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The fate of soluble inorganic carbon in a soil carbon pool was affected by soil active minerals mainly though hydrogen bonds and cationic bridges, which was tightly related to pH values, ionic concentration, and accompanied cations.

This study describes a successful case of preimplantation genetic testing for the monogenic disease (PGT-M) of methylmalonic acidemia (MMA). To avoid the transmission of pathogenic mutations and unnecessary pregnancy termination we applied next-generation sequencing (NGS)-based haplotyping on a couple with a previously deceased MMA offspring. After embryo preparation, all samples were amplified successfully by whole genome amplification. We performed preimplantation genetic testing for aneuploidy (PGT-A) to determine the copy number of embryos' chromosomes. PGT-A results showed five blastocysts (2, 11, 14, 15 and 16) with balanced chromosomes (46, XN). Two techniques were used for PGT-M. Sanger sequencing was used to detect the mutations of

Target-directed dynamic combinatorial chemistry has emerged as a useful tool for hit identification, but has not been widely used, in part due to challenges associated with analyses involving complex mixtures. We describe an operationally simple alternative: in situ inhibitor synthesis and screening (ISISS), which links high-throughput bioorthogonal synthesis with screening for target binding by fluorescence. We exemplify the ISISS method by showing how coupling screening for target binding by fluorescence polarization with the reaction of acyl-hydrazides and aldehydes led to the efficient discovery of a potent and novel acylhydrazone-based inhibitor of human prolyl hydroxylase 2 (PHD2), a target for anemia treatment, with equivalent in vivo potency to an approved medicine.

Increasing evidence shows that human papillomavirus (HPV) E6/E7 deletion in cervical cancer cells may be related to the immunosuppressive tumor microenvironment and adverse reactions or resistance to immune checkpoint blockade. Here, we demonstrate that liposome delivery of CRISPR/cas9 can effectively knock out HPV, which, in turn, induces autophagy and triggers cell death-related immune activation by releasing damage-related molecular patterns. The results of in vivo experiments showed that HPV-targeting guide RNA-liposomes could promote CD8+ T cell infiltration in tumor tissues; enhance the expression of proinflammatory cytokines, such as interleukin-12, tumor necrosis factor-α, and interferon-γ, and reduce regulatory T cells and myeloid suppressor cells. The combination of HPV-targeting guide RNA-liposomes with immune checkpoint inhibitors and antiprogrammed death-1 antibodies produced highly effective antitumor effects. In addition, combination therapy induced immune memory in the cervical cancer model.

Background: Radiation-induced lung injury (RILI) is lacking effective therapeutic strategies. In this study, we conducted TGF-β1-based CRISPR/Cas9 gene therapy for RILI. Objectives: Mouse lungs were irradiated with a single-dose of 20-Gy gamma rays followed by intravenous administration of Ad-CRISPR-TGF-β1 or Ad- CRISPR-Null. Methods: Haematoxylin and eosin staining, as well as Masson staining were performed to observe lung morphology. Albumin and IgM concentrations in bronchoalveolar lavage fluid were measured by ELISA. Cytokine levels were measured using ELISA and/or real-time PCR with terminal deoxynucleotidyl transferase mediated nick-end labelling. Results: Ad-CRISPR-TGFβ1 improved histopathological and biochemical markers of lung injury, reduced secretion and expression of inflammatory cytokines, and inhibited progression of fibrosis. Importantly, the SK1/S1P axis—which is known to play a key role via S1P1 in TGF-β1-dependent S1PR pattern remodelling—is responsible for promoting fibrosis. Conclusion: Our results indicate novel insights for RILI therapy.

Targeted therapy for patients with hepatitis B virus (HBV) infection can lead to objective responses, although response times may be short. At the same time, the response rate to programmed cell death-1 (PD-1) treatment was more durable. It is speculated that HBV targeted therapy can synergistically enhance the antitumor activity with PD-1 blockade. To test this hypothesis, we evaluated the effect of crispr-cas9 on HBV and PD-1 in vitro and in vivo. We found that HBV targeting gRNA/cas9 induced a decrease in the expression of HBsAg, while the PD-1 gene could be knocked out by electroporation targeting gRNA / cas9 by polymerase chain reaction. In HBV transgenic mice, the immunophenotype and cytokine expression of human dendritic cells (DCS) were detected by crispr-cas9 system stimulation, flow cytometry and polymerase chain reaction. These results indicate that gRNA/cas9 treatment upregulates the expression of CD80, CD83 and CD86, and significantly increases the mRNA levels of IL-6, IL-12, IL-23 and tumor necrosis factor alpha. The combination of anti HBV and anti PD-1 therapy can inhibit HBV expression and significantly improve the survival of HBV transgenic mice. In addition, the combination therapy increased the production of interferon by T cells, and then enhanced the expression of Th1 related immunostimulatory genes, thereby reducing the transcription of regulatory / inhibitory immune genes. In general, this response can reshape the tumor microenvironment from immunosuppression to immune stimulation. Finally, anti HBV therapy can induce the expression of interferon dependent programmed cell death ligand-1 in HBV transgenic mice in vivo. To sum up, these results demonstrate that the combination of HBV targeted therapy and PD-1 immune checkpoint block has a strong synergistic effect, thus supporting the transformation potential of this combined therapy strategy in clinical treatment of HBV infection.

