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Abstract Objectives To evaluate the diagnostic value of plasma exosomal miR-223 and its combination with CA125 for the diagnosis of early-stage epithelial ovarian cancer (EOC). Patients and methods Exosomes derived from the plasma of 78 EOC patients, 40 patients with epithelial benign ovarian tumors, and 52 healthy participants were isolated using the ultracentrifugation method and identified by transmission electron microscopy (TEM) and western blot. Results The expression of exosomal miR-223 was significantly upregulated in the plasma of EOC patients compared to that in healthy subjects and patients with benign diseases. The combination of exosomal miR-223 and CA125 from plasma had an equivalent area under the ROC curve (AUC) to CA125 alone for discriminating between EOC and non-EOC cases, including healthy subjects and benign ovarian tumors. However, the AUC value of the combination was 0.944 (95% CI: 0.899–0.990) for differentially diagnosing early-stage EOC from healthy subjects, slightly higher than that of CA125 alone (0.928, 95% CI: 0.875–0.981), with a sensitivity and specificity of 0.9784 and 0.885, respectively. Conclusion Our data suggest that plasma exosomal miR-223 can be used as a complement to CA125 to increase the diagnostic power for differentiating early-stage EOC from healthy subjects.

Evacuation lighting is a crucial component of cinema safety, significantly impacting operational safety and evacuation efficiency. It plays a key role in enhancing evacuation measures and ensuring the safety of cinema patrons. An experiment utilizing virtual reality technology was conducted at Beijing Forestry University with 62 subjects randomly assigned to either a control group or an experimental group. The experimental group was guided by a green flashing light as an evacuation indicator, while the control group relied on static lighting. Although some subjects overlooked the green flashing light, its presence still reduced the number of subjects choosing misleading exits. The flashing light notably improved pathfinding efficiency and evacuation performance, with the experimental group achieving an average evacuation time approximately 30% shorter than the control group. Additionally, subjects rated the sensory, cognitive, and functional aspects of the flashing light lighting from moderate to high. The findings indicate that dynamic and flashing evacuation lighting can effectively enhance fire escape efficiency in cinemas. The design of such systems should consider individual psychological responses and actual behavior patterns to optimize emergency evacuation instructions.

Gastrodia elata Blume is a traditional medicinal and food homology substance that has been used for thousands of years, is mainly distributed in China and other Asian countries, and has always been distinguished as a superior class of herbs. Gastrodin is the main active ingredient of G. elata Blume and has attracted increasing attention because of its extensive pharmacological activities. In addition to extraction and isolation from the original plant, gastrodin can also be obtained via chemical synthesis and biosynthesis. Gastrodin has significant pharmacological effects on the central nervous system, such as sedation and improvement of sleep. It can also improve epilepsy, neurodegenerative diseases, emotional disorders and cognitive impairment to a certain extent. Gastrodin is rapidly absorbed and widely distributed in the body and can also penetrate the blood–brain barrier. In brief, gastrodin is a promising natural small molecule with significant potential in the treatment of brain diseases. In this review, we summarised studies on the synthesis, pharmacological effects and pharmacokinetic characteristics of gastrodin, with emphasis on its effects on central nervous system disorders and the possible mechanisms, in order to find potential therapeutic applications and provide favourable information for the research and development of gastodin.

Seasonal thermal stratification is a common environmental phenomenon in reservoir water bodies and an important research topic for deep water reservoirs. A thermally stratified reservoir is an ideal system for investigating the interaction between factors affecting the environment and microorganism communities under spatial–temporal variation. However, few studies have focused on the effects of water stratification and mixing periods in microbial communities and nitrogen conversion. Therefore, using metagenomic sequencing and quantitative polymerase chain reaction, we investigated the microbial diversity and function in the Xin'anjiang Reservoir during water stratification and mixing period. Principal component analysis indicated that the bacterial communities were mostly affected by water stratification, mainly at 10-m depths, whereas the archaea community was influenced by the entire water profile. The predominant archaeal phyla changed from Candidatus_Woesearchaeota and Euryarchaeota to Thaumarchaeota with the increasing water depth during water stratification. The stratified variations of the dominant archaeal phyla strongly reflected the seasonal changes and vertical gradient in water temperature, dissolved oxygen, and pH. Linear regression analysis indicated that variations in microbial composition altered the overall functional attributes of the communities, especially in the archaeal community. Regarding nitrogen metabolism across the whole reservoir, the number of nitrification and denitrification genes dropped in the same direction as the river flow in spring and summer, while the opposite trend was observed in autumn and winter. The functional genes of the water profiles in the transitional and lacustrine zones varied considerably except in winter. Additionally, the copies of nitrification-related genes were more during the stratification stage than during the mixing stage, whereas copies of denitrification-related genes showed the opposite trend. Overall, this study provides unique insights regarding the effects of seasonal stratification on the distribution and function of microorganisms in large-deep reservoirs, which should be considered when establishing guidelines for reservoirs management.

