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Abstract Background Evidence for the efficacy of pharmacological therapies for heart failure with reduced ejection fraction (HFrEF) is growing. However, there is no consensus on the most effective treatment for HFrEF. This study aimed to evaluate the most effective combination of pharmacological therapy in patients with HFrEF. Methods We systematically searched Medline, Embase, and CENTRAL up to Feb 2022, to include randomized controlled trials (RCTs) that evaluated the efficacy of pharmacological treatment among adults (≥ 18 years) with a diagnosis of HFrEF (defined by a left ventricular ejection fraction ≤ 45%). The outcomes of interest included all-cause death, cardiovascular (CV) death, and hospitalization for heart failure (HHF). A random network meta-analysis using a frequentist framework model was employed to calculate the pooled risk ratio (RR) with 95% confidence interval (CI) and rank the treatments. Results We included 49 RCTs involving 90,529 participants with HFrEF. For reducing all-cause mortality, the combination of angiotensin-converting enzyme inhibitors (ACEI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), and sodium-glucose co-transporter-2 inhibitors (SGLT2i) was most effective (RR, 0.46; 95% CI, 0.32–0.66). For CV death, the combination of ACEI, BB, MRA, and Vericiguat showed the highest efficacy (RR, 0.34; 95% CI, 0.12–0.90). Regarding reducing HHF, the combination of ACEI, BB, MRA, and SGLT2i as well as the combination of ACEI, BB, MRA, and Ivabradine were equally the most effective (both RR, 0.27; 95% CI, 0.18–0.39). Conclusion This study provides robust evidence supporting the use of combination therapies in HFrEF management, with newer agents offering incremental benefits when added to established guideline-directed medical therapy.

Abstract Understanding interplay of breast cancer and microenvironment is critical. Here we identified two transcriptomic subtypes and five immune infiltration patterns from RNA-seq and multiplex immunohistochemistry from 21 ER + /HER2- ILCs. We found proliferative subtype associated with increased suppressive immune infiltration, and defined a signature associated with lower proliferative, pro-inflammatory TAM infiltration, and improved survival in ER+ breast cancer. Our work identified genes related to ILC immune microenvironment and prognosis.

Background: Diabetes Mellitus (DM), a chronic metabolic disease characterized by elevated blood glucose, is caused by various degrees of insulin resistance and dysfunctional insulin secretion, resulting in hyperglycemia. The loss and failure of functional β-cells are key mechanisms resulting in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Aim of review: Elucidating the underlying mechanisms of β-cell failure, and exploring approaches for β-cell neogenesis to reverse β-cell dysfunction may provide novel strategies for DM therapy. Key scientific concepts of review: Emerging studies reveal that genetic susceptibility, endoplasmic reticulum (ER) stress, oxidative stress, islet inflammation, and protein modification linked to multiple signaling pathways contribute to DM pathogenesis. Over the past few years, replenishing functional β-cell by β-cell neogenesis to restore the number and function of pancreatic β-cells has remarkably exhibited a promising therapeutic approach for DM therapy. In this review, we provide a comprehensive overview of the underlying mechanisms of β-cell failure in DM, highlight the effective approaches for β-cell neogenesis, as well as discuss the current clinical and preclinical agents research advances of β-cell neogenesis. Insights into the challenges of translating β-cell neogenesis into clinical application for DM treatment are also offered.

Exosomes are extracellular vesicles that are released from the cell into the extracellular microenvironment, and are a carrier of biological information transmitted over long distances, which have a dual regulatory effect on the immune system. Studies have shown that viruses can hold the endosomal-exosomal pathway hostage to spread. This review describes the role played by exosomes in viral infections. On the one hand, exosomes can transmit antiviral substances and trigger immune responses against viral infections, and on the other hand, exosomes can serve as potential mediators of viral transmission, which have been shown to be closely related to the transmission and immune escape of a variety of viruses. Understanding the role of exosomes in viral infections is essential for the detection of viruses in the blood, for improving blood safety, and for the search and development of antiviral drugs.

Abstract Purpose To develop a radiomics-based model using [68Ga]Ga-PSMA PET/CT to predict postoperative adverse pathology (AP) in patients with biopsy Gleason Grade Group (GGG) 1–2 prostate cancer (PCa), assisting in the selection of patients for active surveillance (AS). Methods A total of 75 men with biopsy GGG 1–2 PCa who underwent radical prostatectomy (RP) were enrolled. The patients were randomly divided into a training group (70%) and a testing group (30%). Radiomics features of entire prostate were extracted from the [68Ga]Ga-PSMA PET scans and selected using the minimum redundancy maximum relevance algorithm and the least absolute shrinkage and selection operator regression model. Logistic regression analyses were conducted to construct the prediction models. Receiver operating characteristic (ROC) curve, decision curve analysis (DCA), and calibration curve were employed to evaluate the diagnostic value, clinical utility, and predictive accuracy of the models, respectively. Results Among the 75 patients, 30 had AP confirmed by RP. The clinical model showed an area under the curve (AUC) of 0.821 (0.695–0.947) in the training set and 0.795 (0.603–0.987) in the testing set. The radiomics model achieved AUC values of 0.830 (0.720–0.941) in the training set and 0.829 (0.624–1.000) in the testing set. The combined model, which incorporated the Radiomics score (Radscore) and free prostate-specific antigen (FPSA)/total prostate-specific antigen (TPSA), demonstrated higher diagnostic efficacy than both the clinical and radiomics models, with AUC values of 0.875 (0.780–0.970) in the training set and 0.872 (0.678–1.000) in the testing set. DCA showed that the net benefits of the combined model and radiomics model exceeded those of the clinical model. Conclusion The combined model shows potential in stratifying men with biopsy GGG 1–2 PCa based on the presence of AP at final pathology and outperforms models based solely on clinical or radiomics features. It may be expected to aid urologists in better selecting suitable patients for AS.

IntroductionGene regulatory networks (GRNs) reveal the intricate interactions between and among genes, and understanding these interactions is essential for revealing the molecular mechanisms of cancer. However, existing algorithms for constructing GRNs may confuse regulatory relationships and complicate the determination of network directionality.MethodsWe propose a new method to construct GRNs based on causal strength and ensemble regression (CSER) to overcome these issues. CSER uses conditional mutual inclusive information to quantify the causal associations between genes, eliminating indirect regulation and marginal genes. It considers linear and nonlinear features and uses ensemble regression to infer the direction and interaction (activation or regression) from regulatory to target genes.ResultsCompared to traditional algorithms, CSER can construct directed networks and infer the type of regulation, thus demonstrating higher accuracy on simulated datasets. Here, using real gene expression data, we applied CSER to construct a colorectal cancer GRN and successfully identified several key regulatory genes closely related to colorectal cancer (CRC), including ADAMDEC1, CLDN8, and GNA11.DiscussionImportantly, by integrating immune cell and microbial data, we revealed the complex interactions between the CRC gene regulatory network and the tumor microenvironment, providing additional new biomarkers and therapeutic targets for the early diagnosis and prognosis of CRC

Abstract Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2β rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2β controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which reduces Mi-2β ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.

Abstract Background O-GlcNAcylation modification affects multiple physiological and pathophysiolocal functions of cells. Altered O-GlcNAcylation was reported to participate in antivirus response. Stimulator of interferon genes (STING) is an adaptor mediating DNA virus-induced innate immune response. Whether STING is able to be modified by O-GlcNAcylation and how O-GlcNAcylation affects STING-mediated anti-DNA virus response remain unknown. Methods Metabolomics analysis was used for detecting metabolic alterations in HSV-1 infection cells. Succinylated wheat germ agglutinin (sWGA), co-immunoprecipitation, and pull-down assay were employed for determining O-GlcNAcylation. Mutagenesis PCR was applied for the generation of STING mutants. WT and Sting1 −/− C57BL/6 mice (KOCMP-72512-Sting1-B6NVA) were infected with HSV-1 and treated with O-GlcNAcylation inhibitor for validating the role of STING O-GlcNAcylation in antiviral response. Results STING was functionally activated by O-GlcNAcylation in host cells challenged with HSV-1. We demonstrated that this signaling event was initiated by virus infection-enhanced hexosamine biosynthesis pathway (HBP). HSV-1 (or viral DNA mimics) promotes glucose metabolism of host cells with a marked increase in HBP, which provides donor glucosamine for O-GlcNAcylation. STING was O-GlcNAcylated on threonine 229, which led to lysine 63-linked ubiquitination of STING and activation of antiviral immune responses. Mutation of STING T229 to alanine abrogated STING activation and reduced HSV-1 stimulated production of interferon (IFN). Application of 6-diazo-5-oxonorleucine (DON), an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAcylation, markedly attenuated the removal of HSV-1 in wild type C57BL/6 mice, leading to an increased viral retention, elevated infiltration of inflammatory cells, and worsened tissue damages to those displayed in STING gene knockout mice. Together, our data suggest that STING is O-GlcNAcylated in HSV-1, which is crucial for an effective antiviral innate immune response. Conclusion HSV-1 infection activates the generation of UDP-Glc-NAc by upregulating the HBP metabolism. Elevated UDP-Glc-NAc promotes the O-GlcNAcylation of STING, which mediates the anti-viral function of STING. Targeting O-GlcNAcylation of STING could be a useful strategy for antiviral innate immunity.