Background The purpose of present study was to determine whether obesity was associated with increased adverse outcomes after cardiac surgery. Methods This is a retrospective cohort study from a large international database called the Medical Information Mart for Intensive Care III (MIMIC-III). Patients who underwent cardiac surgery and greater than 18 years old were divided into either nonobese (BMI 2) or obese (BMI ≥ 30 kg/m2). The primary outcome of this study was 28-day mortality from the date of operation. Secondary outcomes included ICU mortality, 1-year mortality, incidence of postoperative atrial fibrillation (POAF), hospital length of stay (HOS_LOS) and ventilation-free days within 28 days (VFD_28). Results Multivariate logistic regression analysis revealed a negative effect of obesity on 28-day mortality, with an adjusted odds ratio (OR) of 1.57 (95% CI 1.14–2.16; p = 0.005). The association remained significant when PSM analysis and double robust analysis with all covariates were performed. In terms of 28-day mortality, the mediating effect of longer ventilation duration on obese patients was noticeable, and the proportion of the effect mediated was 8.2% (95% CI 2.1–25.5%; p = 0.012). Conclusions Among patients with cardiac surgery, obesity is associated with higher 28-day mortality. The longer ventilation duration may have mediated this effect. In future, considering the elevated incidence of the obese patients undergoing cardiac surgery, obesity stat should be included as one of the predictive variables for stratification of perioperative death risk.

This study aimed to determine the predictive relevance of mechanical power in the clinical outcomes (such as ICU mortality, hospital mortality, 90-day mortality, length of ICU stay, and number of ventilator-free days at day 28) of neurocritical patients. This is a retrospective cohort analysis of an open-access clinical database known as MIMIC–III. The study included patients who had sustained an acute brain injury and required invasive ventilation for at least 24 h. Demographic parameters, disease severity scores (Glasgow coma scale), comorbidities, vital signs, laboratory parameters and ventilator parameters were collected within the first 24 h of ICU admission. The main outcome was the relationship between MP and ICU mortality. A total of 529 patients were selected for the study. The critical value of MP was 12.16 J/min, with the area under the curve (AUC) of the MP was 0.678 (95% CI 0.637–0.718), and compared to the GCS scores, the MP performed significantly better in discrimination (DeLong’s test: p p p = 0.009; OR 1.01, 95% CI 1.00–1.02, p = 0.018, respectively) or obesity (OR 1.01, 95% CI 1.00–1.02, p = 0.012; OR 1.01, 95% CI 1.01–1.02, p

Liposomes are one of the most widely investigated carriers for CRISPR/Cas9 delivery. The surface properties of liposomal carriers, including the surface charge, PEGylation, and ligand modification can significantly affect the gene silencing efficiency. Three barriers of systemic CRISPR/Cas9 delivery (long blood circulation, efficient tumor penetration, and efficient cellular uptake/endosomal escape) are analyzed on liposomal carriers with different surface charges, PEGylations, and ligand modifications. Cationic formulations dominate CRISPR/Cas9 delivery and neutral formulations also have good performance while anionic formulations are generally not proper for CRISPR/Cas9 delivery. The PEG dilemma (prolonged blood circulation vs. reduced cellular uptake/endosomal escape) and the side effect of repeated PEGylated formulation (accelerated blood clearance) were discussed. Effects of ligand modification on cationic and neutral formulations were analyzed. Finally, we summarized the achievements in liposomal CRISPR/Cas9 delivery, outlined existing problems, and provided some future perspectives.

Targeted therapy results in objective responses in cervical cancer. However, the responses are short. In contrast, treatment with immune checkpoint inhibitors results in a lower responses rate, but the responses tend to be more durable. Based on these findings, we hypothesized that HPV16 E6/E7-targeted therapy may synergize with the PD-1 pathway blockade to enhance antitumor activity. To test hypothesis, we described for the first time the effects of the CRISPR/Cas9 that was targeted to the HPV and PD1 in vitro and in vivo. Our data showed that gRNA/cas9 targeted HPV16 E6/E7 induced cervical cancer cell SiHa apoptosis, and suggested that overexpression of PD-L1, induced by HPV16 E6/E7, may be responsible for lymphocyte dysfunction. In established SiHa cell- xenografted humanized SCID mice, Administration of gRNA-PD-1 together with gRNA-HPV16 E6/E7 treatment improved the survival and suppressed the tumor growth obviously. In addition, combination treatment increased the population of dendritic cells, CD8+ and CD4+ T lymphocyte cells. According, it enhanced the expression of Th1-associated immune-stimulating genes while reducing the transcription of regulatory/suppressive immune genes, reshaping tumor microenvironment from an immunosuppressive to a stimulatory state. These results demonstrate potent synergistic effects of combination therapy using HPV16 E6/E7-targeted therapy and immune checkpoint blockade PD1, supporting a direct translation of this combination strategy in clinic for the treatment of cervical cancer.

Background Mechanical power (MP), defined as the amount of energy produced by mechanical ventilation and released into the respiratory system, was reportedly a determining factor in the pathogenesis of ventilator-induced lung injury. However, previous studies suggest that the effects of MP were proportional to their involvement in the total lung function size. Therefore, MP normalized to the predicted body weight (norMP) should outperform the absolute MP value. The objective of this research is to determine the connection between norMP and mortality in critically ill patients who have been on invasive ventilation for at least 48 h. Methods This is a study of data stored in the databases of the MIMIC–III, which contains data of critically ill patients for over 50,000. The study involved critically ill patients who had been on invasive ventilation for at least 48 h. norMP was the relevant exposure. The major endpoint was ICU mortality, the secondary endpoints were 30-day, 90-day mortality; ICU length of stay, the number of ventilator-free days at day 28. Result The study involved a total of 1301 critically ill patients. This study revealed that norMP was correlated with ICU mortality [OR per quartile increase 1.33 (95% CI 1.16–1.52), p p = 0.004; OR 1.32, 95% CI 1.08–1.62, p = 0.008, respectively). But high norMP was associated with ICU mortality only in low PIP (OR 1.18, 95% CI 1.01–1.38, p = 0.034). Conclusion Our findings indicate that higher norMP is independently linked with elevated ICU mortality and various other clinical findings in critically ill patients with a minimum of 48 h of invasive ventilation.

