Moderate oxidation of algae-laden water: Principals and challenges.

The occurrence of seasonal algae blooms represents a huge dilemma for water resource management and has garnered widespread attention. Therefore, finding methods to control algae pollution and improve water quality is urgently needed. Moderate oxidation has emerged as a feasible way of algae-laden water treatment and is an economical and prospective strategy for controlling algae and endogenous and exogenous pollutants. Despite this, a comprehensive understanding of algae-laden water treatment by moderate oxidation, particularly principles and summary of advanced strategies, as well as challenges in moderate oxidation application, is still lacking. This review outlines the properties and characterization of algae-laden water, which serve as a prerequisite for assessing the treatment efficiency of moderate oxidation. Biomass, cell viability, and organic matter are key components to assessing moderate oxidation performance. More importantly, the recent advancements in employing moderate oxidation as a treatment or pretreatment procedure were examined, and the suitability of different techniques was evaluated. Generally, moderate oxidation is more promising for improving the solid-liquid separation process by the reduction of cell surface charge (stability) and removal/degradation of the soluble algae secretions. Furthermore, this review presents an outlook on future research directions aimed at overcoming the challenges encountered by existing moderate oxidation technologies. This comprehensive examination aims to provide new and valuable insights into the moderate oxidation process.

Hydrogen Sulfide Splitting into Hydrogen and Sulfur through Off-Field Electrocatalysis.

Hydrogen sulfide (H2S), a toxic gas abundant in natural gas fields and refineries, is currently being removed mainly via the Claus process. However, the emission of sulfur-containing pollutants is hard to be prevented and the hydrogen element is combined to water. Herein, we report an electron-mediated off-field electrocatalysis approach (OFEC) for complete splitting of H2S into H2 and S under ambient conditions. Fe(III)/Fe(II) and V(II)/V(III) redox mediators are used to fulfill the cycles for H2S oxidation and H2 production, respectively. Fe(III) effectively removes H2S with almost 100% conversion during its oxidation process. The H+ ions are reduced by V(II) on a nonprecious metal catalyst, tungsten carbide. The mediators are regenerated in an electrolyzer at a cell voltage of 1.05 V, close to the theoretical potential difference (1.02 V) between Fe(III)/Fe(II) and V(II)/V(III). In a laboratory bench-scale plant, the energy consumption for the production of H2 from H2S is estimated to be 2.8 kWh Nm-3 H2 using Fe(III)/Fe(II) and V(II)/V(III) mediators and further reduced to about 0.5 kWh Nm-3 H2 when employing well-designed heteropolyacid/quinone mediators. OFEC presents a cost-effective approach for the simultaneous production of H2 and elemental sulfur from H2S, along with the complete removal of H2S from industrial processes. It also provides a practical platform for electrochemical reactions involving solid precipitation and organic synthesis.

Response patterns of lncRNAs of the Spodoptera frugiperda (Lepidoptera: Noctuidae) larvae under 23 pesticide treatments.

The response of Spodoptera frugiperda genes toward insecticides is crucial for guiding insecticide use. The regulation of the S. frugiperda genes via long noncoding RNAs (lncRNAs) under insecticide treatment should be investigated. In this study, 452 differentially expressed lncRNAs were identified by analyzing RNA-sequencing data of S. frugiperda under 23 pesticide treatments. We found 59 and 43 differentially expressed lncRNAs that could regulate detoxification-related cytochrome P450 and UDP-glucuronosyltransferase genes, respectively. Furthermore, the target genes of differentially expressed lncRNAs were enriched in Pfam, including chitin bind 4 and gene ontology terms such as structural constituent of the cuticle, revealing their potential mechanism of action on the growth inhibition of S. frugiperda larvae. Insecticide-specific expression of lncRNAs highlights the properties and commonalities of different insecticide-induced lncRNA regulatory mechanisms. To conclude, the results of this study provide new insights and perspectives on the use of 23 insecticides via lncRNA regulation of mRNAs.

Pan-genome of Citrullus genus highlights the extent of presence/absence variation during domestication and selection.