Abstract Cytoplasmic projections (CPs) formed by the generative and sperm cells link the male gametes with the vegetative cell (VC) nucleus, which are required to build the male germ unit (MGU) assemblage in the angiosperm pollen grain. As molecular and genetic controls underlying CP development and formation of the MGU are unknown, it was hypothesized that physical association between germ cells and the VC nucleus might be lost in germ unit malformed (gum) mutants or in those which either block generative cell (GC) division or that additionally prevent gamete differentiation. In vivo, analysis of marked cellular components demonstrated a linkage of sperm cells (SCs) and the VC nucleus in gum mutant alleles despite their increased physical separation. Similarly, for several independent classes of bicellular pollen mutants, undivided GCs were associated with the VC nucleus like GCs in wild‐type pollen. We conclude that the early formation of GC CPs to establish the MGU is regulated independently of DUO1‐DAZ1 and DUO3 transcription factors as well as cyclin‐dependent kinase function (CDKA;1). As the absence of cytoplasmic protrusion was expected in the gum mutants in Arabidopsis, early histological studies reported temporal disappearance of cytoplasmic protrusion in several organisms. Our findings demonstrated the striking importance of live imaging to verify the broad conservation of the persistent MGU contact in all the angiosperms and its important role in successful double fertilization.

BackgroundPost-stroke depression (PSD) is a prevalent psychiatric disorder affecting about one-third of stroke survivors, significantly hindering recovery and quality of life. PSD also imposes a substantial burden on caregivers and healthcare systems. Aromatherapy has shown promise in alleviating depression, anxiety, and sleep disorders. This pilot randomized controlled trial aims to assess the feasibility and preliminary efficacy of mixed herb aromatherapy in treating PSD. Feasibility outcomes encompass recruitment, intervention adherence, assessment completion and safety assessment. Secondary outcomes include evaluations of depression, anxiety, cognitive function, sleep quality, quality of life, and brain function using EEG and fNIRS.MethodsThis single-blind pilot randomized controlled trial will be conducted at the Second Rehabilitation Hospital of Shanghai, enrolling ninety-nine post-stroke patients with PSD. Participants will be randomized into three groups: a Non-Active Control Group receiving standardized rehabilitation therapy, a CBT Group receiving conventional rehabilitation with bi-weekly CBT sessions, and an Aromatherapy Group receiving conventional rehabilitation with daily aromatic inhalation sessions. Interventions will last for four weeks, with efficacy assessed at baseline, post-intervention, and one month post-intervention. Rating scales will be used to measure changes in depression, sleep quality, cognitive function, and quality of life. EEG and fNIRS will specifically be used to measure changes in cerebral cortex activity and their correlations with depression. Feasibility will be evaluated through recruitment, intervention adherence, assessment completion and safety assessment.DiscussionThis pilot study highlights the potential of mixed herb aromatherapy inhalation for treating PSD, addressing limitations of CBT by promoting self-management. While demonstrating feasibility through recruitment, adherence, assessment completion and safety assessment, the study also acknowledges limitations such as unequal intervention times, the lack of physical function data. And the use of culturally relevant plant powders may enhance compliance but limits generalizability. Despite these constraints, the study provides valuable preliminary data and insights into the mechanisms of aromatherapy, encouraging further research and development of effective PSD treatments.

Abstract Background The cultivation of bananas encounters substantial obstacles, particularly due to the detrimental effects of cold stress on their growth and productivity. A potential remedy that has gained attention is the utilization of ethyl mesylate (EMS)-induced mutagenesis technology, which enables the creation of a genetically varied group of banana mutants. This complex procedure entails subjecting the mutants to further stress screening utilizing L-Hyp in order to identify those exhibiting improved resistance to cold. This study conducted a comprehensive optimization of the screening conditions for EMS mutagenesis and L-Hyp, resulting in the identification of the mutant cm784, which exhibited remarkable cold resistance. Subsequent investigations further elucidated the physiological and transcriptomic responses of cm784 to low-temperature stress. Results EMS mutagenesis had a substantial effect on banana seedlings, resulting in modifications in shoot and root traits, wherein a majority of seedlings exhibited delayed differentiation and limited elongation. Notably, mutant leaves displayed altered biomass composition, with starch content exhibiting the most pronounced variation. The application of L-Hyp pressure selection aided in the identification of cold-resistant mutants among seedling-lethal phenotypes. The mutant cm784 demonstrated enhanced cold resistance, as evidenced by improved survival rates and reduced symptoms of chilling injury. Physiological analyses demonstrated heightened activities of antioxidant enzymes and increased proline production in cm784 when subjected to cold stress. Transcriptome analysis unveiled 946 genes that were differentially expressed in cm784, with a notable enrichment in categories related to ‘Carbohydrate transport and metabolism’ and ‘Secondary metabolites biosynthesis, transport, and catabolism’. Conclusion The present findings provide insights into the molecular mechanisms that contribute to the heightened cold resistance observed in banana mutants. These mechanisms encompass enhanced carbohydrate metabolism and secondary metabolite biosynthesis, thereby emphasizing the adaptive strategies employed to mitigate the detrimental effects induced by cold stress.

ObjectivesTo investigate the risk of atrial fibrillation (AF) with sodium-glucose cotransporter-2 inhibitors (SGLT2is) compared to dipeptidyl peptidase-4 inhibitor (DPP4i) use in older US adults and across diverse subgroups.MethodsWe conducted a retrospective cohort analysis using claims data from 15% random samples of Medicare fee-for-service beneficiaries. Patients were adults with type 2 diabetes (T2D), no preexisting AF, and were newly initiated on SGLT2i or DPP4i. The outcome was the first incident AF. Inverse probability treatment weighting (IPTW) was used to balance the baseline covariates between the treatment groups including sociodemographics, comorbidities, and co-medications. Cox regression models were used to assess the effect of SGLT2i compared to DPP4i on incident AF.ResultsOf the 97,436 eligible individuals (mean age 71.2 ± 9.8 years, 54.6% women), 1.01% (n = 983) had incident AF over a median follow-up of 361 days. The adjusted incidence rate was 8.39 (95% CI: 6.67–9.99) and 11.70 (95% CI: 10.9–12.55) per 1,000 person-years in the SGLT2i and DPP4i groups, respectively. SGLT2is were associated with a significantly lower risk of incident AF (HR 0.73; 95% CI, 0.57 to 0.91; p = 0.01) than DPP4is. The risk reduction of incident AF was significant in non-Hispanic White individuals and subgroups with existing atherosclerotic cardiovascular diseases and chronic kidney disease.ConclusionCompared to the use of DPP4i, that of SGLT2i was associated with a lower risk of AF in patients with T2D. Our findings contribute to the real-world evidence regarding the effectiveness of SGLT2i in preventing AF and support a tailored therapeutic approach to optimize treatment selection based on individual characteristics.