Inhibition of the dioxygen sensing hypoxia-inducible factor prolyl hydroxylases has potential therapeutic benefit for treatment of diseases, including anaemia. We describe the discovery of a small-molecule probe useful for monitoring binding to human prolyl hydroxylase domain 2 (PHD2) via fluorescence polarisation. The assay is suitable for high-throughput screening of PHD inhibitors with both weak and strong affinities, as shown by work with clinically used inhibitors and naturally occurring PHD inhibitors.

The Warburg effect, characterized by energy production through a high rate of aerobic glycolysis, is a metabolic hallmark of cancer cells. We previously found that ginsenoside 20(S)-Rg3 upregulated miR-603 and impaired the malignancy of ovarian cancer cells by inhibiting the Warburg effect. However, the precise functional role of miR-603 in ovarian cancer progression remains poorly defined. Here, we report that the level of miR-603 in ovarian cancer tissues is significantly lower than that in para-tumor tissues. Overexpression of miR-603 in ovarian cancer cells inhibits the Warburg effect as evidenced by a decrease in glucose consumption, lactate production and hexokinase-2 (HK2) expression, reduces cell proliferation in vitro, and weakens their migration and invasion. Further, miR-603 directly targets HK2 as indicated in a luciferase reporter assay. In contrast to agomiR-NC, agomiR-603 treatment significantly inhibits tumor growth in vivo and the Warburg effect, which is illustrated by a decreased uptake of 18F-FDG in subcutaneous xenografts and HK2 downregulation. Finally, miR-603 is negatively regulated by DNMT3A-mediated DNA methylation in the promoter region of its precursor gene, suggesting that 20(S)-Rg3 antagonizes DNMT3A-mediated DNA methylation to impair growth, migration and invasion of ovarian cancer cells. In conclusion, miR-603 is a tumor suppressor targeting HK2 in ovarian cancer and its low level may result from DNMT3A-mediated methylation.

Long noncoding RNAs (LncRNA), a class of transcripts with lengths200 nt, play a master role in the regulation of cancer pathogenesis. Recently, the CRISPR-Cas9 system has been explored as a revolutionary genome editing tool for molecular biology. Growing evidence shows that LncRNAs can be targeted by the CRISPR-Cas9 system used for evaluating its function. Thus, the CRISPR-Cas9 systems provide a novel gene-editing strategy for the modification of LncRNA expression. This review summarizes current knowledge of the functions and underlying mechanisms of LncRNA by CRISPR-Cas9. Emerging strategies for non-viral/viral delivery of CRISPR-Cas9 in a clinical context are also discussed.

The stay-green leaf phenotype is typically associated with increased yields and improved stress resistance in maize breeding, due to higher nitrogen (N) nutrient levels that prolong greenness. The application of N fertilizer can regulate the N status of plants, and furthermore, impact the photosynthetic rates of leaves at the productive stage, however, N deficiencies and N excesses will reduce maize yields. Consequently, it is necessary to develop N fertilizer management strategies for different types of stay-green maize. For this study, the senescent cultivar Lianchuang 808 (LC808), moderate-stay-green cultivar Zhengdan 958 (ZD958), and over stay-green cultivar Denghai 685 (DH685) were selected as experimental models. Our results revealed that yields of ZD958 were slightly higher than DH685 and notably improved over than LC808. Compared with a non-stay-green cultivar LC808, ZD958 and DH685 still maintained higher chlorophyll contents and cell activities following the silking stage, while efficiently slowing the senescence rate. The supply of N fertilizer significantly prolonged leaf greenness and delayed senescence for ZD958 and DH685, however, the effect was not obvious for LC808. The stem remobilization efficiency of N was higher in the moderate-stay-green cultivar ZD958, in contrast to LC808, while the transfer of leaf N was lower than LC808, which guaranteed high leaf N levels, and that sufficient N was transferred to grains in ZD958. To obtain the highest yields, the optimal N fertilizer rates were 228.1 kg hm&minus, 2 for LC0808, 180 kg hm&minus, 2 for ZD958, and 203.8 kg hm&minus, 2 for DH685. In future, the selection of stay-green type crops might serve as an important agricultural strategy to reduce the quantity of N fertilizer and increase N efficiency.

Lateral flow assay (LFA) is user-friendly diagnostic tools but suffering limitations in poorer sensitivities and specificities especially for double-stranded DNA and single-base mutation quantification. Here, to improve the sensitivity and specificity for the LFA based nucleic acid detection, CRISPR-Cas12a mediated Surface enhanced Raman scattering (SERS) LFA was developed. By combination of ultra-sensitive SERS tags and target-specific signal amplification ability of CRISPR-Cas12a, HIV-1 dsDNA can be directly quantified with a LOD of 0.3 fM without any pre-amplification steps, which is almost 4 orders of magnitude lower than that of traditional colorimetric LFA methods. The whole detection process can be finished less than 1 h. Moreover, based on the target specificity of Cas12a, HIV-1 single-based drug resistance mutation (M184V) can be recognized as low as 0.01%. The HIV-1 dsDNA can also be successfully detected in serum samples with good comparable of that in buffer setting. Therefore, the simple and inexpensive paper-based CRISPR-SERS strip has great potential for point-of-care testing (POCT) of nucleic acid targets especially in resource-poor or non-laboratory environments.