In this narrative review article, we discuss the role of sleep deprivation (SD) in memory processing in rodent models. Numerous studies have examined the effects of SD on memory, with the majority showing that sleep disorders negatively affect memory. Currently, a consensus has not been established on which damage mechanism is the most appropriate. This critical issue in the neuroscience of sleep remains largely unknown. This review article aims to elucidate the mechanisms that underlie the damaging effects of SD on memory. It also proposes a scientific solution that might explain some findings. We have chosen to summarize literature that is both representative and comprehensive, as well as innovative in its approach. We examined the effects of SD on memory, including synaptic plasticity, neuritis, oxidative stress, and neurotransmitters. Results provide valuable insights into the mechanisms by which SD impairs memory function.

Ca2+ overload-induced mitochondrial dysfunction is considered a contributing factor alcohol-associated liver disease pathogenesis. Here the authors report that PDK4 promotes Ca2 + -channelling complex formation at the endoplasmic reticulum-mitochondria contact sites, which contributes to the pathogenesis of alcohol-associated liver disease in studies with male mouse and hepatocyte models.

Sleep disorders are the most widespread mental disorders after stroke and hurt survivors’ functional prognosis, response to restoration, and quality of life. This review will address an overview of the progress of research on the biological mechanisms associated with stroke-complicating sleep disorders. Extensive research has investigated the negative impact of stroke on sleep. However, a bidirectional association between sleep disorders and stroke exists; while stroke elevates the risk of sleep disorders, these disorders also independently contribute as a risk factor for stroke. This review aims to elucidate the mechanisms of stroke-induced sleep disorders. Possible influences were examined, including functional changes in brain regions, cerebrovascular hemodynamics, neurological deficits, sleep ion regulation, neurotransmitters, and inflammation. The results provide valuable insights into the mechanisms of stroke complicating sleep disorders.

Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a secreted protein of incompletely understood physiological function. Here the authors show that scEMC10 is upregulated in people with obesity, and that that genetic EMC10 deletion or antibody-based neutralization of EMC10 prevents diet-induced obesity in mice.

Traditional supervised learning methods require large quantities of labeled data. However, labeling sleep data according to polysomnography by well-trained sleep experts is a very tedious job. In the present day, the development of self-supervised learning methods is making significant progress in many fields. It is also possible to apply some of these methods to sleep staging. This is to remove the dependency on labeled data at the stage of representation extraction. Nevertheless, they often rely too much on negative samples for sample selection and construction. Therefore, we propose PSNSleep, a novel self-supervised learning method for sleep staging based on Siamese networks. The crucial step to the success of our method is to select appropriate data augmentations (the time shift block) to construct the positive sample pair. PSNSleep achieves satisfactory results without relying on any negative samples. We evaluate PSNSleep on Sleep-EDF and ISRUC-Sleep and achieve accuracy of 80.0% and 74.4%. The source code is publicly available at https://github.com/arthurxl/PSNSleep.

Alcohol‐associated liver disease is the leading cause of chronic liver disease. We hypothesized that the expression of specific coding genes is critical for the progression of alcoholic cirrhosis (AC) from compensated to decompensated states. For the discovery phase, we performed RNA sequencing analysis of 16 peripheral blood RNA samples, 4 healthy controls (HCs) and 12 patients with AC. The DEGs from the discovery cohort were validated by quantitative polymerase chain reaction in a separate cohort of 17 HCs and 48 patients with AC (17 Child‐Pugh A, 16 Child‐Pugh B, and 15 Child‐Pugh C). We observed that the numbers of differentially expressed messenger RNAs (mRNAs) were more pronounced with worsening disease severity. Pathway analysis for differentially expressed genes for patients with Child‐Pugh A demonstrated genes involved innate immune responses; those in Child‐Pugh B belonged to genes related to oxidation and alternative splicing; those in Child‐Pugh C related to methylation, acetylation, and alternative splicing. We found significant differences in the expression of heme oxygenase 1 (HMOX1) and ribonucleoprotein, PTB binding 1 (RAVER1) in peripheral blood of those who died during the follow‐up when compared to those who survived. Conclusion: Unique mRNAs that may implicate disease progression in patients with AC were identified by using a transcriptomic approach. Future studies to confirm our results are needed, and comprehensive mechanistic studies on the implications of these genes in AC pathogenesis and progression should be further explored.

IntroductionPromoting the development of digital technology is an important step in meeting the challenge of global climate change and achieving carbon peaking and carbon neutrality goals.MethodsBased on panel data of Chinese cities from 2006 to 2020, this paper used econometrics to investigate the impact and mechanism of digital technology on carbon emissions.ResultsThe results showed that digital technology can significantly reduce carbon emission intensity and improve carbon emission efficiency. These results remained robust after changing the estimation method, adding policy omission variables, replacing core variables, and solving the endogeneity problem. Digital technology can indirectly reduce carbon emissions by promoting green technological innovation and reducing energy intensity, and it plays a significant role in the carbon emission reduction practices of carbon emission trading policies and comprehensive national big data pilot zones. The replicability, non-exclusivity, and high mobility of digital technology help to accelerate the spread of knowledge and information between different cities, which leads to a spillover effect on carbon emission reductions. Our unconditional quantile regression model results showed that digital technology’s carbon emission reduction effect continuously decreases with increases in carbon dioxide emissions.DiscussionThe results of this paper provide evidence for the potential use of digital technology in achieving the goal of carbon neutrality, which is of great significance for achieving high-quality innovation and promoting the green transformation of the economy and society.