BackgroundParkinson’s disease (PD) is a common neurodegenerative disorder that affects motor and non-motor functions, significantly reducing patients’ quality of life. No effective drug-based treatments are known to solve this problem. Non-drug therapies such as Yijinjing exercise have shown potential in improving cognitive and motor functions in PD patients. However, solid evidence must still be provided to support their clinical efficacy. This study aims to evaluate the clinical efficacy of Yijinjing exercise interventions in PD patients and explore the underlying mechanisms between the cognitive and motor functions in PD.MethodsThis is a single-center randomized controlled trial in which 96 eligible PD patients will be randomly assigned to receive either Yijinjing exercise group or brisk walking group or control group in a ratio of 1:1:1. Interventions (Yijinjing exercise or brisk walking training, 40 min per session) will be provided in 3 sessions per week (Monday, Wednesday, Friday) for 12 weeks, with a total of 36 sessions. After the treatment, there will be a 1-month follow-up period. The primary outcomes will be measured using the Montreal Cognitive Assessment (MoCA) and the Unified Parkinson’s Disease Rating Scale motor section (UPDRS-III). Secondary outcomes include balance function, executive function, walking function, sleep quality, and quality of life. Additionally, the prefrontal cerebral and sensorimotor cortex blood oxygen signal level will be collected to explore the underlying mechanisms. All outcomes will be assessed at baseline, at the end of 12 weeks of treatment and after an additional 1-month follow-up period.DiscussionThe results of the study protocol will provide high-quality evidence for the potential of intervention measures based on the Yijinjing exercise to improve the cognitive and activity levels of Parkinson’s disease patients. We envision the Yijinjing exercise as a non-pharmacological family activity that can provide a new and more effective method for the treatment of Parkinson’s disease patients or those at risk.Clinical trial registrationThis study was approved by the Ethics Committee of the Second Rehabilitation Hospital of Shanghai (2020-05-01). The trial has been registered in the China Clinical Trials Registry (ChiCTR2200055636).

Abstract Tandemly arrayed genes (TAGs) with functional redundancy and chromosomal linkage constitute 14 ~ 35% in sequenced plant genomes. The multiplex CRISPR system is the tool of choice for creating targeted TAG deletions. Here, we show that up to ~80% of CRISPR-mediated TAG knockout alleles in Arabidopsis and rice are deletion-inversion (delinver) bi-alleles, which are easily misidentified as homozygous deletion alleles by routine PCR-based genotyping. This can lead to misinterpretation of experimental data and production of progenies with genetic heterogeneity in an unnoticed manner. In ~2,650 transgenic events, delinver mutation frequencies are predominantly correlated with deletion frequencies but unrelated to chromosomal locations or deletion sizes. Delinver mutations also occur frequently at genomic non-TAG loci during multiplexed CRISPR editing. Our work raises the alarm about delinver mutations as common unwanted products of targeted TAG deletions in plants and helps prevent false interpretation of plant TAG functions due to this hidden genotype issue.

Morels (Morchella spp.) are a kind of rare and precious edible fungus and have been successfully cultivated in many places. Currently, the widespread cultivation of morels poses a significant challenge owing to their demanding environmental requirements. Soil properties and the soil microbiome are thought to play pivotal roles in morel growth. However, it remains unknown what factors exert a decisive influence on morel growth. In this study, soils with different morel yields were studied in nine sites from four locations. The basic soil physical and chemical properties were measured. In addition, the soil microbiome was analyzed using high-throughput metagenomic sequencing. We found that soil pH, nitrogen, carbon and conductivity were key indicators for the impact on microbial communities in soil for cultivating morels. Among these, nitrate was more positively associated with morel yield. The soil microbial diversity was more abundant in the soil with a high morel yield. Moreover, certain unknown archaea might be unfavorable to morel growth. The microbes that perform incomplete denitrification (no step of N2O reduction to N2) and nitrogen fixation were positively and negatively correlated with morel growth, respectively. In summary, morels prefer to live in nutrient-rich soils with a variety of microbes and are supported by nitrate and microbiome components involved in denitrification. The findings elucidate a pivotal mechanism in eliciting morel fructification and provide valuable insights for guiding production practices.

To scientifically enhance user perception in decision-making for designing interactive spaces in schools for children with intellectual disabilities, we propose an innovative design model that integrates the Kano model, Analytic Hierarchy Process (AHP), and Axiomatic Design (AD) theories based on user needs. Initially, multi-method research was used to gather the original user requirements which were then refined through data cleaning to establish the initial user needs. The Kano model was then employed to categorize these initial user needs. AHP was then used to construct a hierarchical analysis model for the interactive spaces in schools for children with intellectual disabilities, creating a judgment matrix to accurately calculate demand weight values at each level. Subsequently, AHP was used to select the most important demand items. The independence axiom of AD theory was used to achieve a “Z”-shaped mapping between the functional requirements (FRs) and design parameters (DPs) for the interactive spaces in schools for children with intellectual disabilities. This mapping was analyzed using a matrix approach to assess the design rationality and optimize solutions, thereby transforming user needs into design parameters. Finally, the design parameters were used to create interactive spaces through computer-aided design, and the resulting design plans were evaluated. Experimental results indicate that this design scheme effectively translates subjective concepts into specific design parameters through a qualitative and quantitative approach. This significantly enhances the user needs of interactive spaces in schools for children with intellectual disabilities and provides a scientific basis for the architectural design of these schools.

The development and deployment of diverse resistance sources in novel wheat cultivars underpin the durable control of stripe rust. The objectives of this study were to identify quantitative trait loci (QTL) associated with stripe rust resistance in the Chinese wheat breeding line YN1813 and to provide wheat breeders with original genes with potentially durable resistance. A total of 306 F7:8 recombinant inbred lines (RIL), derived from a cross between YN1813 (infection type 0–3 and disease severity 1–36%) and the moderately susceptible landrace Chinese Spring (IT 7–9 and DS 41–65%), were assessed for stripe rust disease severity in the field at Qingshui in Gansu and Pixian in Sichuan in 2020 and 2021 following inoculation with a mixture of the currently predominant Pst races. The parents and RIL were genotyped using the Wheat 55K single-nucleotide polymorphism (SNP) array. The total length of the constructed genetic linkage map was 3896.30 cm, with an average interval of 1.30 cm between adjacent markers. Two major QTL were identified on chromosome 7B and 7D across all tested environments. QYr.hau-7B was mapped to a 2.26 cm interval between the SNP markers AX-110908486–AX-89658728–AX-109489314 on chromosome 7B, explaining 0.9% to 16.9% of the phenotypic variation. QYr.hau-7D was positioned in a 0.67 cm interval flanked by the SNP markers AX-111654594 and AX-89378255, explaining 0.4% to 21.4% of the phenotypic variation. The QTL on 7D likely correspond to the previously known gene Yr18, whereas QYr.hau-7B was presumed to be a novel gene adjacent to YrZH84 or the core part of YrZH84. SNP markers closely linked with QYr.hau-7B were converted to allele-specific quantitative PCR-based genotyping assay (AQP) markers and validated in a panel of 712 wheat accessions. The group possessing a positive allele (TT) of AQP_AX-89658728 significantly (p < 0.05) decreased the IT by 45.8% and the DS by 63.2%. QYr.hau-7B and its markers could be useful in breeding programs to improve the level and durability of stripe rust resistance.

Due to the molding-free property and dry shrinkage of extrusion-based three-dimensional printable concrete (3DPC), the precision issues of 3DPC have not been solved effectively. One of the viable solutions for 3DPC precision improvement is to print using ultra-thin filaments. The challenges of ultra-thin-filament printing are extrudability, flowability, and fast solidification. To overcome these challenges and enhance precision, a customized 3D concrete printer with an ultra-thin diameter nozzle (6 mm) and fully sealed extrusion system was developed, and the mix design of ultra-thin-filament 3DPC (UTF-3DPC) was studied, including ingredients such as fly ash (FA), silica fume (SF), ordinary Portland cement (OPC), sodium dodecyl sulfate and cellulose (SDSC), water reducer, water, and sand. The function of UTF-3DPCs flowability and fast solidification with the proportion of water and SDSC was explored to obtain the optimal mix design. The standard compressive and flexural strengths of UTF-3DPC specimens were compared with the mold-cast vibrated and the mold-cast non-vibrated concrete. Their meso-scale and micro-scale structures were analyzed to expose the strength mechanism, according to the scanning electron microscope (SEM) images. A suitable mix design of UTF-3DPC was obtained and UTF-3DPC strength reached 80% of standard mold-cast concrete. The findings reported here provide a pathway to improve the precision of 3DPC and extend the application of 3D printing technology in engineering.