Targeted therapy produces objective responses in bladder cancer patients, although the responses can be short. Meanwhile, response rates to immune therapy are lower, but the effects are more durable. Based on these findings, it was hypothesized that urothelial carcinoma associated 1 (UCA1)-targeted therapy could synergize with programmed cell death 1 (PD-1) blockade to enhance antitumor activity. To test this hypothesis, the effects of CRISPR-Cas9 targeting of UCA1 and PD-1 were assessed in vitro and in vivo. It was found that gRNA/cas9-targeted UCA1 induced apoptosis of 5637 bladder cancer cells, whereas PD-1 gene knockout could be achieved by electroporation of gRNA/cas9 targeting PD-1, as detected by polymerase chain reaction. In 5637 cell-xenografted humanized SCID mice, stimulation with CRISPR-Cas9 systems, immune phenotypes, and cytokine expression of human dendritic cells (DCs) was detected by flow cytometry, and polymerase chain reaction, respectively. The results of these assays suggested that the gRNA/cas9 treatment upregulated expression of CD80, CD83, and CD86 and significantly increased interleukin (IL)-6, IL-12, and IL-23 and tumor necrosis factor alpha mRNA levels. Co-administration of anti-PD-1 and anti-UCA1 treatment suppressed tumor growth and markedly improved survival of 5637 xenografted mice. Additionally, the combination treatment increased interferon gamma production by T cells that subsequently enhanced the expression of Th1-associated immune-stimulating genes to reduce transcription of regulatory/suppressive immune genes and reshape the tumor microenvironment from an immunosuppressive to a stimulatory state. Finally, anti-UCA1 treatment was shown to induce interferon gamma-dependent programmed cell death ligand 1 expression within 5637 xenograft tumors in vivo. Together, these results demonstrate potent synergistic effects of a combination therapy using LncRNA UCA1-targeted therapy and immune checkpoint blockade of PD-1, thus supporting the translational potential of this combination strategy for clinical treatment of bladder cancer.

Background: Ovarian cancer is a highly malignant gynecological cancer. Aerobic glycolysis is one of the features of cancer cell metabolism. Studying the molecular modulation of the Warburg effect in ovarian cancer is significantly valuable for understanding the progression mechanism of ovarian cancer. Materials and Methods: The expression level and prognostic significance of DNMT3A were analyzed using public databases. DNMT3A was overexpressed by plasmid transfection, and DNMT3A was interfered with specific siRNAs transfection. miR-603 was overexpressed by mimic transfection or inhibited by inhibitor transfection. The expression of the molecules was detected by qPCR or western blotting. CCK-8 and transwell assays were used to determine the cell proliferation, migration, and invasion abilities of ovarian cancer. Results: We found that the DNMT3A protein level was higher in ovarian cancer tissues than in normal ovary tissues, but the mRNA level had no significant difference in ovarian cancer tissues and normal ovary tissues. The higher the RNA level of DNMT3A, the poorer prognosis of patients. DNMT3A knocking down impeded the Warburg effect, cell proliferation, migration, and invasion of ovarian cancer cells. Further investigations discovered that DNMT3A promoted ovarian cancer cell malignancy via silencing miR-603. Conclusion: We found that patients who overexpressed DNMT3A showed a poor prognosis. DNMT3A was found to promote the Warburg effect, cell proliferation, migration, and invasion of ovarian cancer by inhibiting the expression of miR-603. As a result, the research revealed that DNMT3A/miR-603/HK2 axis contributed to the Warburg effect of ovarian cancer and DNMT3A may be a potential therapeutic target for ovarian cancer.

Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) technology enables targeted gene editing, but cancer gene therapy with this approach requires improvements to enable safe and efficient delivery of CRISPR/Cas9 to tumors. We developed and evaluated a self-assembled liposome to selectively deliver CRISPR/Cas9 to cancer tissues. Our CRISPR/Cas9 system effectively inhibited proliferation of human papillomavirus (HPV) 16-positive cervical cancer cells and induced apoptosis by inactivating the HR-HPV16E6/E7 oncogene. Based on this system, we prepared a long-circulating pH-sensitive cationic nano-liposome complex with a high cell targeting and gene knockout rate. Intratumoral injection of cationic liposomes targeted to splicing HPV16 E6/E7 in nude mice significantly inhibited tumor growth without significant toxicity in vivo. Liposomes that targeted HPV16 E6/E7 splicing were established as a basis for treatment of HPV16-positive cervical cancer drug candidates. Our study demonstrates that this liposome offers an efficient delivery system for nonviral gene editing, adding to the armamentarium of gene editing tools to advance safe and effective precision medicine-based cancer therapeutics.

