural biopsy showed no pathological changes in patient 1 and mild axonal neuropathies with demyelination in patients 2 and 3. Genetic analysis revealed HINT1 with novel compound heterozygous c.112T > C (p.C38R) and c.171G > C (p.K57N) mutations in patient 1, homozygous c.112T > C (p.C38R) mutation in patient 2, as well as compound heterozygous c.112T > C (p.C38R) and c.98T > C (p.F33S) mutations in patient 3. Our study, for the first time, confirms ARAN NM in the Chinese population. These genetic findings can help expand the genotypic spectrum of HINT1 mutations.

In order to realize sustainable development of the whole economic society, the evaluation of the energy efficiency level of energy consumption sectors (ECSs) is urgent and necessary. This study elaborated the concept of the energy efficiency improvement from the perspective of whole society to establish a macro-evaluating system (MES). Industry, transport, civil buildings are the three major ECSs in China at present. By analyzing the status of each energy consumption sector (ECS) and the relative energy efficiency technologies, a hierarchical evaluation model, including evaluation factors, sub-factors, weights for each factor and sub-factor, was proposed for each ECS. With the help of the Analytic Hierarchy Process with Delphi (AHPD) and Grey Correlation Degree (GCD) method, the comprehensive scores, namely, the weighted incidence degree was obtained. Three cases in Tianjin, China were taken as examples to prove the feasibility of the evaluation system. Typical cities, including Shenyang, Beijing, Wuhan, Guangzhou, Chengdu, Xi'an, located in different regions of China were evaluated and compared. Results demonstrated that the technical level was mainly influenced by policy and economic level. Recommendations for energy efficiency policy making and energy efficiency targets allocating were proposed for regions based on the evaluation results.

Mitochondrial disease (MD) is a rare mitochondrial respiratory chain disorder with a high mortality and extremely challenging to treat. Although genomic, transcriptomic, and proteomic analyses have been performed to investigate the pathogenesis of MD, the role of metabolomics in MD, particularly of lipidomics remains unclear. This study was undertaken to identify potential lipid biomarkers of MD. An untargeted lipidomic approach was used to compare the plasma lipid metabolites in 20 MD patients and 20 controls through Liquid Chromatography coupled to Mass Spectrometry. Volcano plot analysis was performed to identify the different metabolites. Receiver operating characteristic (ROC) curves were constructed and the area under the ROC curves (AUC) was calculated to determine the potentially sensitive and specific biomarkers. A total of 41 lipids were significantly different in MD patients and controls. ROC curve analysis showed the top 5 AUC values of lipids (phosphatidylinositols 38:6, lysoPC 20:0, 19:0, 18:0, 17:0) are more than 0.99. Multivariate ROC curve based exploratory analysis showed the AUC of combination of top 5 lipids is 1, indicating they may be potentially sensitive and specific biomarkers for MD. We propose combination of these lipid species may be more valuable in predicting the development and progression of MD, and this will have important implications for the diagnosis and treatment of MD.

Exosomes are regarded as a promising biomarker in the diagnosis of disease due to their close relationship with the change of physiology and pathology. However, it is still a hard challenge to come up with a highly sensitive method for the exosomes detection. Herein, we propose a spherical nucleic acids (SNAs)-based cascade signal amplification strategy for the exosomes detection with high sensitivity. In this method, SNAs anchoring on exosomes membrane can be extended to form polyT sequence by terminal deoxynucleotidyl transferase (TdT), generating a template strand for the Exo III-catalyzed excision of the designed signal probe (probe A), which may finally induce significant decrease of electrochemical signal due to the consumption of probe A. Benefiting from the SNAs-based cascade signal amplification, this fabricated biosensor achieves a limit of detection for exosomes as low as 44 particles/μL. Moreover, this method shows good performance in the differentiation of healthy and malignancy colorectal cancer patients. Therefore, without complicated nucleic acids sequences design, our approach provides a cascade signal amplification strategy for the highly sensitive detection of exosomes and shows the potential applications in clinical diagnosis.