As an integration of artificial intelligence and advanced manufacturing technology, intelligent manufacturing has realized the innovation of manufacturing mode and created conditions for the green development of industry. After constructing a theoretical framework between intelligent manufacturing and industrial green total factor productivity, this paper uses panel data of 30 provinces in China from 2006 to 2020, and expresses the level of intelligent manufacturing with industrial robot density, to discuss the economic effects and mechanisms of intelligent manufacturing. The results show that intelligent manufacturing has a positive effect on industrial green total factor productivity, and the panel quantile regression model indicates that there is an increasing marginal effect. With the quantile points going from low to high, the coefficient and statistical significance become larger. Human capital is the mechanism for intelligent manufacturing to improve industrial green total factor productivity. Green technology innovation and producer service industry agglomeration have strengthened the positive effect. There is also heterogeneity in the effect, and the stronger the effect in regions launched local pilot schemes for carbon emissions trading and industrial green transformation development policy. In order to give full play to the technological dividend and empower sustainable industrial development, the paper argues that we need to accelerate the integration of artificial intelligence and manufacturing technology, thus improving the level of industrial intelligence and empowering green development.

Abstract Although advances in wireless technologies such as miniature and wearable electronics have improved the quality of our lives, the ubiquitous use of electronics comes at the expense of increased exposure to electromagnetic (EM) radiation. Up to date, extensive efforts have been made to develop high-performance EM absorbers based on synthetic materials. However, the design of an EM absorber with both exceptional EM dissipation ability and good environmental adaptability remains a substantial challenge. Here, we report the design of a class of carbon heterostructures via hierarchical assembly of graphitized lignocellulose derived from bamboo. Specifically, the assemblies of nanofibers and nanosheets behave as a nanometer-sized antenna, which results in an enhancement of the conductive loss. In addition, we show that the composition of cellulose and lignin in the precursor significantly influences the shape of the assembly and the formation of covalent bonds, which affect the dielectric response-ability and the surface hydrophobicity (the apparent contact angle of water can reach 135°). Finally, we demonstrate that the obtained carbon heterostructure maintains its wideband EM absorption with an effective absorption frequency ranging from 12.5 to 16.7 GHz under conditions that simulate the real-world environment, including exposure to rainwater with slightly acidic/alkaline pH values. Overall, the advances reported in this work provide new design principles for the synthesis of high-performance EM absorbers that can find practical applications in real-world environments.

Gestational diabetes mellitus (GDM) amplifies the intergenerational risk for early-onset metabolic diseases in offspring, yet the pathogenesis remains unclear. We investigated the impacts of GDM on islets development and maturation in offspring mice and whether probiotics (BiLaEn) have protective effects. Strikingly, GDM caused abnormal prenatal development of islets in offspring mice, with abnormally high-expression insulin and glucagon at birth, showing premature or quasi-mature state; the process of β-cell maturation and mTORC1 signalling were not synchronized with normal offspring mice within 14 days after birth. Furthermore, BiLaEn treatment benefited the normal development and maturation of GDM-offspring islets, avoiding “quasi-mature” at birth, which were based on the improvement of intestinal flora disturbance and leaky gut in GDM maternal mice. These data highlight the premature development of GDM-offspring islets as potential cause of early-onset metabolic diseases in GDM offspring, and targeted regulation of intestinal flora is expected to be safe and effective intervention.

Abstract Light affects many physiological processes in mammals such as entrainment of the circadian clock, regulation of mood, and relaxation of blood vessels. At the molecular level, a stimulus such as light initiates a cascade of kinases that phosphorylate CREB at various sites, including serine 133 (S133). This modification leads CREB to recruit the co-factor CRCT1 and the histone acetyltransferase CBP to stimulate the transcription of genes containing a CRE element in their promoters, such as Period 1 (Per1). However, the details of this pathway are poorly understood. Here we provide evidence that PER2 acts as a co-factor of CREB to facilitate the formation of a transactivation complex on the CRE element of the Per1 gene regulatory region in response to light or forskolin. Using in vitro and in vivo approaches, we show that PER2 modulates the interaction between CREB and its co-regulator CRTC1 to support complex formation only after a light or forskolin stimulus. Furthermore, the absence of PER2 abolished the interaction between the histone acetyltransferase CBP and CREB. This process was accompanied by a reduction of histone H3 acetylation and decreased recruitment of RNA Pol II to the Per1 gene. Collectively, our data show that PER2 supports the stimulus-dependent induction of the Per1 gene via modulation of the CREB/CRTC1/CBP complex.