Background: Current research focuses on reducing the level of HBV virus. We designed CRISPR/Cas9s that target the HBV genome. Methods: To prevent the emergence of escape mutant viruses, we mixed HBV-CRISPR/Cas9s (HBV-CRISPR/Cas9 complex). These HBV-CRISPR/Cas9s complexes were encapsulated in a nano-liposome complex, which is a hepatocyte-specific drug delivery system. CRISPR/Cas9 was used to assess delivery and knockout efficiencies of nano-liposome-gRNA-HBV complexes in the treatment of mice. The potency of the nano-liposome-gRNA-HBV complexes was evaluated in HepG2.2.15 cells and in HBV-Tg mice. Findings: Effective knockout of targets, efficient delivery of CRISPR/Cas9, and liver-specific delivery were observed with nano-liposome-gRNA-HBV complex treatment. Nano-liposome-gRNA-HBV complexes efficiently reduced HBsAg in vitro and in vivo. However, ETV treatment did not efficiently reduce HBsAg when compared with nano-liposome-gRNA-HBV complex treatment. In addition, the suppressive effects of nano-liposome-gRNA-HBV complexes persisted for 21 days in vitro and in vivo. We indicated that treatment with nano-liposome-gRNA-HBV complexes controlled HBV infection more efficiently than ETV treatment did. Furthermore, the effect of a single dose of nano-liposome-gRNA-HBV complexes persisted for a long time. Interpretation: The results demonstrate that nano-liposome-gRNA-HBV complex may be a promising novel HBV treatment that is more effective than reverse transcriptase inhibitors. Funding Statement: This study was supported by grants from the National Natural Science Foundation of China (Grant nos. 81602295 to Shuai Zhen). This study was supported by grants from Special Talent Training Program in Northwest Women and Children Hospital (2020ZD02) Declaration of Interests: The other authors declare that they have no competing interests. Ethics Approval Statement: All mouse experiments were conducted according to the National Institutes of Health Guidelines for Animal Care. All animal procedures were performed according to the guidelines developed by the China Council on Animal Care and the protocol was approved by the Xi’an jiaotong university.

Liposomes are one of the most widely investigated carriers for CRISPR/Cas9 delivery. The surface properties of liposomal carriers, including the surface charge, PEGylation, and ligand modification can significantly affect the gene silencing efficiency. Three barriers of systemic CRISPR/Cas9 delivery (long blood circulation, efficient tumor penetration, and efficient cellular uptake/endosomal escape) are analyzed on liposomal carriers with different surface charges, PEGylations, and ligand modifications. Cationic formulations dominate CRISPR/Cas9 delivery and neutral formulations also have good performance while anionic formulations are generally not proper for CRISPR/Cas9 delivery. The PEG dilemma (prolonged blood circulation vs. reduced cellular uptake/endosomal escape) and the side effect of repeated PEGylated formulation (accelerated blood clearance) were discussed. Effects of ligand modification on cationic and neutral formulations were analyzed. Finally, we summarized the achievements in liposomal CRISPR/Cas9 delivery, outlined existing problems, and provided some future perspectives. Liposomes are one of the most widely investigated carriers for CRISPR/Cas9 delivery. The surface properties of liposomal carriers, including the surface charge, PEGylation, and ligand modification can significantly affect the gene silencing efficiency. Three barriers of systemic siRNA delivery (long blood circulation, efficient tumor penetration, and efficient cellular uptake/endosomal escape) are analyzed on liposomal carriers with different surface charges, PEGylations, and ligand modifications. Cationic formulations dominate CRISPR/Cas9 delivery and neutral formulations also have good performance while anionic formulations are generally not proper for CRISPR/Cas9 delivery. The PEG dilemma (prolonged blood circulation vs. reduced cellular uptake/endosomal escape) and the side effect of repeated PEGylated formulation (accelerated blood clearance) were discussed. Effects of ligand modification on cationic and neutral formulations were analyzed. Finally, we summarized the achievements in liposomal CRISPR/Cas9 delivery, outlined existing problems, and provided some future perspectives.

A novel Eu-TiO₂ nanocomposite prepared by a sol-gel method is used for the degradation of rhodamine B (RhB) present in dyes wastewater. The X-ray diffraction (XRD), Raman spectroscopy and transmission electron microscopy (TEM) show the anatase phase and globular shape of Eu- TiO₂ nanocomposite, UV-vis diffuse reflectance spectroscopy and low temperature N₂ adsorption (BET) indicate Eu-TiO₂ possesses a narrow band gap (2.98 eV) and a high specific surface area (112.1 m² · g

Targeted therapy results in objective responses in cervical cancer. However, the responses are short. In contrast, treatment with immune checkpoint inhibitors results in a lower responses rate, but the responses tend to be more durable. Based on these findings, we hypothesized that HPV16 E6/E7-targeted therapy may synergize with the PD-1 pathway blockade to enhance antitumor activity. To test hypothesis, we described for the first time the effects of the CRISPR/Cas9 that was targeted to the HPV and PD1 in vitro and in vivo. Our data showed that gRNA/cas9 targeted HPV16 E6/E7 induced cervical cancer cell SiHa apoptosis, and suggested that overexpression of PD-L1, induced by HPV16 E6/E7, may be responsible for lymphocyte dysfunction. In established SiHa cell- xenografted humanized SCID mice, Administration of gRNA-PD-1 together with gRNA-HPV16 E6/E7 treatment improved the survival and suppressed the tumor growth obviously. In addition, combination treatment increased the population of dendritic cells, CD8+ and CD4+ T lymphocyte cells. According, it enhanced the expression of Th1-associated immune-stimulating genes while reducing the transcription of regulatory/suppressive immune genes, reshaping tumor microenvironment from an immunosuppressive to a stimulatory state. These results demonstrate potent synergistic effects of combination therapy using HPV16 E6/E7-targeted therapy and immune checkpoint blockade PD1, supporting a direct translation of this combination strategy in clinic for the treatment of cervical cancer.