Background & aims: Although ferroptosis holds promise as a new strategy for treating hepatocellular carcinoma (HCC), there are several obstacles that need to be overcome. One major challenge is the lack of understanding about the mechanisms underlying ferroptosis. Additionally, while the m6A modification has been shown to regulate various forms of cell death, its role in regulating ferroptosis in HCC has been largely overlooked. Bridging this knowledge gap, our study aimed to elucidate the regulatory influence of m6A modification on HCC ferroptosis. Materials: Dot blot and EpiQuik m6A RNA Methylation Quantitative kit detected changes in overall m6A modification level during ferroptosis in HCC. MeRIP-qPCR and RIP-qPCR identified that the m6A modification of ATG5 mRNA was significant changed. BALB/c nude mice were used to construct xenograft tumor models to verify the phenotypes upon YTHDC2 silencing. In addition, patient-derived organoid models were used to demonstrate that induction of ferroptosis was an effective strategy against HCC. Results: Our study has shown that inducing ferroptosis is a promising strategy for combatting HCC. Specifically, we have found a significant correlation between ferroptosis and high levels of m6A modification in HCC. Notably, we discovered that the elevation of ATG5 mRNA m6A modification mediated by WTAP is dependent on the reading protein YTHDC2. Importantly, inhibition of either WTAP or YTHDC2 effectively prevented ferroptosis and suppressed HCC development in both in vitro and in vivo models. Conclusion: Our study revealed that WTAP upregulates ATG5 expression post-transcriptionally in an m6A-YTHDC2-dependent manner, thereby promoting the translation of ATG5 mRNA during ferroptosis in HCC. These findings have significant implications for the development of innovative and effective therapeutic approaches for HCC treatment.

BackgroundPrior studies have shown disparities in the uptake of cardioprotective newer glucose-lowering drugs (GLDs), including sodium-glucose cotranwsporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1a). This study aimed to characterize geographic variation in the initiation of newer GLDs and the geographic variation in the disparities in initiating these medications.MethodsUsing 2017-2018 claims data from a 15% random nationwide sample of Medicare Part D beneficiaries, we identified individuals diagnosed with type 2 diabetes (T2D), who had ≥1 GLD prescriptions, and did not use SGLT2i or GLP1a in the year prior to the index date,1/1/2018. Patients were followed up for a year. The cohort was spatiotemporally linked to Dartmouth hospital-referral regions (HRRs), with each patient assigned to 1 of 306 HRRs. We performed multivariable Poisson regression to estimate adjusted initiation rates, and multivariable logistic regression to assess racial disparities in each HRR.ResultsAmong 795,469 individuals with T2D included in the analyses, the mean (SD) age was 73 (10) y, 53.3% were women, 12.2% were non-Hispanic Black, and 7.2% initiated a newer GLD in the follow-up year. In the adjusted model including clinical factors, compared to non-Hispanic White patients, non-Hispanic Black (initiation rate ratio, IRR [95% CI]: 0.66 [0.64-0.68]), American Indian/Alaska Native (0.74 [0.66-0.82]), Hispanic (0.85 [0.82-0.87]), and Asian/Pacific islander (0.94 [0.89-0.98]) patients were less likely to initiate newer GLDs. Significant geographic variation was observed across HRRs, with an initiation rate spanning 2.7%-13.6%.ConclusionsThis study uncovered substantial geographic variation and the racial disparities in initiating newer GLDs.

MicroRNAs (miRNAs) bind on the 3′ untranslated region (3′UTR) of messenger RNAs (mRNAs) and regulate mRNA expression in physiological and pathological conditions, including cancer. Thus, studies have identified miRNAs as potential biomarkers by correlating the miRNA expression with the expression of important mRNAs and/or clinical outcomes in cancers. However, tumors undergo pervasive 3′UTR shortening/lengthening events through alternative polyadenylation (APA), which varies the number of miRNA target sites in mRNA, raising the number of miRNA target sites (numTS) as another important regulatory axis of the miRNA binding effects. In this study, we developed the first statistical method, BIOMATA-APA, to identify predictive miRNAs based on numTS features. Running BIOMATA-APA on The Cancer Genome Atlas (TCGA) and independent cohort data both with immunotherapy and no immunotherapy, we demonstrated for the first time that the numTS feature 1) distinguishes different cancer types, 2) predicts tumor proliferation and immune infiltration status, 3) explains more variation in the proportion of tumor-infiltrating immune cells, 4) predicts response to immune checkpoint blockade (ICB) therapy, and 5) adds prognostic power beyond clinical and miRNA expression. To the best of our knowledge, this is the first pan-cancer study to systematically demonstrate numTS as a novel type of biomarker representing the miRNA binding effects underlying tumorigenesis and pave the way to incorporate miRNA target sites for miRNA biomarker identification. Another advantage of examining the miRNA binding effect using numTS is that it requires only RNA-Seq data, not miRNAs, thus resulting in high power in the miRNA biomarker identification.

Circular RNAs (circRNAs), a novel type of single-stranded noncoding RNAs with a covalently closed loop structure, are generated in a circular conformation via non-canonical splicing or back-splicing events. Functionally, circRNAs have been elucidated to soak up microRNAs (miRNAs) and RNA binding proteins (RBPs), serve as protein scaffolds, maintain mRNA stability, and regulate gene transcription and translation. Notably, circRNAs are strongly implicated in the regulation of β-cell functions, insulin resistance, adipocyte functions, inflammation as well as oxidative stress via acting as miRNA sponges and RBP sponges. Basic and clinical studies have demonstrated that aberrant alterations of circRNAs expressions are strongly associated with the initiation and progression of diabetes mellitus (DM) and its complications. Here in this review, we present a summary of the biogenesis, transportation, degradation and functions of circRNAs, and highlight the recent findings on circRNAs and their action mechanisms in DM and its complications. Overall, this review should contribute greatly to our understanding of circRNAs in DM pathogenesis, offering insights into the further perspectives of circRNAs for DM diagnosis and therapy.

Abstract Background The most significant cause of treatment failure in chronic myeloid leukemia (CML) is a persistent population of minimal residual cells. Emerging evidences showed that methylation of SHP-1 contributed to Imatinib (IM) resistance. Baicalein was reported to have an effect on reversal of chemotherapeutic agents resistance. However, the molecular mechanism of Baicalein on JAK2/STAT5 signaling inhibition against drug resistance in bone marrow (BM) microenvironment that had not been clearly revealed. Methods We co-cultured hBMSCs and CML CD34+ cells as a model of SFM-DR. Further researches were performed to clarify the reverse mechanisms of Baicalein on SFM-DR model and engraftment model. The apoptosis, cytotoxicity, proliferation, GM-CSF secretion, JAK2/STAT5 activity, the expression of SHP-1 and DNMT1 were analyzed. To validate the role of SHP-1 on the reversal effect of Baicalein, the SHP-1 gene was over-expressed by pCMV6-entry shp-1 and silenced by SHP-1 shRNA, respectively. Meanwhile, the DNMT1 inhibitor decitabine was used. The methylation extent of SHP-1 was evaluated using MSP and BSP. The molecular docking was replenished to further explore the binding possibility of Baicalein and DNMT1. Results BCR/ABL-independent activation of JAK2/STAT5 signaling was involved in IM resistance in CML CD34+ subpopulation. Baicalein significantly reversed BM microenvironment-induced IM resistance not through reducing GM-CSF secretion, but interfering DNMT1 expression and activity. Baicalein induced DNMT1-mediated demethylation of the SHP-1 promoter region, and subsequently activated SHP-1 re-expression, which resulted in an inhibition of JAK2/STAT5 signaling in resistant CML CD34+ cells. Molecular docking model indicated that DNMT1 and Baicalein had binding pockets in 3D structures, which further supported Baicalein might be a small-molecule inhibitor targeting DNMT1. Conclusions The mechanism of Baicalein on improving the sensitivity of CD34+ cells to IM might be correlated with SHP-1 demethylation by inhibition of DNMT1 expression. These findings suggested that Baicalein could be a promising candidate by targeting DNMT1 to eradicate minimal residual disease in CML patients. Video Abstract

Ultra-high spectral purity lasers are of considerable research interests in numerous fields such as coherent optical communication, microwave photonics, distributed optical fiber sensing, gravitational wave detection, optical clock, and so on. Herein, to deeply purify laser spectrum with compact size under normal condition, we propose a novel and practical idea to effectively suppress the spontaneous radiation of the laser cavity through weak external distributed perturbation. Subsequently, a laser configuration consisting of a main lasing cavity and an external distributed feedback cavity is proposed. The feedback signal with continuous spatio-temporal phase transition controlled by a distributed feedback structure is injected into the main cavity, which can deeply suppress the coupling rate from the spontaneous radiation to the stimulated emission and extremely purify the laser spectrum. Eventually, an ultra-narrow linewidth on-chip laser system with a side mode suppression ratio greater than 80 dB, an output linewidth of 10 Hz, and a relative intensity noise less than -150 dB/Hz is successfully obtained under normal conditions. The proposed concept in this work provides a new perspective for extreme regulation of laser parameters by using weak external distributed perturbation, which can be valid for various gain-type lasers with wide wavelength bands.