Solid-state high-order harmonic generation (HHG) now is a strong tool for detecting target properties, like band structure, Berry curvature and transition dipole moments (TDMs). However, the physical mechanism of high-order harmonic generation (HHG) in solids has not been fully elucidated. According to previously published works, in addition to the inter-band polarization, intra-band currents, and anomalous currents due to Berry curvature, there is another term which will be called the mixture term (MT). Taking monolayer ZnO as a sample, it is found that the intensity of the mixture term, which has been ignored for a long time in previous works, actually is comparable with other terms. Additionally, we compare the orientation-dependent HHG spectra that originated from different mechanisms. It is found that the inter-band and mixture HHG show similar orientation features. Meanwhile, Berry curvature only produces perpendicularly polarized even harmonics, and intra-band perpendicularly polarized even harmonics show special orientation features which can be explained by the orientation-dependent group velocity. This work will help people understand the mechanisms of solid-HHG better.

One of the manifestations of renal aging is podocyte dysfunction and loss, which are associated with proteinuria and glomerulosclerosis. Studies show a male bias in glomerular dysfunction and chronic kidney diseases, and the underlying mechanisms remain obscure. Recent studies demonstrate the role of an age-associated increase in arginase-II (Arg-II) in proximal tubules of both male and female mice. However, it is unclear whether Arg-II is also involved in aging glomeruli. The current study investigates the role of the sex-specific elevation of Arg-II in podocytes in age-associated increased albuminuria. Young (3–4 months) and old (20–22 months) male and female mice of wt and arginase-II knockout (arg-ii−/−) were used. Albuminuria was employed as a readout of glomerular function. Cellular localization and expression of Arg-II in glomeruli were analyzed using an immunofluorescence confocal microscope. A more pronounced age-associated increase in albuminuria was found in male than in female mice. An age-associated induction of Arg-II in glomeruli and podocytes (as demonstrated by co-localization of Arg-II with the podocyte marker synaptopodin) was also observed in males but not in females. Ablation of the arg-ii gene in mice significantly reduces age-associated albuminuria in males. Also, age-associated decreases in podocyte density and glomerulus hypertrophy are significantly prevented in male arg-ii−/− but not in female mice. However, age-associated glomerulosclerosis is not affected by arg-ii ablation in both sexes. These results demonstrate a role of Arg-II in sex-specific podocyte injury in aging. They may explain the sex-specific differences in the development of renal disease in humans during aging.

Objective: Hepatocellular carcinoma (HCC), the main type of liver cancer, has a high morbidity and mortality, and a poor prognosis. RNA helicase DDX5, which acts as a transcriptional co-regulator, is overexpressed in most malignant tumors and promotes cancer cell growth. Heat shock protein 90 (HSP90) is an important molecular chaperone in the conformational maturation and stabilization of numerous proteins involved in cell growth or survival. Methods: DDX5 mRNA and protein expression in surgically resected HCC tissues from 24 Asian patients were detected by quantitative real-time PCR and Western blot, respectively. The interaction of DDX5-HSP90 was determined by molecular docking, immunoprecipitation, and laser scanning confocal microscopy. The autophagy signal was detected by Western blot. The cell functions and signaling pathways of DDX5 were determined in 2 HCC cell lines. Two different murine HCC xenograft models were used to determine the function of DDX5 and the therapeutic effect of an HSP90 inhibitor. Results: HSP90 interacted directly with DDX5 and inhibited DDX5 protein degradation in the AMPK/ULK1-regulated autophagy pathway. The subsequent accumulation of DDX5 protein induced the malignant phenotype of HCC by activating the β-catenin signaling pathway. The silencing of DDX5 or treatment with HSP90 inhibitor both blocked in vivo tumor growth in a murine HCC xenograft model. High levels of HSP90 and DDX5 protein were associated with poor prognoses. Conclusions: HSP90 interacted with DDX5 protein and subsequently protected DDX5 protein from AMPK/ULK1-regulated autophagic degradation. DDX5 and HSP90 are therefore potential therapeutic targets for HCC.

Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neuhi), but low levels of CD8+ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neuhi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.

Abstract The aging kidney undergoes complex changes and is vulnerable to injury and development of chronic kidney disease (CKD) with preponderance affecting more women than men. Evidence has been presented that the type-II L-arginine:ureohydrolase, arginase-II (Arg-II) plays a role in the acceleration of aging. Arg-II is highly expressed in the kidney. However, the role of Arg-II in renal aging is not known. This study is to investigate whether Arg-II is involved in the kidney aging process dependently on sex. Arg-II level in the kidney of wild type (WT) mice is significantly elevated with aging, which is accompanied by an increase in expression of the inflammatory cytokines/chemokines, tissue macrophages, factors involved in fibrosis, and tubulointestitial fibrosis in both males and females. This renal aging phenotype is significantly suppressed in arg-II −/− mice, mainly in the females in which Arg-II level is higher than in the males. Importantly, numerous factors such as IL-1β, MCP1, VCAM-1, and TGFβ1 are mainly localized in the proximal tubular S3 segment cells expressing Arg-II in the aging kidney. In human proximal tubular cells (HK-2), TNF-α enhances adhesion molecule expression dependently on Arg-II upregulation. Overexpression of Arg-II in the cells enhances TGFβ1 levels which is prevented by mitochondrial ROS inhibition. In summary, our study reveals that renal proximal tubular Arg-II plays an important role in the kidney aging process in females. Arg-II could be a promising therapeutic target for the treatment and prevention of aging-associated kidney diseases.