Rationale The chromosome 18p deletion syndrome is a syndrome with a deletion of all or a portion of the short arm of the chromosome 18. The phenotypes of the chromosome 18p deletion syndrome vary widely among individuals due to differences in size and breakpoints and the involved genes on the deletions. Given the varied and untypical clinical presentation of this syndrome, the prenatal diagnosis of the syndrome still presents as a challenge. Patient concerns We described 4 China cases with different chromosomal breakpoints. In case 1, a woman who with mild phenotypes gave birth to a severely deformed fetus. Three other cases were for prenatal diagnosis. Their phenotypes are the increased nuchal translucency (INT) and the noninvasive prenatal testing (NIPT) indicated deletions on the chromosome 18p and severe hydronephrosis respectively. Diagnosis The 4 cases were diagnosed with chromosome 18p deletion syndrome through karyotype analysis and array-based comparative genomic hybridization (array-CGH). Interventions Karyotype analysis and array-based comparative genomic hybridization were used to analyze the abnormal chromosome. Outcomes Case 1 and case 2 revealed 11.51 and 12.39 Mb deletions in 18p11.32p11.21. Case 3 revealed 7.1 Mb deletions in 18p11.3218p11.23. Case 4 revealed 9.9 Mb deletions in 18p11.3218p11.22. Lessons In our report, we are the first to report that mother and progeny who have the same chromosomal breakpoint have different phenotypes, significantly. In addition, we found a new phenotype of chromosome 18p deletion syndrome in fetus, which can enrich the phenotypes of this syndrome in the prenatal diagnosis. Finally, we demonstrate that the individuals with different chromosomal breakpoints of 18p deletion syndrome have different phenotypes. On the other hand, the individuals with the same chromosomal breakpoints of 18p deletion syndrome may also have remarkably different phenotypes.

Objective Carfilzomib is a second-generation tetrapeptide epoxyketone proteasome inhibitor used in current clinical therapy of hematologic malignancies. The mechanism of proteasome inhibition in endometrial cancer is not very clear. Carfilzomib inhibition of type I endometrial carcinoma cell proliferation by inducing cell cycle arrest at the G2/M phase was investigated in our study. Materials and methods HEC-1-A and Ishikawa endometrial carcinoma cell lines and three tumor cell lines were treated by different concentrations of carfilzomib. Methyl thiazolyl tetrazolium (MTT) assay was used to detect cell viability. Flow cytometry was used to analyze the cell cycle. Western blot was used to detect proteins involved in cell cycle progression. Results Carfilzomib impaired viability of myelogenous leukemia cell line K562, cervical cancer cell line HeLa, hepatocellular carcinoma cell line SMCC-7721, and endometrial carcinoma cell lines HEC-1-A and Ishikawa. The cell cycle was arrested at the G2/M phase in carfilzomib-treated HEC-1-A endometrial carcinoma cells, while it was arrested at both S and G2/M phases in carfilzomib-treated Ishikawa cells. Carfilzomib treatment significantly induced p21 Waf1/ Cip1 and p27, while substantially reduced cyclin D3 and cyclin-dependent kinase 1. Conclusion This study showed that carfilzomib inhibited endometrial cancer proliferation by upregulating cyclin-dependent kinase inhibitors p21 Waf1/Cip1 and p27 Kip1 , and reducing cyclin-dependent kinase 1 to arrest the cell cycle at the G2/M phase.

Load forecasting plays a vital role in economic construction and national security. The accuracy of short-term load forecasting will directly affect the quality of power supply and user experience, and will indirectly affect the stability and safety of the power system operation. In this paper, we present a novel short-term load forecasting model, which combines influencing factors analysis, Wavelet Decomposition feature extraction, Radial Basis Function (RBF) neural networks and Bidirectional Long Short-Term Memory (Bi-LSTM) networks (WRL below). The model uses wavelet decomposition to extract the main features of load data, analyzes its correlation with influencing factors, and then constructs corresponding adjustment factors. The RBF neural networks are used to forecast the feature subsequence related to external factors. Other subsequences are input into Bidirectional LSTM networks to forecast future values. Finally, the forecasting results are obtained by wavelet inverse transform. Experiments show that the proposed short-term load forecasting method is effective and feasible.

Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. In the hope of developing a gene-specific therapy for HPV-related cancer, we established CRISPR/Cas9 targeting promoter of HPV 16 E6/E7 and targeting E6, E7 transcript, transduced the CRISPR/Cas9 into cervical HPV-16-positive cell line SiHa. The results showed that CRISPR/Cas9 targeting promoter, as well as targeting E6 and E7 resulted in accumulation of p53 and p21 protein, and consequently remarkably reduced the abilities of proliferation of cervical cancer cells in vitro. Then we inoculated subcutaneously cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9 targeting (promoter+E6+E7)-transcript. Our results may provide evidence for application of CRISPR/Cas9 targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy.

With the development of society, the energy as the restriction of human society's development is tension increasingly, solar energy as one kind of green non-pollution energy is developed and used gradually. The combination of solar energy water heating system and buildings become more and more closely, however, the power consumption of the pump as the main energy consumption of a solar energy water heating system, the setting of the pump circulating temperature influent the power consumption of the whole system directly. This paper mainly analyze the content above. In order to give some useful advice on the design and operate of the solar energy water heating system in the future.