The rich genetic diversity in Citrullus lanatus and the other six species in the Citrullus genus provides important sources in watermelon breeding. Here, we present the Citrullus genus pan-genome based on the 400 Citrullus genus resequencing data, showing that 477 Mb contigs and 6249 protein-coding genes were absent in the Citrullus lanatus reference genome. In the Citrullus genus pan-genome, there are a total of 8795 (30.5%) genes that exhibit presence/absence variations (PAVs). Presence/absence variation (PAV) analysis showed that a lot of gene PAV were selected during the domestication and improvement, such as 53 favorable genes and 40 unfavorable genes were identified during the C. mucosospermus to C. lanatus landrace domestication. We also identified 661 resistance gene analogs (RGAs) in the Citrullus genus pan-genome, which contains 90 RGAs (89 variable and 1 core gene) located on the pangenome additional contigs. By gene PAV-based GWAS, 8 gene presence/absence variations were found associated with flesh color. Finally, based on the results of gene PAV selection analysis between watermelon populations with different fruit colors, we identified four non-reference candidate genes associated with carotenoid accumulation, which had a significantly higher frequency in the white flesh. These results will provide an important source for watermelon breeding.

Split AAV8 Mediated ABCA4 Expression for Gene Therapy of Mouse Stargardt Disease (STGD1).

Adeno-associated virus (AAV)-based gene therapy has been shown to be safe and effective in numerous animal models and clinical trials for various ophthalmic diseases. Stargardt disease (STGD1; MIM #248200) is the most common autosomal recessive macular dystrophy disease, and the most common form is caused by mutations in the ABCA4 gene, a gene with 6.8 kb coding sequence. Split intein approaches increase the capacity of dual AAV gene therapy, but at the cost of reduced protein expression, which may be insufficient to achieve a therapeutic effect. In this study, we designed various dual split intein ABCA4 vectors and showed that the efficiency of expression of full-length ABCA4 protein is dependent on combinations of types and split sites of the intein system. The most efficient vectors were identified through in vitro screening, and a novel dual AAV8-ABCA4 vector was constructed and subsequently proven to express full-length ABCA4 protein at a high level, reducing bisretinoid formation and correcting the visual function of ABCA4-knockout mice. Furthermore, we evaluated therapeutic effects of different dosages by subretinal injection in mice model. Both therapeutic effects and safety were guaranteed under the treatment of 1.00 × 109 GC/eye. These results support the optimized dual AAV8-ABCA4 approach in future clinical translation for treatment of Stargardt disease.

Multiple Natural Polymers in Drug and Gene Delivery Systems.

BACKGROUND: Natural polymers are organic compounds produced by living organisms. In nature, they exist in three main forms, including proteins, polysaccharides and nucleic acids. In recent years, with the continuous research on drug and gene delivery systems, scholars have found that natural polymers have promising applications in drug and gene delivery systems due to their excellent properties such as biocompatibility, biodegradability, low immunogenicity and easy modification. However, since the structure, physicochemical properties, pharmacological properties and biological characteristics of biopolymer molecules have not yet been entirely understood, further studies are required before large-scale clinical application. METHODS: This review focuses on recent advances in the representative natural polymers such as proteins (albumin, collagen, elastin), polysaccharides (chitosan, alginate, cellulose) and nucleic acids. RESULTS: We introduce the characteristics of various types of natural polymers, and further outline the characterization methods and delivery forms of these natural polymers. CONCLUSION: Finally, we discuss possible challenges for natural polymers in subsequent experimental studies and clinical applications. It provides an important strategy for the clinical application of natural polymers in drug and gene delivery systems.

Short-Term Effect of Moderate Level Air Pollution on Outpatient Visits for Multiple Clinic Departments: A Time-Series Analysis in Xi'an China.