The typical effects of daily social experiences for most children are short-term solitude, and for some children, these sensations become cumulative and impair their academic success, general welfare, and mental health. Social partnerships are important to children's welfare, and there may be significant consequences of these relationships. In solitude and social anxiety, such disorders play a central role. In the absence of resolution of the dispute between peers, records of soleness, social anxiety, and social evasion are associated with youth. Although such relationships are well known, the relationship between peer conflict-avoidance and various adjustment features has not been investigated. The findings showed that children who report being lonely and anxious for others who have not reported being lonely are anxious. Essentially, the former spoke more often about family matters and intimate subjects and made up for their poor social skills and encountered new people. The research aimed to investigate the significance of the relation between anxiety and loneliness of social support and self-esteem. The modelling of structural equation revealed partial stabilization results between anguish and loneliness through social reinforcement and self-esteem. In addition, a multi-group study has found, relative to their counterparts, which infants appear to have more adverse assessments. The research obtains the results: Fear of negative evaluation ratio is 87.6%, Intercept loneliness ratio is 88.77%, Reduce social anxiety ratio is 84.5%, Depression reduction ratio is 82.25%, Improving the self-confidence ratio is 93.80%.

Mutations in the ganglioside-induced differentiation-associated protein 1 gene ( GDAP1 ) cause rare subtypes of Charcot–Marie–Tooth disease (CMT2K and CMT4A). CMT2K is an axonal neuropathy while CMT4A is a demyelinating type. In a series of 169 Chinese CMT patients (79 CMT1, 52 CMT2 and 38 unclassified), four unrelated patients (2.37%) were identified with GDAP1 mutations, including two with autosomal recessive CMT2K (AR-CMT2K) and two dominant CMT2K (AD-CMT2K). All patients had disease onset before 5 years of age, and presented with muscle weakness, atrophy, and mild sensory disturbance in distal limbs. Motor nerve conduction velocities of the median nerve were within normal ranges, and compound muscle action potential ranged from 1.5 to 3.8 mV. Sural nerve biopsy revealed loss of large myelinated fibers with regeneration clusters and a few onion bulbs. Electron microscopy showed mitochondrial aggregation in both axons and Schwann cells, and neurofilament accumulation in giant unmyelinated fibers. The p.H256R mutation was found in all patients with GDAP1 compound heterozygous mutations, suggesting that it might be a common mutation in Chinese patients. This study observed no difference in the disease onset, phenotype severity, electrophysiological findings, or pathological changes between AR-CMT2K and AD-CMT2K patients.

In order to keep sustainable development, the Chinese government has issued series of policies to reduce CO2 emissions. Renewable energy technologies applied in building field, mainly including solar energy and geothermal energy technologies, are recommended because of advances of energy efficiency, environmental protection and economic sustainability. Carbon trading has been widely accepted as an effective market approach, but it hasn’t covered the renewable energy application in building projects in China as yet. Reasonable solutions should be proposed to encourage building projects to participate in the carbon trading market. This paper aims at establishing a feasible mechanism to help improve the carbon market for renewable energy application in buildings. To attend this goal, this paper introduces and analyzes the status of carbon trading market and the position for building projects in China. By comparing the present mechanisms, Programmatic CDM with building portfolio is considered appropriate for building projects with renewable energy application. Volume verifying method, the core of the mechanism, is modified to fit the building projects. Then five different specific cases are studied to prove the practicality and reasonableness of the methodology. Programmatic CDM with modified verifying method is concluded as the proper mechanism for renewable energy application in buildings in carbon trading market.