In actual operation the centralized solar hot water system whether can more energy saving, influenced by the collector area design, system operation and control mode , installation accuracy and various factors so on. The analysis in this paper is mainly based on the measured data of the collector area key design parameters such as average daily water use, water temperature, the thermal collection efficiency, water tank and pipeline heat loss and other parameters, as well as the problem found in the test of the construction and operation control , put forward reasonable suggestions for energy saving potential, provide reference for the centralized solar hot water system design and operation in future.

Carfilzomib is a second-generation tetrapeptide epoxyketone proteasome inhibitor used in current clinical therapy of hematologic malignancies. The mechanism of proteasome inhibition in endometrial cancer is not very clear. Carfilzomib inhibition of type I endometrial carcinoma cell proliferation by inducing cell cycle arrest at the G2/M phase was investigated in our study.HEC-1-A and Ishikawa endometrial carcinoma cell lines and three tumor cell lines were treated by different concentrations of carfilzomib. Methyl thiazolyl tetrazolium (MTT) assay was used to detect cell viability. Flow cytometry was used to analyze the cell cycle. Western blot was used to detect proteins involved in cell cycle progression.Carfilzomib impaired viability of myelogenous leukemia cell line K562, cervical cancer cell line HeLa, hepatocellular carcinoma cell line SMCC-7721, and endometrial carcinoma cell lines HEC-1-A and Ishikawa. The cell cycle was arrested at the G2/M phase in carfilzomib-treated HEC-1-A endometrial carcinoma cells, while it was arrested at both S and G2/M phases in carfilzomib-treated Ishikawa cells. Carfilzomib treatment significantly induced p21This study showed that carfilzomib inhibited endometrial cancer proliferation by upregulating cyclin-dependent kinase inhibitors p21

PURPOSE: Human papillomavirus (HPV) type 16 is one of the major etiologic factors of cervical cancer. Our study aims to investigate the potentiality of the antiviral clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated Cas9 system (CRISPR/Cas9) targeting the E6 and E7 oncogenes of HPV16 as a potential chemosensitizer of cisplatin (cis-diaminedichloroplatinum II; CDDP) for cervical cancer. METHODS: Specifically, the therapeutic efficacy of combination of CDDP and HPV16 E6 + E7-CRISPR/Cas9 was assessed in cervical cancer cells and cervical cancer xenograft models. RESULTS: In vitro experiments showed that long-term exposure of SiHa cells to the HPV16 E6 + E7-CRISPR/Cas9 induced apoptosis, and its pro-apoptosis effect became more obvious when combined with CDDP. In vivo study found the efficacy of the combination of HPV16 E6 + E7-CRISPR/Cas9 and CDDP were superior to either of the treatments in term of apoptosis induction and metastasis inhibition. CONCLUSION: Collectively, our results suggested that HPV16 E6 + E7-CRISPR/Cas9 could be an effective sensitizer of CDDP chemotherapy in cervical cancer.

A new type of Fe-C-Si-B alloy was developed. The investigation on microstructure details and the mechanical properties were performed for different austempering combinations. The results indicated that the Fe-C-Si-B alloy comprises ferrite, pearlite and interdendritic eutectic borides in as-cast condition. The distribution of eutectic boride with a chemical formula of M2B (M represents Cr, Fe, Mn or Mo) and is much like that of carbide in high chromium white cast iron. Pure ausferrite structure that is consisted of bainitic ferrite and carbon-riched retained austenite can be obtained by austempering treatment to the Fe-C-Si-B alloy. No carbide would precipitate in the structure and there is not any morphology change of borides. The hardness of the Fe-C-Si-B alloy decreases with increasing of the austempering temperature, and decreases greatly in at the early stages (within 5 to 10 min) of austempering transformation. The transformation is almost finished after about 5 to 10 min when thehardness of the alloy does not change anymore. The Fe-C-Si-B alloy is a new kind of wear resistance material with bright application prospect.

// Shuai Zhen 1, 2, * , Ling Hua 3, * , Yun-Hui Liu 4 , Xiao-Min Sun 5 , Meng-Meng Jiang 6 , Wei Chen 5 , Le Zhao 1, 2 , Xu Li 1, 2 1 Center for Translational Medicine, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, P.R. China 2 Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P.R. China 3 Department of Veterinary Medicine, Rongchang Campus of Southwest University, Chongqing 402460, P.R. China 4 Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China 5 Center for Laboratory Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P.R. China 6 State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi’an 710032, Shaanxi, China * These authors have contributed equally to this work Correspondence to: Xu Li, email: lixu56@mail.xjtu.edu.cn Le Zhao, email: zhaole2@mail.xjtu.edu.cn Keywords: CRISPR/Cas9, long non-coding RNA, UCA1, bladder cancer Received: January 16, 2016 Accepted: December 12, 2016 Published: December 25, 2016 ABSTRACT CRISPR/Cas9 is a novel and effective genome editing technique, but its application is not widely expanded to manipulate long non-coding RNA (lncRNA) expression. The lncRNA urothelial carcinoma-associated 1 (UCA1) is upregulated in bladder cancer and promotes the progression of bladder cancer. Here, we design gRNAs specific to UCA1 and construct CRISPR/Cas9 systems targeting UCA1. Single CRISPR/Cas9-UCA1 can effectively inhibit UCA1 expression when transfected into 5637 and T24 bladder cancer cells, while the combined transfection of the two most effective CRISPR/Cas9-UCA1s can generate more satisfied inhibitory effect. CRISPR/Cas9-UCA1s attenuate UCA1 expression via targeted genome-specific DNA cleavage, resulting in the significant inhibition of cell proliferation, migration and invasion in vitro and in vivo . The mechanisms associated with the inhibitory effect of CRISPR/Cas9-UCA1 on malignant phenotypes of bladder cancer are attributed to the induction of cell cycle arrest at G1 phase, a substantial increase of apoptosis, and an enhanced activity of MMPs. Additionally, urinary UCA1 can be used as a non-invasive diagnostic marker for bladder cancer as revealed by a meta-analysis. Collectively, our data suggest that CRISPR/Cas9 technique can be used to down-modulate lncRNA expression, and urinary UCA1 may be used as a non-invasive marker for diagnosis of bladder cancer.