ABSTRACT Currently approved vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused solely on the spike protein to provide immunity. The first vaccines were developed rapidly using spike mRNA delivered by lipid nanoparticles but required ultralow-temperature storage and have had limited immunity against variations in spike. Subsequently, protein-based vaccines were developed, which offer broader immunity but require significant time for development and the use of an adjuvant to boost the immune response. Here, exosomes were used to deliver a bivalent protein-based vaccine in which two independent viral proteins were used. Exosomes were engineered to express either SARS-CoV-2 delta spike (Stealth X-Spike [STX-S]) or the more conserved nucleocapsid (Stealth X-Nucleocapsid [STX-N]) protein on the surface. When administered as a single product (STX-S or STX-N) or in combination (STX-S+N), both STX-S and STX-N induced strong immunization with the production of potent humoral and cellular immune responses. Interestingly, these results were obtained with the administration of only nanograms of protein and without an adjuvant. In two independent animal models (mouse and rabbit), the administration of nanograms of the STX-S+N vaccine resulted in increased antibody production, potent neutralizing antibodies with cross-reactivity to other variants of spike, and strong T-cell responses. Importantly, no competition of immune responses was observed, allowing the delivery of nucleocapsid with spike to offer improved SARS-CoV-2 immunity. These data show that the StealthX exosome platform has the enormous potential to revolutionize vaccinology by combining the advantages of mRNA and recombinant protein vaccines into a superior, rapidly generated, low-dose vaccine resulting in potent, broader immunity. IMPORTANCE The pandemic emergency has brought to light the need for a new generation of rapidly developed vaccines that induce longer-lasting, potent, and broader immune responses. While the mRNA vaccines played a critical role during the emergency in reducing SARS-CoV-2 hospitalization rates and deaths, more efficient approaches are needed. A multivalent, protein-based vaccine delivered by exosomes could meet this urgent need due to the high speed of development, manufacturability, and the ability to produce a strong antibody response, with neutralizing antibodies and a strong T-cell response able to broadly combat viral infection with a minimum number of injections.

The path-dependent strength of three-dimensional printed concrete (3DPC) hinders further engineering application. Printing path optimization is a feasible solution to improve the strength of 3DPC. Here, the mix ratio of 3DPC was studied to print standard concrete specimens with different printing paths using our customized concrete 3D printer, which features fully sealed extrusion and ultrathin nozzles. These paths include crosswise, vertical, arched, and diagonal patterns. Their flexural and compressive strengths were tested. In order to verify the tested results and expose the mechanism of strength enhancement, digital image correlation (DIC) was used to capture the dynamic gradual fracture in the flexural tests. Also, the meso- and microstructures of the 3D-printed concrete specimens were pictured. The results reported here show that arched-path concrete has 30% more flexural strength than others because it makes better use of filament-wise strength. The findings here provide a pathway to improve the strength of 3D-printed concrete by path optimization, boosting 3DPC’s extensive application in civil engineering.

Soft robots are compliant, impact resistant, and relatively safe in comparison to hard robots. However, the development of untethered soft robots is still a major challenge because soft legs cannot effectively support the power and control systems. Most untethered soft robots apply a crawling or walking gait, which limits their locomotion speed and mobility. This paper presents an untethered soft robot that can move with a bioinspired dynamic trotting gait. The robot is driven by inflatable soft legs designed on the basis of the pre-charged pneumatic (PCP) actuation principle. Experimental results demonstrate that the developed robot can trot stably with the fastest speed of 23 cm/s (0.97 body length per second) and can trot over different terrains (slope, step, rough terrain, and natural terrains). The robotic dog can hold up to a 5.5 kg load in the static state and can carry up to 1.5 kg in the trotting state. Without any rigid components inside the legs, the developed robotic dog exhibits resistance to large impacts, i.e., after withstanding a 73 kg adult (46 times its body mass), the robotic dog can stand up and continue its trotting gait. This innovative robotic system has great potential in equipment inspection, field exploration, and disaster rescue.

Cytonemes are signaling filopodia that mediate target-specific long-distance communications of signals like FGFs. Du et al. show that a Drosophila FGF is anchored to the FGF-producing cell surface, inhibiting free FGF secretion and activating contact-dependent bidirectional FGF-FGFR interactions, controlling target-specific cytoneme contacts and contact-dependent FGF release.

It is valuable to search for novel and economical agents for inhibiting STAT3 activation and blocking increases in IL-6 levels, due to the important roles of STAT3 and IL-6 in inflammation. Since Methylene Blue (MB) has shown therapeutical potential for multiple diseases, it has become increasingly important to investigate the mechanisms underlying the effects of MB on inflammation. Using a mouse model of lipopolysaccharide (LPS)-induced inflammation, we investigated the mechanisms underlying the effects of MB on inflammation, obtaining the following findings: First, MB administration attenuated the LPS-induced increases in the serum levels of IL-6; second, MB administration attenuated LPS-induced STAT3 activation of the brain; and third, MB administration attenuated LPS-induced STAT3 activation of the skin. Collectively, our study has suggested that MB administration can decrease the levels of IL-6 and STAT3 activation - two important factors in inflammation. Since MB is a clinically used and relatively economical drug, our findings have suggested therapeutic potential of MB for multiple inflammation-associated diseases due to its effects on STAT3 activation and IL-6 levels.

Objective To investigate the effect of exosomes produced by hepatitis B virus (HBV)-infected cells on the phenotype and function of macrophages. Methods The exosomes secreted by HepAD38 cells, which were capable of producing HBV and HepG2 cells, were collected by ultracentrifugation combined with immunosorbent method.The quality and purity of the extracted exosomes were verified by nanoparticle tracking analysis (NTA), scanning electron microscope and Western blot.The M0 THP-1 macrophages differentiated by PMA were stimulated by HepAD38 derived- or HepG2 derived exosomes.Total RNA and protein samples were collected at different time points after stimulation.Real-time fluorescence quantitative PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect cytokine mRNA and protein expressions, respectively.Meanwhile, neutral red assay was performed to analyze macrophage pinocytosis activity, and a commercial kit was used to measure reactive oxygen species (ROS) in THP-1 macrophages.Human reverse transcription chip detection was performed to obtain the microRNAs profile of the exosomes.And the effect of selected miRNA on macrophages was further confirmed by qRT-PCR. Results Compared with HepG2-derived exosomes, HepAD38-derived exosomes increased the mRNA and protein expressions of IL-1β, MCP-1 and TNFα significantly.However, no difference of pinocytosis capacity or ROS production was found between the HepAD38-derived exosomes group and HepG2-derived exosomes group.Human reverse transcription chip detection results were verified by KEGG analysis and qRT-PCR, and it was found that miR-6824-3p could also significantly increase the expression levels of IL-1β, MCP-1 and TNFα after high expression. Conclusion This study found that exosomes produced by HepAD38 cells may stimulate macrophages to produce inflammatory factors such as IL-1β, MCP-1 and TNFα through miR-6824-3p, thereby playing a role in HBV infection.