There is limited evidence concerning the association between air pollution and different outpatient visits in moderately polluted areas. This paper investigates the effects of moderate-level air pollution on outpatient visits associated with six categories of clinic department. We analyzed a total of 1,340,791 outpatient visits for the pediatric, respiratory, ear-nose-throat (ENT), cardiovascular, ophthalmology, and orthopedics departments from January 2016 to December 2018. A distributed lag nonlinear model was used to analyze the associations and was fitted and stratified by age and season (central heating season and nonheating season). We found SO2 had the largest effect on pediatrics visits (RR = 1.105 (95%CI: 1.090, 1.121)). Meanwhile, PM2.5 and SO2 had greater effects on ENT visits for people under 50 years old. The results showed a strong association between O3 and cardiovascular outpatient visits in the nonheating season (RR = 1.273, 95% CI: 1.189,1.358). The results showed every 10 µg/m3 increase in SO2 was associated with a lower number of respiratory outpatient visits. Significant different associations were observed in PM2.5, NO2, CO, and O3 on ophthalmology visits between the heating and nonheating seasons. Although no significant association has been found in existing studies, our findings showed PM2.5 and NO2 were significantly related to orthopedic outpatient visits for people under 60 (RR = 1.063 (95%CI: 1.032, 1.095), RR = 1.055 (95%CI: 1.011, 1.101)). This study also found that the effect-level concentrations of air pollutants for some clinic departments were lower than the national standards, which means that people should also pay more attention when the air quality is normal.

Multiple variation patterns of terpene synthases in 26 maize genomes.

Terpenoids are important compounds associated with the pest and herbivore resistance mechanisms of plants; consequently, it is essential to identify and explore terpene synthase (TPS) genes in maize. In the present study, we identified 31 TPS genes based on a pan-genome of 26 high-quality maize genomes containing 20 core genes (present in all 26 lines), seven dispensable genes (present in 2 to 23 lines), three near-core genes (present in 24 to 25 lines), and one private gene (present in only 1 line). Evaluation of ka/ks values of TPS in 26 varieties revealed that TPS25 was subjected to positive selection in some varieties. Six ZmTPS had ka/ks values less than 1, indicating that they were subjected to purifying selection. In 26 genomes, significant differences were observed in ZmTPS25 expression between genes affected by structural variation (SV) and those not affected by SV. In some varieties, SV altered the conserved structural domains resulting in a considerable number of atypical genes. The analysis of RNA-seq data of maize Ostrinia furnacalis feeding revealed 10 differentially expressed ZmTPS, 9 of which were core genes. However, many atypical genes for these responsive genes were identified in several genomes. These findings provide a novel resource for functional studies of ZmTPS.

Enhancing COVID-19 Epidemic Forecasting Accuracy by Combining Real-time and Historical Data From Multiple Internet-Based Sources: Analysis of Social Media Data, Online News Articles, and Search Queries.

BACKGROUND: The SARS-COV-2 virus and its variants pose extraordinary challenges for public health worldwide. Timely and accurate forecasting of the COVID-19 epidemic is key to sustaining interventions and policies and efficient resource allocation. Internet-based data sources have shown great potential to supplement traditional infectious disease surveillance, and the combination of different Internet-based data sources has shown greater power to enhance epidemic forecasting accuracy than using a single Internet-based data source. However, existing methods incorporating multiple Internet-based data sources only used real-time data from these sources as exogenous inputs but did not take all the historical data into account. Moreover, the predictive power of different Internet-based data sources in providing early warning for COVID-19 outbreaks has not been fully explored. OBJECTIVE: The main aim of our study is to explore whether combining real-time and historical data from multiple Internet-based sources could improve the COVID-19 forecasting accuracy over the existing baseline models. A secondary aim is to explore the COVID-19 forecasting timeliness based on different Internet-based data sources. METHODS: We first used core terms and symptom-related keyword-based methods to extract COVID-19-related Internet-based data from December 21, 2019, to February 29, 2020. The Internet-based data we explored included 90,493,912 online news articles, 37,401,900 microblogs, and all the Baidu search query data during that period. We then proposed an autoregressive model with exogenous inputs, incorporating real-time and historical data from multiple Internet-based sources. Our proposed model was compared with baseline models, and all the models were tested during the first wave of COVID-19 epidemics in Hubei province and the rest of mainland China separately. We also used lagged Pearson correlations for COVID-19 forecasting timeliness analysis. RESULTS: Our proposed model achieved the highest accuracy in all 5 accuracy measures, compared with all the baseline models of both Hubei province and the rest of mainland China. In mainland China, except for Hubei, the COVID-19 epidemic forecasting accuracy differences between our proposed model (model i) and all the other baseline models were statistically significant (model 1, t198=-8.722, P<.001; model 2, t198=-5.000, P<.001, model 3, t198=-1.882, P=.06; model 4, t198=-4.644, P<.001; model 5, t198=-4.488, P<.001). In Hubei province, our proposed model's forecasting accuracy improved significantly compared with the baseline model using historical new confirmed COVID-19 case counts only (model 1, t198=-1.732, P=.09). Our results also showed that Internet-based sources could provide a 2- to 6-day earlier warning for COVID-19 outbreaks. CONCLUSIONS: Our approach incorporating real-time and historical data from multiple Internet-based sources could improve forecasting accuracy for epidemics of COVID-19 and its variants, which may help improve public health agencies' interventions and resource allocation in mitigating and controlling new waves of COVID-19 or other relevant epidemics.

Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration.

Inhibition of vascular endothelial growth factor (VEGF) is the standard therapy for neovascular age-related macular degeneration (nAMD). However, anti-VEGF agents used in the clinic require repeated injections, causing adverse effects. Gene therapy could provide sustained anti-VEGF levels after a single injection, thereby drastically decreasing the treatment burden and improving visual outcomes. In this study, we developed a novel VEGF Trap, nVEGFi, containing domains 1 and 2 of VEGFR1 and domain 3 of VEGFR2 fused to the Fc portion of human IgG. The nVEGFi had a higher expression level than aflibercept under the same expression cassettes of adeno-associated virus (AAV)8 in vitro and in vivo. nVEGFi was found to be noninferior to aflibercept in binding and blocking VEGF in vitro. AAV8-mediated expression of nVEGFi was maintained for at least 12 weeks by subretinal delivery in C57BL/6J mice. In a mouse laser-induced choroidal neovascularization (CNV) model, 4 × 108 genome copies of AAV8-nVEGFi exhibited a significantly increased reduction in the CNV area compared with AAV8-aflibercept (78.1% vs. 63.9%, p < 0.05), while causing no structural or functional changes to the retina. In conclusion, this preclinical study showed that subretinal injection of AAV8-nVEGFi was long lasting, well tolerated, and effective for nAMD treatment, supporting future translation to the clinic.

Carrier strategies boost the application of CRISPR/Cas system in gene therapy.

Emerging clustered regularly interspaced short palindromic repeat/associated protein (CRISPR/Cas) genome editing technology shows great potential in gene therapy. However, proteins and nucleic acids suffer from enzymatic degradation in the physiological environment and low permeability into cells. Exploiting carriers to protect the CRISPR system from degradation, enhance its targeting of specific tissues and cells, and reduce its immunogenicity is essential to stimulate its clinical applications. Here, the authors review the state-of-the-art CRISPR delivery systems and their applications, and describe strategies to improve the safety and efficacy of CRISPR mediated genome editing, categorized by three types of cargo formats, that is, Cas: single-guide RNA ribonucleoprotein, Cas mRNA and single-guide RNA, and Cas plasmid expressing CRISPR/Cas systems. The authors hope this review will help develop safe and efficient nanomaterial-based carriers for CRISPR tools.

Examining the Relationships Between Air Pollutants and the Incidence of Acute Aortic Dissection with Electronic Medical Data in a Moderately Polluted Area of Northwest China.

This paper explored whether air pollutants influenced acute aortic dissection (AAD) incidence in a moderately polluted area. A total of 494 AAD patients' data from 2013 to 2016 were analyzed. The results showed that AAD had the strongest associations with PM10, SO2, NO2, CO, and O3 on the day before an AAD incident (lag1) and with PM2.5 two days before an incident (lag2) in single-pollutant model. In the three-pollutant model, PM10 was associated with the highest risk of adverse effects (RR = 1.37, 95% CI: 1.22, 1.53), whereas PM2.5 was associated with the lowest risk (RR = .83, 95% CI: .79, .88). Both PM2.5 and PM10 were affected by season, and SO2 was significantly different between heating and non-heating seasons as well. This study revealed significant associations between short-term PM2.5, PM10, and SO2 exposure and daily AAD incidence, showing that PM10 and SO2 were strong predictors of AAD incidence in a moderately polluted area.