The cytochrome CYP1A1 gene has been implicated in the etiology of oral cancer. However, the results have been inconsistent. In this study, a meta-analysis was performed to clarify the associations of polymorphisms in CYP1A1 gene with oral cancer risk. Published literatures from PubMed, MEDLINE, EMBASE, and China National Knowledge infrastructure (CNKI) databases were retrieved. A total of 12 studies were included in this meta-analysis. We found that significant positive associations between CYP1A1*2A polymorphism and oral cancer risk in recessive model (CC vs. TC + TT, OR = 1.93), dominant model (CC + TC vs. TT, OR = 1.33), and additive model (CC vs. TT, OR = 1.97). In subgroup analysis based on the ethnicity of study population, significant associations were found in all three genetic models for Asians (recessive OR = 2.29, 95 % CI = 1.42–3.71; dominant OR = 1.54, 95 % CI = 1.03–2.31; additive OR = 2.39, 95 % CI = 1.47–3.88) but not non-Asians. For the smoking stratification, the result indicated a significant association between CYP1A1*2A polymorphism and oral cancer among the smoking subjects (OR = 1.83, 95 % CI = 1.47–2.26). This meta-analysis indicated a marked association of CYP1A1*2A polymorphisms with oral cancer risk, particularly among Asians, whereas there were significant interactions between the polymorphisms and cigarette smoking on oral cancer risk.

Whey acidic proteins (WAP) belong to a large gene family of antibacterial peptides that perform critical immune system functions. The function of human epididymis protein 4 (HE4), a 124-amino acid long polypeptide that has two whey acidic protein four-disulfide core (WFDC) domains, is not well studied. Here, a fusion gene encoding the HE4 protein fused to an IgG1 Fc domain was constructed. The recombinant HE4 protein was expressed as a secretory protein in Pichia pastoris and mammalian HEK293-F cells and was subsequently purified. Our data suggested that the HE4 protein produced by these two expression systems bound to both gram-negative and gram-positive bacteria, but demonstrated slightly inhibitory activity towards the growth of Staphylococcus aureus. Moreover, HE4 exhibited proteinase inhibitory activity towards trypsin, elastase, matrix metallopeptidase 9, and the secretory proteinases from Bacillus subtilis. The effects of glycosylation on the biochemical characterization of HE4 were also investigated. LC-ESI-MS glycosylation analysis showed that the high-mannose glycosylated form of HE4 expressed by P. pastoris has lower biological activity when compared to its complex-glycosylated form produced from HEK293-F cells. The implications of this are discussed, which may be provide theoretical basis for its important role in the development of cancer and innate immune system.

A Program for constructing of the virtual laboratory in the distance education is proposed. The implementation of the system and the interaction process are studied. It also points out the problems needed to be solved in the construction of the virtual laboratory.

Background Human papillomavirus (HPV) infection is considered the major cause of cervical cancer (CC), but a number of infected women do not develop invasive lesions, suggesting the role of genetic susceptibility and environmental co-factors for cancer outbreak. Glutathione S- transferases (GSTs) are multifunctional enzymes that play a key role in the detoxification of varieties of both endogenous products of oxidative stress and exogenous carcinogens. Methods MEDLINE, EMBASE, and Cochrane databases were searched. All studies evaluating the association between GSTM1 polymorphisms and cervical cancer were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed-or random-effects model. Results A total of 23 case-control studies were included in the meta-analysis. The overall result showed that the association between GSTM1 null genotype and risk for cervical cancer was statistically significant (OR = 1.56; 95%CI, 1.39–1.75). Subgroup analyses were performed based on ethnicity, smoking and HPV infection. Our results showed that smokers with null GSTM1 genotype had higher risk of cervical cancer (OR = 2.27, 95%CI, 1.46–3.54). For the ethnicity stratification, significant increased risk of null GSTM1 genotype was found in Chinese and Indian population, but no increased risk in other population was found. Conclusions this meta-analysis provided strong evidence that the GSTM1 genotype is associated with CC development, especially in Chinese and Indian populations. Smoking and HPV infection modified the association between the null GSTM1 genotype and CC.

Electricity information tracking systems are increasingly being adopted across China. Such systems can collect real-time power consumption data from users, and provide opportunities for artificial intelligence (AI) to help power companies and authorities make optimal demand-side management decisions. In this paper, we discuss power utilization improvement in Shandong Province, China with a deployed AI application - the Power Intelligent Decision Support (PIDS) platform. Based on improved short-term power consumption gap prediction, PIDS uses an optimal power adjustment plan which enables fine-grained Demand Response (DR) and Orderly Power Utilization (OPU) recommendations to ensure stable operation while minimizing power disruptions and improving fair treatment of participating companies. Deployed in August 2018, the platform is helping over 400 companies optimize their power consumption through DR while dynamically managing the OPU process for around 10,000 companies. Compared to the previous system, power outage under PIDS through planned shutdown has been reduced from 16% to 0.56%, resulting in significant gains in economic activities.