Microbial fermentation for the production of tetramethylpyrazine (TTMP) is considered to be the most promising method, and the development of a cheap fermentation substrate is of great importance for large-scale TTMP production. In this study, inexpensive by-products from the food industry, i.e., molasses and soybean meal (instead of glucose and tryptone), were used as substrates for TTMP fermentation. The pretreatment of soybean meal was explored in order to achieve a better fermentation effect. The contents of each component in the fermentation medium were optimized by central composite design (CCD). The optimum contents were as follows: 72.5 g/L of molasses, 37.4 g/L of diammonium hydrogen phosphate (DAP), 53.4 g/L of soybean meal, and 5 g/L of yeast powder. The software predicted a maximum TTMP yield of 1469.03 mg/L, and the actual TTMP yield was 1328.95 mg/L for the validation experiment in the optimum medium. Under the optimum conditions (72.5 g/L of molasses, 37.4 g/L of DAP, 53.4 g/L of soybean meal, and 5 g/L of yeast powder), the actual maximum TTMP yield (1328.95 mg/L) in this study was much higher than the TTMP yield (895.13 mg/L) under the conditions (150 g/L of molasses, 30 g/L of DAP, 30 g/L of tryptone, and 10 g/L of yeast powder) of our previous study published in Molecules. In this study, the TTMP yield improved by 48.46%, with decreased molasses (more than half), decreased yeast powder (half) and by-product soybean meal instead of tryptone compared to our previous study. In summary, the cheaper fermentation medium had a higher TTMP yield in this study, which improves the application potential of Bacillus sp. TTMP20.

Abstract Background Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp1 is frequently upregulated in many cancers and is closely implicated in tumorigenesis. However, the mechanism underling Drp1 to influence tumor progression is largely unknown, especially in esophageal squamous cell carcinoma (ESCC). Methods Immunohistochemistry was used to examine Drp1 and LC3B expression in tissues of ESCC patients. Autophagic vesicles were investigated by transmission electron microscopy. Fluorescent LC3B puncta and mitochondrial nucleoid were observed by fluorescent and confocal microscopy. Mitochondrial function was evaluated by mitochondrial membrane potential, ROS and ATP levels. Xenograft tumor model was performed in BALB/c nude mice to analyze the role of Drp1 on ESCC progression. Results We found that Drp1 high expression is correlated with poor overall survival of ESCC patients. Drp1 overexpression promotes cell proliferation and xenograft ESCC tumor growth by triggering autophagy. Furthermore, we demonstrated that Drp1 overexpression disturbs mitochondrial function and subsequent induces mitochondrial DNA (mtDNA) released into the cytosol thereby inducing cytosolic mtDNA stress. Mechanistically, cytosolic mtDNA activates the cGAS-STING pathway and facilitates autophagy, which promotes ESCC cancer growth. Moreover, mtDNA digestion with DNase I and autophagy inhibition with chloroquine attenuates the cGAS-STING pathway activation and ESCC cancer growth. Conclusions Our finding reveals that Drp1 overexpression induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the cGAS-STING pathway, triggers autophagy and promotes ESCC progression.

Mushrooms of the edible and medicinal which are highly nutritious and environmentally friendly crops carry numerous medicinal benefits. For the abundant and high diversity of bioactive metabolites they possess, which are considered to be an important pool of bioresources. The efficient breeding technique is always a challenging task in mushrooms for obtaining better character strains, which are essential for developing healthy products and even consumption. This review comprehensively summarizes the breeding techniques applied to the edible and medicinal mushrooms. Including the traditional mutagenesis method, and even modern gene-editing breeding techniques, the effects of each method, and the comparison of each breeding technique are systematic illustrations. Strategies for mushroom breeding techniques in the future are also discussed in this review paper. With the ongoing sequencing of the mushroom genome, knowledge of the gene background of the strains and functions can be available for developing better markers for gene-editing breeding as CRISPR/Cas9 systems. Combine the metabolism engineering and in-silico tools analysis was the rational design of the novel strains. Modern physical mutagenesis techniques such as the ARTP and the combination of the other physical, and chemical breeding mutagens with cross-breeding techniques or the protoplasts fusion will also lead to superior strains for cultivation and pave the way for higher quality and yield.

IntroductionThe rapid development of fintech has brought opportunities for business operations and economic development. Currently, few researches have focused on how fintech level affects word-of-mouth (WOM) from the perspective of user psychology. Therefore, studying the effect of fintech level on WOM is a worthwhile scientific question.MethodsBased on motivation theory and reinforcement theory, this paper proposes a new psychology-based theoretical framework model to study the relationship between fintech level and WOM and constructs a structural equation model including fintech level, user experience, user trust, user stickiness and WOM through the analysis of 732 questionnaires.ResultsThe results indicate that the improvement of fintech level can enhance WOM. More specifically, fintech level has a significantly positive influence on user stickiness through two mediation variables (user experience and user trust), and further, user stickiness has a significantly positive influence on WOM.DiscussionThis paper analyzes the internal mechanism of fintech level's influence on WOM from the micro psychological perspective, which enriches the psychology theoretical research. And, the conclusions provide specific suggestions for marketing and promotion of financial platforms in the future.

Exosomes are emerging as potent and safe delivery carriers for use in vaccinology and therapeutics. A better vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to provide improved, broader, longer lasting neutralization of SARS-CoV-2, a more robust T cell response, enable widespread global usage, and further enhance the safety profile of vaccines given the likelihood of repeated booster vaccinations. Here, we use Capricor's StealthXTM platform to engineer exosomes to express native SARS-CoV-2 spike Delta variant (STX-S) protein on the surface for the delivery of a protein-based vaccine for immunization against SARS-CoV-2 infection. The STX-S vaccine induced a strong immunization with the production of a potent humoral immune response as demonstrated by high levels of neutralizing antibody not only against the delta SARS-CoV-2 virus but also two Omicron variants (BA.1 and BA.5), providing broader protection than current mRNA vaccines. Additionally, both CD4+ and CD8+ T cell responses were increased significantly after treatment. Quantification of spike protein by ELISA showed that only nanograms of protein were needed to induce a potent immune response. This is a significantly lower dose than traditional recombinant protein vaccines with no adjuvant required, which makes the StealthXTM exosome platform ideal for the development of multivalent vaccines with a better safety profile. Importantly, our exosome platform allows novel proteins, or variants in the case of SARS-CoV-2, to be engineered onto the surface of exosomes in a matter of weeks, comparable with mRNA vaccine technology, but without the cold storage requirements necessary for mRNA vaccines. The ability to utilize exosomes for cellular delivery of proteins, as demonstrated by STX-S, has enormous potential to revolutionize vaccinology by rapidly facilitating antigen presentation at an extremely low dose resulting in a potent, broad antibody response.

Abstract Background Esophageal squamous cell carcinoma (ESCC) is the most predominant primary malignant tumor among worldwide, especially in China. To date, the successful treatment remains a mainly clinical challenge, it is imperative to develop successful therapeutic agents. Methods The anti-proliferative effect of ivermectin on ESCC is investigated in cell model and in nude mice model. Cell apoptosis was assessed using flow cytometry, TUNEL assay and western blotting. Mitochondrial dysfunction was determined by reactive oxygen species accumulation, mitochondrial membrane potential and ATP levels. Results Our results determined that ivermectin significantly inhibited the proliferation of ESCC cells in vitro and in vivo. Furthermore, we found that ivermectin markedly mediated mitochondrial dysfunction and induced apoptosis of ESCC cells, which indicated the anti-proliferative effect of ivermectin on ESCC cells was implicated in mitochondrial apoptotic pathway. Mechanistically, ivermectin significantly triggered ROS accumulation and inhibited the activation of NF-κB signaling pathway and increased the ratio of Bax/Bcl-2. Conclusions These finding indicated that ivermectin has significant anti-tumour potential for ESSC and may be a potential therapeutic candidate against ESCC.

Abstract Background Although interferon regulatory factor 2 (IRF2) was reported to stimulate virus replication by suppressing the type I interferon signaling pathway, because cell cycle arrest was found to promote viral replication, IRF2-regulated replication fork factor (FAM111A and RFC3) might be able to affect ZIKV replication. In this study, we aimed to investigate the function of IRF2, FAM111A and RFC3 to ZIKV replication and underlying mechanism. Methods siIRF2, siFAM111A, siRFC3 and pIRF2 in ZIKV-infected A549, 2FTGH and U5A cells were used to explore the mechanism of IRF2 to inhibit ZIKV replication. In addition, their expression was analyzed by RT-qPCR and western blots, respectively. Results In this study, we found IRF2 expression was increased in ZIKV-infected A549 cells and IRF2 inhibited ZIKV replication independent of type I IFN signaling pathway. IRF2 could activate FAM111A expression and then enhanced the host restriction effect of RFC3 to inhibit replication of ZIKV. Conclusions We speculated the type I interferon signaling pathway might not play a leading role in regulating ZIKV replication in IRF2-silenced cells. We found IRF2 was able to upregulate FAM111A expression and thus enhance the host restriction effect of RFC3 on ZIKV.