Traditional analysis and design for networked control systems (NCSs) with state quantization have been investigated under single wired/wireless network environment. This paper studies the quantized control of distributed event-triggered NCSs under hybrid wiredwireless networks environment. Unlike the most existing NCSs, the controller communicates with distributed sensors through multiple wiredwireless channels and the measured signals from sensors might suffer from communication constraints of hybrid wiredwireless networks, which makes the quantized control of distributed event-triggered NCSs more complex. To reduce the communication burden of each channel, a distributed event-triggered mechanism and multiple quantization scheme are firstly proposed. The communication characters of hybrid wiredwireless networks are then analyzed, which are described by different Markov chains. Furthermore, a novel system model is presented, and a sufficient condition of the stochastic stability is derived. The relationship between the system stability criteria and the maximum hybrid wiredwireless network-induced delays, the event-generators parameters and multiple quantization parameters is established. Finally, simulation results confirm the effectiveness and feasibility of the proposed method.

Background: Emerging research indicates that long non-coding RNAs are involved in physiological and pathological processes, especially cancer. AFAP1-AS1 is a 6810-nt lncRNA located on chromosome 4p16.1 that was first reported to be up-regulated in esophageal adenocarcinoma tissues. However, its biological activities and underlying mechanisms in non-small cell lung cancer (NSCLC) remain to be fully elucidated. Methods: qRT-PCR was performed to determine AFAP1-AS1 expression in 96 paired NSCLC tissues and cell lines. The effect of AFAP1-AS1 on cell phenotype was assessed by CCK-8, colony formation, flow cytometry and EdU experiments, and a xenograft mouse model was used for in vivo studies. Transwell assays were arranged to detect cell migration. RNA transcriptome sequencing, RIP, ChIP and rescue assays were used to highlights the potential molecular mechanism. Findings: AFAP1-AS1 was generally up-regulated in NSCLC, and higher AFAP1-AS1 expression was significantly correlated with larger tumor size (p=0.008), lymph node metastasis (p=0.025), higher TNM stage (p=0.024), and worse overall survival in NSCLC patients. In vitro experiments revealed that AFAP1-AS1 down-regulation inhibited cell proliferation, migration and induced cell apoptosis; AFAP1-AS1 knockdown also hindered tumorigenesis in vivo. Moreover, mechanistic investigations revealed that AFAP1-AS1 repressed HBP1 (HMG box-containing protein 1) expression via recruiting demethylase LSD1 to the HBP1 promoter regions. Furthermore, rescue assays showed that the oncogenic function of AFAP1-AS1 is partially dependent on the epigenetic silencing of the tumor suppressor HBP1. Interpretation: Our results indicate that AFAP1-AS1 is carcinogenic and that the AFAP1-AS1 / LSD1 / HBP1 axis may constitute a potential factor or a new therapeutic direction for NSCLC. Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 81672307, 81871871), the Medical Innovation Team Foundation of the Jiangsu Provincial Enhancement Health Project (No. CXTDA2017021), the “333 high class Talented Man Project” (No. BRA2016509), the Nanjing Science and Technology Development Project (No. 2017sc512046), and the Jiangsu Graduate Scientific Research Innovation Program (No. KYCX18_1494). Declaration of Interest: The authors have no conflicts of interest to declare. Ethical Approval: We obtained written informed consent from all patients before surgery and the study was approved by the Research Ethics Committee of The Second Affiliated Hospital of Nanjing Medical University.

In addition to text data analysis, image analysis is an area that has increasingly gained importance in recent years because more and more image data have spread throughout the internet and real life. As an important segment of image analysis techniques, image restoration has been attracting a lot of researchers’ attention. As one of AI methodologies, Self-organizing Maps (SOMs) have been applied to a great number of useful applications. However, it has rarely been applied to the domain of image restoration. In this paper, we propose a novel image restoration method by leveraging the capability of SOMs, and we name it “boundary precedence image inpainting method based on SOMs”. In the proposed method, SOMs are used to separate a damaged image into different layers according to the pixel information of the image. Each pixel in the damaged area is considered to be a center of a square area, which is called a waiting-for-inpainting patch. The waiting-for-inpainting patch filling order is calculated by the boundary precedence method in which the information of the separated image layers obtained by SOMs is analyzed and used to calculate the filling order. According to the proposed method, the waiting-for-inpainting patches on the boundaries of the damaged region are restored first and the filling order of this proposed method depends on the precedence values of each waiting-for-inpainting patch. Case studies demonstrate the effectiveness of this proposed method. Both textural and structural information can be nicely repaired by the proposed method.