Materials that can harvest electromagnetic (EM) waves and harness the resulting energy would have many applications. Here, the authors present a hybrid composite that produces thermoelectricity from the heating in the EM absorption under microwave radiation.

Abstract Background The microRNAs(miRNA)-derived secondary phased small interfering RNAs (phasiRNAs) participate in post-transcriptional gene silencing and play important roles in various bio-processes in plants. In rice, two miRNAs, miR2118 and miR2275, were mainly responsible for triggering of 21-nt and 24-nt phasiRNAs biogenesis, respectively. However, relative fewer phasiRNA biogenesis pathways have been discovered in rice compared to other plant species, which limits the comprehensive understanding of phasiRNA biogenesis and the miRNA-derived regulatory network. Results In this study, we performed a systematical searching for phasiRNA biogenesis pathways in rice. As a result, five novel 21-nt phasiRNA biogenesis pathways and five novel 24-nt phasiRNA biogenesis pathways were identified. Further investigation of their regulatory function revealed that eleven novel phasiRNAs in 21-nt length recognized forty-one target genes. Most of these genes were involved in the growth and development of rice. In addition, five novel 24-nt phasiRNAs targeted to the promoter of an OsCKI1 gene and thereafter resulted in higher level of methylation in panicle, which implied their regulatory function in transcription of OsCKI1,which acted as a regulator of rice development. Conclusions These results substantially extended the information of phasiRNA biogenesis pathways and their regulatory function in rice.

Due to the anti-peak shaving characteristics of wind power under the operation mode of “power determined by heat”, a large number of wind power is abandoned at night. In order to solve the problem, this paper proposes a method of coordinated operation of ground source heat pump (GSHP) and combined heat and power (CHP) units. Through indirectly reducing the generation power of CHP units, the accommodation space of wind power in power grid is improved. A two-stage robust optimal scheduling model of regional integrated heat-power system (RIHPS) considering the uncertainty of wind power generation and power load is established. And a distributed solution method based on Alternating Direction Method of Multipliers (ADMM) method and column-and-constraint generation (C&CG) algorithm is designed. Then, the Locational marginal pricing strategy with the goal of guiding users to participate in wind power accommodation is analyzed. The numerical simulation results show that the wind power accommodation capacity of the integrated system under the operation mode of “power determined by heat” can be improved through installing GSHP at CHP units and using price signal guidance.

Introduction Carotid atherosclerosis (CAS) is a disease of the aorta caused by lipid metabolism disorders and local inflammation. Acupuncture combined with traditional western medicine (such as aspirin or atorvastatin) for the treatment of CAS has been widely applied in clinical practice, but there is still a lack of supporting evidence for its efficacy and safety on CAS. Therefore, this systematic review and network meta-analysis (NMA) will summarise the effects of different types of acupuncture treatments on CAS, and a ranking of the therapeutic classes will also be presented, aiming to provide evidence-based medicine for its extensive clinical application.Methods and analysis Systematic and NMA searches will be conducted in seven electronic databases: PubMed, EMBASE, Medline, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang Database and Chongqing VIP databases. The search time is from their inception to December 2020, regardless of language and publication type. Randomised controlled trials and controlled clinical trials that include patients with CAS receiving acupuncture therapy compared with a control group will be considered eligible. The primary outcomes include the carotid intima-media thickness and vessel plaque quantification; the secondary outcomes include the carotid plaque Crouse score, greyscale median, lipid levels, the incidence of cardiovascular events, safety and adverse events. The selection of studies, data extraction, quality assessment and risk of bias assessment will be conducted by two independent reviewers. The NMA will be analysed with Stata V.15.0, RevMan V.5.3 software and WinBUGS V.1.4.3.Ethics and dissemination Ethical approval will not be required for this study as it will be based on de-identified, aggregated published data. We will publish the findings in a peer-reviewed journal.PROSPERO registration number CRD42020207260.

Low phase noise lasers based on the combination of III–V semiconductors and silicon photonics are well established in the near-infrared spectral regime. Recent advances in the development of low-loss silicon nitride-based photonic integrated resonators have allowed them to outperform bulk external diode and fiber lasers in both phase noise and frequency agility in the 1550 nm-telecommunication window. Here, we demonstrate for the first time a hybrid integrated laser composed of a gallium nitride-based laser diode and a silicon nitride photonic chip-based microresonator operating at record low wavelengths as low as 410 nm in the near-ultraviolet wavelength region suitable for addressing atomic transitions of atoms and ions used in atomic clocks, quantum computing, or for underwater LiDAR. By self-injection locking of the Fabry–Pérot diode laser to a high-Q (0.4 × 106) photonic integrated microresonator, we reduce the optical phase noise at 461 nm by a factor greater than 100×, limited by the device quality factor and back-reflection.