A common dilemma with deep-learning-based solar power forecasting models is their heavy dependence on a large amount of training data. Few-Shot Solar Power Forecasting (FSSPF) has been investigated in this paper, which aims to obtain accurate forecasting models with limited training data. Integrating Transfer Learning and Meta-Learning, approaches of Feature Transfer and Rapid Adaptation (FTRA), have been proposed for FSSPF. Specifically, the adopted model will be divided into Transferable learner and Adaptive learner. Using massive training data from source solar plants, Transferable learner and Adaptive learner will be pre-trained through a Transfer Learning and Meta-Learning algorithm, respectively. Ultimately, the parameters of the Adaptive learner will undergo fine-tuning using the limited training data obtained directly from the target solar plant. Three open solar power forecasting datasets (GEFCom2014) were utilized to conduct 24-h-ahead FSSPF experiments. The results illustrate that the proposed FTRA is able to outperform other FSSPF approaches, under various amounts of training data as well as different deep-learning models. Notably, with only 10-day training data, the proposed FTRA can achieve an RMSR of 8.42%, which will be lower than the 0.5% achieved by the state-of-the-art approaches.

Bacterial communities in high-temperature Daqu and fermented grains are important for brewing Jiang-flavor Baijiu such as Danquan Baijiu. Daqu is a saccharifying and fermenting agent, which has a significant impact on the flavor of Baijiu. However, bacterial communities in three different types of samples from the Danquan distillery (dqjq_ck, dqjqcp, and dqjp3) were still unclear, which limited further development of Danquan Baijiu. “dqjq_ck” and “dqjqcp” indicate high-temperature Daqu at days 45 and 135, respectively. “dqjp3” indicates fermented grains. In this study, the bacterial communities of three samples were analyzed by Illumina Miseq high-throughput sequencing. The bacterial communities of three samples primarily composed of thermophilic bacteria and bacteria with stress resistance. The most abundant species in dqjq_ck, dqjqcp, and dqjp3 were Comamonas, Bacillus, and unclassified Lactobacillales, respectively. The main bacteria included Bacillus, Comamonas, Myroides, Paenibacillus, Acetobacter, Kroppenstedtia, Staphylococcus, Saccharopolyspora, Planifilum, Lactobacillus, Acinetobacter, Oceanobacillus, Enterococcus, Thermoactinomyces, Lactococcus, Streptomyces, Saccharomonospora, Tepidimicrobium, Anaerosalibacter, unclassified_Lactobacillales, unclassified_Thermoactinomycetaceae_1, unclassified_Bacillaceae_2, unclassified_Bacillales, unclassified_Microbacteriaceae, unclassified_Rhodobacteraceae, unclassified_Actinopolysporineae, and unclassified_Flavobacteriaceae in three samples (percentage was more than 1% in one of three samples). In our study, the succession of microbiota in three samples representing three important stages of Danquan Baijiu brewing was revealed. This article lays a good foundation for understanding the fermentation mechanism and screening some excellent indigenous bacteria to improve the quality of Danquan Baijiu in future.

Patients with metastatic cancer refractory to standard systemic therapies have a poor prognosis and few therapeutic options. Radiotherapy can shape the tumor microenvironment (TME) by inducing immunogenic cell death and promoting tumor recognition by natural killer cells and T lymphocytes. Granulocyte macrophage-colony stimulating factor (GM-CSF) was known to promote dendric cell maturation and function, and might also induce the macrophage polarization with anti-tumor capabilities. A phase II trial (ChiCTR1900026175) was conducted to assess the clinical efficacy and safety of radiotherapy, PD-1 inhibitor and GM-CSF (PRaG regimen). This trial was registered at http://www.chictr.org.cn/index.aspx. A PRaG cycle consisted of 3 fractions of 5 or 8 Gy delivered for one metastatic lesion from day 1, followed by 200 μg subcutaneous injection of GM-CSF once daily for 2 weeks, and intravenous infusion of PD-1 inhibitor once within one week after completion of radiotherapy. The PRaG regimen was repeated every 21 days for at least two cycles. Once the PRaG therapy was completed, the patient continued PD-1 inhibitor monotherapy until confirmed disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). A total of 54 patients were enrolled with a median follow-up time of 16.4 months. The ORR was 16.7%, and the disease control rate was 46.3% in intent-to-treat patients. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.3 to 4.8), and median overall survival was 10.5 months (95% CI, 8.7 to 12.2). Grade 3 treatment-related adverse events occurred in five patients (10.0%) and grade 4 in one patient (2.0%). Therefore, the PRaG regimen was well tolerated with acceptable toxicity and may represent a promising salvage treatment for patients with chemotherapy-refractory solid tumors. It is likely that PRaG acts via heating upthe TME with radiotherapy and GM-CSF, which was further boosted by PD-1 inhibitors.

Microorganisms are the most abundant and diverse organisms in soils and have important effects on soil fertility. In this study, effects of the long-term fertilization treatments no fertilizer (CK), chemical fertilizer (nitrogen–phosphorus–potassium (NPK)), and organic–inorganic fertilizer (NPK and organic fertilizer (NPKM)) on rice yield and soil bacterial and fungal community diversity, structure, composition, and interaction networks were evaluated. Of the three treatments, the highest rice yield was in NPKM. Bacterial richness was significantly higher in NPKM than in NPK. Fertilization treatment significantly altered β diversity of communities, species composition of bacterial and fungal communities, and structure of soil microbial networks. The most complex bacterial and fungal interaction co-occurrence network with the highest average degree and numbers of edges and nodes was in NPKM. Relative abundance of the plant growth-promoting fungus Trichoderma increased significantly in NPKM compared with CK and NPK. The results of the study indicate that bacterial richness and microbial community member interactions (network complexity) might be suitable indicators of soil biological fertility. This research provides new insights on the effects of different fertilization regimes on responses of soil bacterial and fungal communities and their contributions to crop yield. New indicators such as bacterial richness and complexity of microbial interaction networks are also identified that can be used to evaluate soil biological fertility.

Carotenoids are widely distributed and structurally diverse, which have significant roles in the photosynthesis of plants. As a precursor of vitamin A, carotenoids are also antioxidants that reduce various chronic diseases, which are beneficial for human health. Currently, the existing studies concerned the biological roles of APETALA2 (AP2)/ethylene-responsive factor (ERF) genes originated from higher plants. The AP2 superfamily of the transcriptional regulator was identified in higher plants, which was related to growth, development, carotenoid metabolism, and responses to various stresses. However, the regulatory mechanisms of the AP2-modulating carotenoid metabolism have not been reported in microalgae, which remain to be elucidated. Dunaliella parva AP2 (i.e., DpAP2), an important transcription factor, promotes carotenoid accumulation by binding to the promoter of target gene. Here, we identified an important AP2/ERF transcription factor, DpAP2, which could promote carotenoid accumulation by binding to the promoter of target gene. To demonstrate the function of DpAP2, the interacting proteins were identified by the yeast two-hybrid system. The results showed that DpAP2 could interact with three proteins with different activities (DNA-binding transcription factor activity, protein kinase activity, and alpha-D-phosphohexomutase activity); these proteins may be associated with multiple biological processes. This paper laid a good foundation for a deep understanding of the regulatory mechanisms of DpAP2 and genetic engineering breeding in D. parva.

2,3,5,6-Tetramethylpyrazine (TTMP) is an active ingredient of Ligusticum wallichii Franch. It can be used in medicine and food fields. In this study, Bacillus sp. TTMP20 was applied to produce TTMP using cane molasses as a carbon source. After pretreatment with phosphoric acid, 170 mL/L treated molasses, combined with 10 g/L yeast powder, 30 g/L tryptone and 30 g/L (NH4)2HPO4 were used for fermentation. After 36 h, TTMP output reached the highest value of 208.8 mg/L. The yield of TTMP using phosphoric acid-treated molasses as carbon source was 145.59% higher than control. Under the sulfuric acid treatment process of molasses (150 g), the maximum yield of TTMP was 895.13 mg/L, which was 183.18% higher than that of untreated molasses (316.1 mg/L). This study demonstrated that molasses is a high-quality and inexpensive carbon source for the manufacture of TTMP, laying the groundwork for the future industrial production of TTMP.