We consider a single degree freedom oscillator in order to accurately represent some modeling with ship roll damping. The proposed oscillator is a nonsmooth Rayleigh–Duffing equation x + a x + b x | x | + c x + d x 3 = 0 . The main goal of this paper is to study the global dynamics of the nonsmooth Rayleigh–Duffing oscillator in the case d 0 , i.e., the saddle case. The nonsmooth Rayleigh–Duffing oscillator is only C 1 so that many classical theory cannot be applied directly. In order to see the tendency of evolutions in a large range, we study not only its finite equilibria but also the equilibria at infinity. We find necessary and sufficient conditions for existence of limit cycles and heteroclinic loops respectively. Finally, we give the complete global bifurcation diagram and classify all global phase portraits in the Poincare disc in global parameters.

Predicted cooling load is a valuable tool for assessing the operation of air-conditioning systems. Compared with exterior cooling load, interior cooling load is more unpredictable. According to principle components analysis, occupancy was proved to be a typical factor influencing interior cooling loads in buildings. By exploring the regularity of interior disturbances in an office building, a simplified evaluation model for interior cooling load was established in this paper. The stochastic occupancy rate was represented by a Markov transition model. Equipment power, lighting power and fresh air were all related to occupancy rate based on time sequence. The superposition of different types of interior cooling loads was also considered in the evaluation model. The error between the evaluation results and measurement results was found to be lower than 10%. In reference to the cooling loads calculated by the traditional design method and area-based method in case study office rooms, the evaluated cooling loads were suitable for operation regulation.

Hepatitis C virus (HCV) can cause persistent infection and chronic liver disease, and viral factors are involved in HCV persistence. HCV core protein, a highly conserved viral protein, not only elicits an immunoresponse, but it also regulates it. In addition, HCV core protein interacts with toll-like receptors (TLRs) on monocytes, inducing them to produce cytokines. Polyinosinic acid:polycytodylic acid (polyI:C) is a synthetic analogue of double-stranded RNA that binds to TLR3 and can induce secretion of type I IFN from monocytes. Cytokine response against HCV is likely to affect the natural course of infection as well as HCV persistence. However, possible effects of cytokines induced by HCV core protein and polyI:C remain to be investigated. In this study, we isolated CD14(+) monocytes from healthy donors, cultured them in the presence of HCV core protein and/or polyI:C, and characterized the induced cytokines, phenotypes and mechanisms. We demonstrated that HCV core protein- and polyI:C-stimulated CD14(+) monocytes secreted tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-10, and type I interferon (IFN). Importantly, TNF-α and IL-1β regulated the secretion of IL-10, which then influenced the expression of signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 1 (IRF1) and subsequently the production of type I IFN. Interestingly, type I IFN also regulated the production of IL-10, which in turn inhibited the nuclear factor (NF)-κB subunit, reducing TNF-α and IL-1β levels. Therefore, IL-10 appears to play a central role in regulating the production of cytokines induced by HCV core protein and polyI:C.