BackgroundSorafenib, which can induce ferroptosis, is a multikinase inhibitor for enhancing survival in advanced hepatocellular carcinoma (HCC). However, a considerable challenge for the treatment of HCC is sorafenib resistance. Therefore, targeting the relationship between sorafenib resistance and ferroptosis genes may provide a novel approach for the treatment of HCC.Materials and MethodsWe analyzed the gene expression and clinicopathological factors from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases (GSE109211/GSE62813). The statistical analysis was conducted in R. Cell proliferation was assayed by MTT, cell colony-forming assay, and wound healing assay. Immunofluorescence assay and Western blot were used to evaluate the expression of AKT.ResultsMany ferroptosis-related genes were upregulated in the sorafenib-resistant group. Aldo-keto reductase 1C3 (AKR1C3) was highly expressed in sorafenib-resistant patients, and the high expression of AKR1C3 was associated with the poor prognosis of patients from the TCGA and ICGC databases. MTT and colony-forming assays showing AKR1C3 overexpression enhanced the proliferation of HCC cells and acute sorafenib resistance. Knockdown of AKR1C3 inhibited the proliferation of HCC cells and increased the drug sensitivity of sorafenib. Immunofluorescence assay and Western blot proved that AKR1C3 promoted the phosphorylation of AKT.ConclusionAKR1C3 can induce sorafenib resistance through promoting the phosphorylation of AKT in HCC. AKR1C3 inhibitors may be used in conjunction with sorafenib to become a better therapeutic target for HCC.

Long non-coding RNAs (lncRNAs), a class of transcribed RNA molecules with the lengths exceeding 200 nucleotides, are not translated into protein. They can modulate protein-coding genes by controlling transcriptional and posttranscriptional processes. The dysregulation of lncRNAs has been related to various pathological disorders. In this review, we summarized the current knowledge of lncRNAs and their implications in the pathogenesis of three common liver diseases: nonalcoholic fatty liver disease, alcohol-related liver disease, and cholestatic liver disease. Future studies to further define the role of lncRNAs and their mechanisms in various types of liver diseases should be explored. An improved understanding from these studies will provide us a useful perspective leading to mechanism-based intervention by targeting specific lncRNAs for the treatment of liver diseases.

Drug delivery systems have shown tremendous promise to improve the diagnostic and therapeutic effects of drugs due to their special property. Targeting tissue damage, tumors, or drugs with limited toxicity at the site of infection is the goal of successful pharmaceuticals. Targeted drug delivery has become significantly important in enhancing the pharmaceutical effects of drugs and reducing their side effects of therapeutics in the treatment of various disease conditions. Unfortunately, clinical translation of these targeted drug delivery system mechanisms faces many challenges. At present, only a few targeted drug delivery systems can achieve high targeting efficiency after intravenous injection, even though numerous surface markers and targeting approaches have been developed. Thus, cell-mediated drug-delivery targeting systems have received considerable attention for their enhanced therapeutic specificity and efficacy in the treatment of the disease. This review highlights the recent advances in the design of the different types of cells that have been explored for cell-mediated drug delivery and targeting mechanisms. A better understanding of cell biology orientation and a new generation of delivery strategies that utilize these endogenous approaches are expected to provide better solutions for specific site delivery and further facilitate clinical translation.

Hypoxia is an important risk for renal disease. The mitochondrial enzyme arginase-II (Arg-II) is expressed and/or induced by hypoxia in proximal tubular epithelial cells (PTECs) and in podocytes, leading to cellular damage. Because PTECs are vulnerable to hypoxia and located in proximity to podocytes, we examined the role of Arg-II in the crosstalk of PTECs under hypoxic conditions with podocytes. A human PTEC cell line (HK2) and a human podocyte cell line (AB8/13) were cultured. Arg-ii gene was ablated by CRISPR/Case9 in both cell types. HK2 cells were exposed to normoxia (21% O2) or hypoxia (1% O2) for 48 h. Conditioned medium (CM) was collected and transferred to the podocytes. Podocyte injuries were then analyzed. Hypoxic (not normoxic) HK2-CM caused cytoskeletal derangement, cell apoptosis, and increased Arg-II levels in differentiated podocytes. These effects were absent when arg-ii in HK2 was ablated. The detrimental effects of the hypoxic HK2-CM were prevented by TGF-β1 type-I receptor blocker SB431542. Indeed, TGF-β1 levels in hypoxic HK2-CM (but not arg-ii−/−-HK2-CM) were increased. Furthermore, the detrimental effects of TGF-β1 on podocytes were prevented in arg-ii−/−-podocytes. This study demonstrates crosstalk between PTECs and podocytes through the Arg-II-TGF-β1 cascade, which may contribute to hypoxia-induced podocyte damage.