YinQiSanHuang Jiedu decoction for the treatment of hepatitis B-related compensated liver cirrhosis: study protocol for a multi-center randomized controlled trial.

INTRODUCTION: Hepatitis B-related compensated liver cirrhosis is related to a higher risk of hepatocellular carcinoma, and antiviral therapy is the preferred method. As the pathological mechanisms of liver fibrosis are complex, drugs developed for a single target are difficult to be effective in clinical practice, so there are no chemical drugs or biological drugs with clear efficacy available for clinical application at present. Traditional Chinese medicine is a kind of medical science that has been gradually formed during thousands of years and continuously enriched by the people of all ethnic groups in China. Traditional Chinese medicine shows curative effects in the treatment of liver diseases, especially in the field of liver fibrosis prevention and treatment. This study aims to test the integrative medicine (Chinese medicine plus antiviral therapy) effective on lowing hepatocellular carcinoma risk among patients with hepatitis-related compensated liver cirrhosis. METHODS AND ANALYSIS: This is a multi-center randomized controlled trial, and a total of 5 hospitals and 802 patients will be involved in. All the subjects are randomly allocated to the YinQiSanHuang Jiedu decoction (YQSHD) group (n = 401) or the placebo group (n = 401). The YQSHD group receives YQSHD granule with entecavir (ETV), and the placebo group receives YQSHD placebo with ETV. The treatment period will last for 52 weeks, and the follow-up period for 52 ± 2 weeks. The primary outcome measure is the annual incidence of HCC. Outcomes will be assessed at baseline and after treatment. The objective of this trial is "the integrative of YQSHD with ETV reduce the annual incidence of HCC to 1%." ETHICS AND DISSEMINATION: The protocol has been approved by the Medical Ethics Committee of Guang'anmen Hospital, China (No.2019-006-KY), and the other centers in the trial will not begin recruiting until the local ethical approval has been obtained. Trial final results will be disseminated via publication. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900021532 . Registered on February 26, 2019.

Microstructure Evolution Mechanism of Wf/Cu82Al10Fe4Ni4 Composites under Dynamic Compression at Different Temperatures and Strain Rates.

Wf/Cu82Al10Fe4Ni4 composites were fabricated by the pressure infiltration method. The composites were compressed by means of a split Hopkinson pressure bar (SHPB) with strain rates of 800 and 1600 s-1 at different temperatures. The microstructure of the composites after dynamic compressing was analyzed by transmission electron microscopy (TEM). Observation revealed that there were high-density dislocations, stacking faults, twins, and recrystallization existing in the copper alloy matrix of the composites. High-density dislocations, stacking faults, and twins were generated due to the significant plastic deformation of the copper alloy matrix under dynamic load impact. We also found that the precipitated phase of the matrix played a role in the second phase strengthening; recrystallized microstructures of copper alloy were generated due to dynamic recrystallization of the copper alloy matrix under dynamic compression at high temperatures.

Direct synthesis of p-methyl benzaldehyde from acetaldehyde via an organic amine-catalyzed dehydrogenation mechanism.

p-Methyl benzaldehyde (p-MBA) is a class of key chemical intermediates of pharmaceuticals. Conventional industrial processes for p-MBA production involve the consecutive photochlorination, amination, and acid hydrolysis of petroleum-derived p-xylene, while producing vast pollutants and waste water. Herein, we report a direct, green route for selective synthesis of p-MBA from acetaldehyde using a diphenyl prolinol trimethylsilyl ether catalyst. The optimized p-MBA selectivity is up to 90% at an acetaldehyde conversion as high as 99.8%. Intermediate structure and 18O-isotope data revealed that the conversion of acetaldehyde to p-methylcyclohexadienal intermediates proceeds in an enamine-iminium intermediate mechanism. Then, controlled experiments and D-isotope results indicated that the dehydrogenation of p-methylcyclohexadienal to p-MBA and H2 is catalyzed by the same amines through an iminium intermediate. This is an example that metal-free amines catalyze the dehydrogenation (releasing H2), rather than using metals or stoichiometric oxidants.