We presented tri-band negative modulus acoustic metamaterials (AM), whose operation characteristics could be flexibly designed by changing the three hole sizes (i.e., a1, a2, and a3) of the tri-layer nested split hollow spheres (NSHSs). We demonstrate numerically that tri-band negative modulus can be obtained and each resonant frequency corresponds to the hole size of each split hollow sphere. However, for the case when a1> a2> a3, the negative modulus band in the high frequency region vanishes. An effective sound-force analogue model with coupling interaction is further developed for the accurate prediction of the three resonant frequencies based on equating the tri-layer NSHSs to three spring oscillators in series. As a result of the analytical formulas, three resonant frequencies could be precisely controlled, and a nested AM with a tri-band negative modulus can be flexibly constructed. The proposed AM could be easily extended to multiple operation bands and can be further coupled with negative mass density structures for constructing multi-band double-negative AMs.

In order to deeply understand the specific patterns of volume, microstructure, and functional changes in Multiple System Atrophy patients with cerebellar ataxia syndrome (MSA-c), we perform the current study by simultaneously applying structural (T1-weighted imaging), Diffusion tensor imaging (DTI), functional (BOLD fMRI) and extended Network-Based Statistics (extended-NBS) analysis. Twenty-nine MSA-c type patients and twenty-seven healthy controls (HCs) were involved in this study. First, we analyzed the whole brain changes of volume, microstructure, and functional connectivity (FC) in MSA-c patients. Then, we explored the correlations between significant multimodal MRI features and the total Unified Multiple System Atrophy Rating Scale (UMSARS) scores. Finally, we searched for sensitive imaging biomarkers for the diagnosis of MSA-c using support vector machine (SVM) classifier. Results showed significant grey matter atrophy in cerebellum and white matter microstructural abnormalities in cerebellum, left fusiform gyrus, right precentral gyrus and lingual gyrus. Extended-NBS analysis found two significant different connected components, featuring altered functional connectivity related to left and right cerebellar sub-regions, respectively. Moreover, the reduced fiber bundle counts at right Cerebellum_3 (Cbe3) and decreased fractional anisotropy (FA) values at bilateral Cbe9 were negatively associated with total UMSARS scores. Finally, the significant features at left Cbe9, Cbe1, and Cbe7b were found to be useful as sensitive biomarkers to differentiate MSA-c from HCs according to the SVM analysis. These findings advanced our understanding of the neural pathophysiological mechanisms of MSA from the perspective of multimodal neuroimaging.

Abstract With the rapid development of data‐driven human interaction, advanced data‐storage technologies with lower power consumption, larger storage capacity, faster switching speed, and higher integration density have become the goals of future memory electronics. Nevertheless, the physical limitations of conventional Si‐based binary storage systems lag far behind the ultrahigh‐density requirements of post‐Moore information storage. In this regard, the pursuit of alternatives and/or supplements to the existing storage technology has come to the forefront. Recently, organic‐based resistive memory materials have emerged as promising candidates for next‐generation information storage applications, which provide new possibilities of realizing high‐performance organic electronics. Herein, the memory device structure, switching types, mechanisms, and recent advances in organic resistive memory materials are reviewed. In particular, their potential of fulfilling multilevel storage is summarized. Besides, the present challenges and future prospects confronted by organic resistive memory materials and devices are discussed.

Abstract Background Cytokinins are one kind of phytohormones essential for plant growth, development and stress responses. In the past half century, significant progresses have been made in the studies of cytokinin signal transduction and metobolic pathways, but the mechanism of cytokinin translocation is poorly understood. Arabidopsis (Arabidopsis thaliana) response regulator 5 (ARR5) is a type-A response factor in cytokinin signaling which is induced by cytokinins and has been used as a reporter gene for the endogenous cytokinins in Arabidopsis. Here, we report a fluorescence-based high-throughput method to screen cytokinin translocation mutants using an ethyl methyl sulfone (EMS) mutagenesis library generated with ARR5::eGFP transgenic plants. Results The seedlings with enhanced green fluorescent protein (GFP) signal in roots were screened in a luminescence imaging system (LIS) in large scale to obtain mutants with over-accumulated cytokinins in roots. The selected mutants were confirmed under a fluorescence microscopy and then performed phenotypic analysis. In this way, we obtained twelve mutants with elevated GFP signal in the roots and further found three of them displayed reduced GFP signal in the aerial tissues. Two of the mutants were characterized and proved to be the atabcg14 allelic mutants which are defective in the long-distance translocation of root-synthesized cytokinins. Conclusions We provide a strategy for screening mutants defective in cytokinin translocation, distribution or signaling. The strategy can be adapted to establish a system for screening mutants defective in other hormone transporters or signaling components using a fluorescence reporter.

Abstract Background Drought stress can severely affect plant growth and crop yield. The cloning and identification of drought-inducible promoters would be of value for genetically-based strategies to improve resistance of crops to drought. Results Previous studies showed that the MaPIP1;1 gene encoding an aquaporin is involved in the plant drought stress response. In this study, the promoter pMaPIP1;1, which lies 1362 bp upstream of the MaPIP1;1 transcriptional initiation site, was isolated from the banana genome..And the transcription start site(A) is 47 bp before the ATG. To functionally validate the promoter, various lengths of pMaPIP1;1 were deleted and fused to GUS to generate pMaPIP1;1::GUS fusion constructs that were then transformed into Arabidopsis to generate four transformants termed M-P1, M-P2, M-P3 and M-P4.Mannitol treatment was used to simulate drought conditions. All four transformants reacted well to mannitol treatment. M-P2 (− 1274 bp to − 1) showed the highest transcriptional activity among all transgenic Arabidopsis tissues, indicating that M-P2 was the core region of pMaPIP1;1. This region of the promoter also confers high levels of gene expression in response to mannitol treatment. Using M-P2 as a yeast one-hybrid bait, 23 different transcription factors or genes that interacted with MaPIP1;1 were screened. In an dual luciferase assay for complementarity verification, the transcription factor MADS3 positively regulated MaPIP1;1 transcription when combined with the banana promoter. qRT-PCR showed that MADS3 expression was similar in banana leaves and roots under drought stress. In banana plants grown in 45% soil moisture to mimic drought stress, MaPIP1;1 expression was maximized, which further demonstrated that the MADS3 transcription factor can synergize with MaPIP1;1. Conclusions Together our results revealed that MaPIP1;1 mediates molecular mechanisms associated with drought responses in banana, and will expand our understanding of how AQP gene expression is regulated. The findings lay a foundation for genetic improvement of banana drought resistance.

Abstract Background Hepatitis B virus (HBV) infection remains as one of the major public health problems in the world. Type I interferon (IFN) plays an essential role in antiviral defense by induced expression of a few hundred interferon stimulated genes (ISGs), including ubiquitin-specific protease 18 (USP18). The expression level of USP18 was elevated in the pretreatment liver tissues of chronic hepatitis B(CHB) patients who did not respond to IFN treatment. Thus, this study was designed to investigate the effects of USP18 on HBV replication/production. Methods The levels of wild type USP18(WT-USP18) and USP18 catalytically inactive form C64S were up-regulated by plasmids transfection in HepAD38 cells, respectively. Real-time PCR and ELISA were used to quantify HBV replication. Type I IFN signaling pathway was monitored at three levels: p-STAT1 (western Blot), interferon stimulated response element (ISRE) activity (dual luciferase assay) and ISGs expression (real time PCR). Results Our data demonstrated that overexpression of either WT-USP18 or USP18-C64S inactive mutant increased the intracellular viral pgRNA, total DNA, cccDNA, as well as HBV DNA levels in the culture supernatant, while silencing USP18 led to opposite effect on HBV production. In addition, upregulated WT-USP18 or USP18-C64S suppressed ISRE activity and the expression levels of p-STAT1 and ISGs. Conclusion USP18 promoted HBV replication via inhibiting type I IFN signaling pathway, which was independent of its protease activity.