The advent of Integrated Energy Systems enabled various distributed energy to access the system through different power electronic devices. The development of this has made the harmonic environment more complex. It needs low complexity and high precision of harmonic detection and analysis methods to improve power quality. To solve the shortages of large data storage capacities and high complexity of compression in sampling under the Nyquist sampling framework, this research paper presents a harmonic analysis scheme based on compressed sensing theory. The proposed scheme enables the performance of the functions of compressive sampling, signal reconstruction and harmonic detection simultaneously. In the proposed scheme, the sparsity of the harmonic signals in the base of the Discrete Fourier Transform (DFT) is numerically calculated first. This is followed by providing a proof of the matching satisfaction of the necessary conditions for compressed sensing. The binary sparse measurement is then leveraged to reduce the storage space in the sampling unit in the proposed scheme. In the recovery process, the scheme proposed a novel reconstruction algorithm called the Spectral Projected Gradient with Fundamental Filter (SPG-FF) algorithm to enhance the reconstruction precision. One of the actual microgrid systems is used as simulation example. The results of the experiment shows that the proposed scheme effectively enhances the precision of harmonic and inter-harmonic detection with low computing complexity, and has good capability of signal reconstruction. The maximum detection error reaches 0.0315%, and the reconstruction signals to noise ratio (SNR) is higher than 89 dB.

In the traditional mechanical design of new buildings, the occupancy number is usually over-estimated and results in over-predicted cooling loads and oversized chillers. When building occupancy is low relative to the design phase assumptions, those oversized chillers run inefficiently. To further explore the influence of occupancy on building cooling load design, the occupancy rate of office building is proposed in this paper and investigated with questionnaires. In a case study for an office building in Tianjin, the interior heat gain from occupants, lighting and equipment accounts for 66.6% of the total cooling load, while the part load ratio (PLR) of the chiller is only 30%. A Markov transition matrix is established based on the survey results. This paper describes the occupancy pattern of the building by using a stationary distribution of a one-step transition probability. A correction coefficient is proposed for the design phase cooling load calculation, which results in a 35.9% cooling load reduction for the building case study. The simulated cooling load is validated by consistency check according to the real cooling load. Assurance analysis is also conducted to calculate the design error and predicted operation error between simulated and actual cooling loads. With above analysis, interior disturbances resulting from occupant behavior are proved to be the most important uncertainty for building cooling load design.

Multiple Acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation. Most patients with late-onset MADD are clinically characterized by lipid storage myopathy with dramatic responsiveness to riboflavin treatment. Abnormalities of peripheral neuropathy have rarely been reported in patients with late-onset MADD. We describe six patients who presented with proximal limb weakness and loss of sensation in the distal limbs. Muscle biopsy revealed typical myopathological patterns of lipid storage myopathy and blood acylcarnitine profiles showed a combined elevation of multiple acylcarnitines supporting the diagnosis of MADD. However, nerve conduction investigations and sural nerve biopsies in these patients indicated severe axonal sensory neuropathy. Causative ETFDH gene mutations were found in all six cases. No other causative gene mutations were identified in mitochondrial DNA and genes associated with hereditary neuropathies through next-generation-sequencing panel. Late-onset patients with ETFDH mutations can present with proximal muscle weakness and distal sensory neuropathy, which might be a new phenotypic variation, but the precise underlying pathogenesis remains to be elucidated.

Accumulation and misincorporation of oxidative damaged 8-oxo-7,8-dihydroguanine triphosphates (8-oxo-dGTP) in genomic DNA may cause serious cellular function disorders. MutT Homolog 1 (MTH1), a protein enzyme that can help to prevent 8-oxo-dGTP misincorporation, plays critical roles in oxidative stress neutralization, oncogene-associated tumor malignancy, and anticancer therapies. So, in this work, a simple and function-oriented method is developed for the assay of MTH1 activity. Specifically, a mismatch-based (“8-oxoG: A” mismatch) DNA chain elongation strategy (MB-DCE) is firstly proposed to reveal the misincorporation efficiency of 8-oxo-dGTP. Then, further coupled with the inherent activity of MTH1 to prevent 8-oxo-dGTP misincorporation, a relationship can be established to reveal the activity of MTH1 through MB-DCE. As the method is designed directly towards the cellular function of MTH1, activity of MTH1 in different breast cancer cell lines has been detected, implying the potential application of this assay method for biomedical research and clinical diagnose in the future.