In vivo PCSK9 gene editing using an all-in-one self-cleavage AAV-CRISPR system.

Adeno-associated virus (AAV)-mediated delivery of the clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9 (CRISPR-Cas9) has shown promising results in preclinical models. However, the long-term expression of Cas9 mediated by AAV in the post-mitotic cells raises concerns with specificity and immunogenicity. Thus, it would be advantageous to limit the duration of Cas9 expression following delivery. In this study, we have engineered an all-in-one self-cleavage AAV-CRISPR-Cas9 system to restrict the expression of Cas9 nuclease, which consists of a Cas9 nuclease from Staphylococcus aureus (SaCas9), a chimeric single guide RNA (sgRNA) molecule targeting PCSK9, and flanking sites targeted by this sgRNA. The self-cleavage system generated a negative feedback loop where Cas9 cut both the target genomic locus and the AAV vector, thus self-limiting the expression of Cas9. We demonstrated that this system could reduce ∼60% expression of SaCas9 protein and had a 20-fold reduction in off-target activity at 24 weeks post-vector administration in vivo. Moreover, the on-target editing efficacy was not compromised and resulted in a stable reduction in circulating PCSK9 and serum cholesterol. The inclusion of this self-cleavage system in gene-editing approaches could increase the safety profile of AAV-delivered genome-editing nucleases and thereby promote its clinical transformation.

BATF2 prevents glioblastoma multiforme progression by inhibiting recruitment of myeloid-derived suppressor cells.

The basic leucine zipper ATF-like transcription factor 2 (BATF2) has been implicated in inflammatory responses and anti-tumour effects. Little, however, is known regarding its extracellular role in maintaining a non-supportive cancer microenvironment. Here, we show that BATF2 inhibits glioma growth and myeloid-derived suppressor cells (MDSCs) recruitment. Interestingly, extracellular vesicles (EVs) from BATF2-overexpressing glioma cell lines (BATF2-EVs) inhibited MDSCs chemotaxis in vitro. Moreover, BATF2 inhibited intracellular SDF-1α and contributes to decreased SDF-1α in EVs. In addition, BATF2 downregulation-induced MDSCs recruitment were reversed by blocking SDF-1α/CXCR4 signalling upon AMD3100 treatment. Specifically, detection of EVs in 24 pairs of gliomas and healthy donors at different stages revealed that the abundance of BATF2-positive EVs in plasma (BATF2+ plEVs) can distinguish stage III-IV glioma from stage I-II glioma and healthy donors. Taken together, our study identified novel regulatory functions of BATF2 in regulating MDSCs recruitment, providing a prognostic value in terms of the number of BATF2+ plEVs in glioma stage.

Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer.

Tumor metastasis is the major cause of poor prognosis and mortality in colorectal cancer (CRC). However, early diagnosis of highly metastatic CRC is currently difficult. In the present study, we screened for a novel biomarker, GDNF family receptor alpha 1 (GFRA1) based on the expression and methylation data in CRC patients from The Cancer Genome Altlas (TCGA), followed by further analysis of the correlation between the GFRA1 expression, methylation, and prognosis of patients. Our results show DNA hypomethylation-mediated upregulation of GFRA1 in invasive CRC, and it was found to be correlated with poor prognosis of CRC patients. Furthermore, GFRA1 methylation-modified sequences were found to have potential as methylation diagnostic markers of highly metastatic CRC. The targeted demethylation of GFRA1 by dCas9-TET1CD and gRNA promoted CRC metastasis in vivo and in vitro. Mechanistically, demethylation of GFRA1 induces epithelial-mesenchymal transition (EMT) by promoting AKT phosphorylation and increasing c-Jun expression in CRC cells. Collectively, our findings indicate that GFRA1 hypomethylation can promote CRC invasion via inducing EMT, and thus, GFRA1 methylation can be used as a biomarker for the early diagnosis of highly metastasis CRC.