Background Charcot–Marie–Tooth 2A (CMT2A) is caused by mutations in mitochondrial fusion protein mitofusin 2 ( MFN2 ). CMT2A had a large variety of clinical symptoms and several cohort studies were published recently. This study is to summarized the clinical, electrophysiological, pathological and genetic features in Han Chinese CMT2A. Methods 20 patients from 12 unrelated Chinese families with MFN2 related CMT2A were collected. Clinical symptom, nerve conduction velocity study, sural nerve pathology and MFN2 gene mutation were retrospectively analyzed. Results We confirmed MFN2 gene mutation in 12 indexes. Nineteen of 20 (95%) patients were classified as early onset phenotypes of CMT2A, including four cases (20%) with infantile onset. Motor nerve conduction velocity (MNCV) of median nerve was above 38 m/s in 50% of patients and not recordable in remaining patients. MNCV was not affected by onset age, disease course and mutation site in different patients and MNCV had no correlation with severity of symptoms. Sural nerve biopsy revealed mixed axonal and demyelination change. Loss of myelinated fibers and atypical onions was found in all cases. Electron microscopic (EM) examination of sural nerve confirmed mitochondrial vacuation and aggregation both in myelinated and unmyelinated axons. Eight mutations were detected in 12 indexes, including two novel mutations. The amino acid residue at position 94 of MFN2 protein was a hot spot in Han Chinese patients, followed by R104W. Conclusions Eraly onset, even infantile onset was more common in our Chinese population. MNCV of median nerve could be either above 38 m/s or unrecordable in CMT2A. Pathologically, mixed axon and myelin change should be considered since onion change was frequently observed in most CMT2A.

Background Muscle pathology usually contributes to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS), even in patients without prominent muscle symptoms. We report a series of patients with MELAS without significant myopathic changes. Methods Twelve patients without ragged-red fibers (RRFs) on muscle pathology (RRF-negative group) and 99 patients with MELAS and RRFs and/or cytochrome c oxidase (COX)-deficient fibers (control RRF-positive group) were recruited. We analyzed clinical features, neuroimaging and pathological findings, gene mutation data, immunofluorescence assay of key respiratory chain subunits of complexes I and IV and mitochondrial DNA (mtDNA) mutation load in biopsied muscle samples. Results None of the RRF-negative patients had RRF or COX-negative fibers, but four patients had strongly succinate dehydrogenase-stained vessels (SSVs). There was a lower proportion of m.3243A>G and higher proportion of mitochondria-encoded ND gene mutations in RRF-negative than RRF-positive patients. The proportion of aphasia was relatively higher, while complex I and IV subunit abundance in muscle and mutation load were lower in RRF-negative than in RRF-positive patients. Conclusion RRF-negative patients had a similar disease course, clinical symptoms, and neuroimaging results to RRF-positive patients with MELAS. SSV is a valuable diagnostic indicator for MELAS. For highly suspected MELAS yet without positive myopathological findings, combined immunofluorescence and genetic studies should be used to achieve final diagnosis.

The accurate prediction of a building's electricity consumption can provide baselines for energy management and indicate the building's energy-saving potential. However, electricity utilization indicators based on the building area are no longer applicable because of the overall increase in the building area per person and occupant energy demand of buildings. To tackle this challenge, the building electricity consumption was split into ‘basic’ and ‘variable’ forms in this study and a two-part building electricity consumption prediction model based on human behavior was established. The basic electricity consumption is related to the building area, while the variable electricity consumption is related to the building occupancy. The probability function and Markov model were used to describe the electricity consumption caused by the randomness of occupancy in buildings. The model was validated using three campus buildings. Based on the comparison of the actual electricity bills of the campus buildings with the model prediction results, the model accuracy error is less than 5%. The results show that the building electricity consumption of a building has a growth limit when multiple people share a room, which is related to a person's initiative or ability to control the electricity use.