Sleep staging is of critical significance to the diagnosis of sleep disorders, and the electroencephalogram (EEG), which is used for monitoring brain activity, is commonly employed in sleep staging. In this paper, we propose a novel method for improving the performance of sleep staging models based on Siamese networks, based on single-channel EEG. Our proposed method consists of a Siamese network architecture and a redesigned loss with distance metrics. Two encoders are used in the Siamese network to generate latent features of the EEG epochs, and the contrastive loss, which is also a distance metric, is used to compare the similarity or differences between EEG epochs from the same or different sleep stages. We evaluated our method on single-channel EEGs from different channels (Fpz-Cz and F4-EOG (left)) from two public datasets SleepEDF and MASS-SS3 and achieved the overall accuracies MF1 and Cohen’s kappa coefficient of 85.2%, 78.3% and 0.79 on SleepEDF and 87.2%, 82.1% and 0.81 on MASS-SS3. The results show that our method can significantly improve the performance of sleep staging models and outperform the state-of-the-art sleep staging methods. The performance of our method also confirms that the features captured by Siamese networks and distance metrics are useful for sleep staging.

The ureohydrolase, type-II arginase (Arg-II), is a mitochondrial enzyme metabolizing L-arginine into urea and L-ornithine and is highly expressed in renal proximal tubular cells (PTC) and upregulated by renal ischemia. Recent studies reported contradictory results on the role of Arg-II in renal injury. The aim of our study is to investigate the function of Arg-II in renal epithelial cell damage under hypoxic conditions. Human renal epithelial cell line HK2 was cultured under hypoxic conditions for 12–48 h. Moreover, ex vivo experiments with isolated kidneys from wild-type (WT) and genetic Arg-II deficient mice (Arg-II–/–) were conducted under normoxic and hypoxic conditions. The results show that hypoxia upregulates Arg-II expression in HK2 cells, which is inhibited by silencing both hypoxia-inducible factors (HIFs) HIF1α and HIF2α. Treatment of the cells with dimethyloxaloylglycine (DMOG) to stabilize HIFα also enhances Arg-II. Interestingly, hypoxia or DMOG upregulates transforming growth factor β1 (TGFβ1) levels and collagens Iα1, which is prevented by Arg-II silencing, while TGFβ1-induced collagen Iα1 expression is not affected by Arg-II silencing. Inhibition of mitochondrial complex-I by rotenone abolishes hypoxia-induced reactive oxygen species (mtROS) and TGFβ1 elevation in the cells. Ex vivo experiments show elevated Arg-II and TGFβ1 expression and the injury marker NGAL in the WT mouse kidneys under hypoxic conditions, which is prevented in the Arg-II–/– mice. Taking together, the results demonstrate that hypoxia activates renal epithelial HIFs-Arg-II-mtROS-TGFβ1-cascade, participating in hypoxia-associated renal injury and fibrosis.

In this study, generative adversarial networks named SleepGAN are proposed to expand the training set for automatic sleep stage classification tasks by generating both electroencephalogram (EEG) epochs and sequence relationships of sleep stages. In order to reach high accuracy, most existing classification methods require substantial amounts of training data, but obtaining such quantities of real EEG epochs is expensive and time-consuming. We introduce few-shot learning, which is a method of training a GAN using a very small set of training data. This paper presents progressive Wasserstein divergence generative adversarial networks (GANs) and a relational memory generator to generate EEG epochs and stage transition sequences, respectively. For the evaluation of our generated data, we use single-channel EEGs from the public dataset Sleep-EDF. The addition of our augmented data and sequence to the training set was shown to improve the performance of the classification model. The accuracy of the model increased by approximately 1% after incorporating generated EEG epochs. Adding both the augmented data and sequence to the training set resulted in a further increase of 3%, from the original accuracy of 79.40% to 83.06%. The result proves that SleepGAN is a set of GANs capable of generating realistic EEG epochs and transition sequences under the condition of insufficient training data and can be used to enlarge the training dataset and improve the performance of sleep stage classification models in clinical practice.

Pharmacokinetic assessment of drug disposition processes in vivo is critical in predicting pharmacodynamics and toxicology to reduce the risk of inappropriate drug development. The blood–brain barrier (BBB), a special physiological structure in brain tissue, hinders the entry of targeted drugs into the central nervous system (CNS), making the drug concentrations in target tissue correlate poorly with the blood drug concentrations. Additionally, once non-CNS drugs act directly on the fragile and important brain tissue, they may produce extra-therapeutic effects that may impair CNS function. Thus, an intracerebral pharmacokinetic study was developed to reflect the disposition and course of action of drugs following intracerebral absorption. Through an increasing understanding of the fine structure in the brain and the rapid development of analytical techniques, cerebral pharmacokinetic techniques have developed into non-invasive imaging techniques. Through non-invasive imaging techniques, molecules can be tracked and visualized in the entire BBB, visualizing how they enter the BBB, allowing quantitative tools to be combined with the imaging system to derive reliable pharmacokinetic profiles. The advent of imaging-based pharmacokinetic techniques in the brain has made the field of intracerebral pharmacokinetics more complete and reliable, paving the way for elucidating the dynamics of drug action in the brain and predicting its course. The paper reviews the development and application of imaging technologies for cerebral pharmacokinetic study, represented by optical imaging, radiographic autoradiography, radionuclide imaging and mass spectrometry imaging, and objectively evaluates the advantages and limitations of these methods for predicting the pharmacodynamic and toxic effects of drugs in brain tissues.

Alcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid ω-hydroxylation of medium- and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and Shp−/− mice were fed with a modified ethanol-binge, National Institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERBα agonist (SR9009, 100 mg/kg/d) or CYP4A antagonist (HET0016, 5 mg/kg/d) in ethanol-fed mice were also evaluated. We found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT mice, but not in Shp−/− mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERBα is the transcriptional repressor of Cyp4a10 and Cyp4a14. Rev-Erbα−/− hepatocytes had a marked induction of both Cyp4a genes and lipid accumulation. REV-ERBα agonist SR9009 or CYP4A antagonist HET0016 attenuated Cyp4a induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP/REV-ERBα/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV-ERBα or CYP4A as the potential therapeutic targets for ALD.

Background: Cholangiocytes are the target cells of cholangiopathies including primary sclerosing cholangitis (PSC). Vimentin is an intermediate filament protein that has been found in various types of mesenchymal cells. The aim of this study is to evaluate the role of vimentin in the progression of biliary damage/liver fibrosis and whether there is a mesenchymal phenotype of cholangiocytes in the Mdr2−/− model of PSC. Methods: In vivo studies were performed in 12 wk. Mdr2−/− male mice with or without vimentin Vivo-Morpholino treatment and their corresponding control groups. Liver specimens from human PSC patients, human intrahepatic biliary epithelial cells (HIBEpiC) and human hepatic stellate cell lines (HHSteCs) were used to measure changes in epithelial-to-mesenchymal transition (EMT). Findings: There was increased mesenchymal phenotype of cholangiocytes in Mdr2−/− mice, which was reduced by treatment of vimentin Vivo-Morpholino. Concomitant with reduced vimentin expression, there was decreased liver damage, ductular reaction, biliary senescence, liver fibrosis and TGF-β1 secretion in Mdr2−/− mice treated with vimentin Vivo-Morpholino. Human PSC patients and derived cell lines had increased expression of vimentin and other mesenchymal markers compared to healthy controls and HIBEpiC, respectively. In vitro silencing of vimentin in HIBEpiC suppressed TGF-β1-induced EMT and fibrotic reaction. HHSteCs had decreased fibrotic reaction and increased cellular senescence after stimulation with cholangiocyte supernatant with reduced vimentin levels. Interpretation: Our study demonstrated that knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes, which leads to decreased biliary senescence and liver fibrosis. Inhibition of vimentin may be a key therapeutic target in the treatment of cholangiopathies including PSC. Fund: National Institutes of Health (NIH) awards, VA Merit awards. Keywords: Ductular reaction, Fibroblast, Fibrosis, Senescence, Transforming growth factor beta 1

Background: Early detection of influenza activity followed by timely response is a critical component of preparedness for seasonal influenza epidemic and influenza pandemic. However, most relevant studies were conducted at the regional or national level with regular seasonal influenza trends. There are few feasible strategies to forecast influenza activity at the local level with irregular trends. Methods: Multi-source electronic data, including historical percentage of influenza-like illness (ILI%), weather data, Baidu search index and Sina Weibo data of Chongqing, China, were collected and integrated into an innovative Self-adaptive AI Model (SAAIM), which was constructed by integrating Seasonal Autoregressive Integrated Moving Average model and XGBoost model using a self-adaptive weight adjustment mechanism. SAAIM was applied to ILI% forecast in Chongqing from 2017 to 2018, of which the performance was compared with three previously available models on forecasting. Findings: ILI% showed an irregular seasonal trend from 2012 to 2018 in Chongqing. Compared with three reference models, SAAIM achieved the best performance on forecasting ILI% of Chongqing with the mean absolute percentage error (MAPE) of 11·9%, 7·5%, and 11·9% during the periods of the year 2014–2016, 2017, and 2018 respectively. Among the three categories of source data, historical influenza activity contributed the most to the forecast accuracy by decreasing the MAPE by 19·6%, 43·1%, and 11·1%, followed by weather information (MAPE reduced by 3·3%, 17·1%, and 2·2%), and Internet-related public sentiment data (MAPE reduced by 1·1%, 0·9%, and 1·3%). Interpretation: Accurate influenza forecast in areas with irregular seasonal influenza trends can be made by SAAIM with multi-source electronic data. Keywords: Influenza, Influenza-like illness, Forecast, AI, Multi-source electronic data

Summary: Insulin-induced AKT activation is dependent on phosphoinositide 3-kinase and opposed by tumor suppressor phosphatase and tensin homolog (PTEN). Our previous study demonstrates that myosin 1b (MYO1B) mediates arginase-II-induced activation of mechanistic target of rapamycin complex 1 that is regulated by AKT. However, the role of MYO1B in AKT activation is unknown. Here we show that silencing MYO1B in mouse embryonic fibroblasts (MEF) inhibits insulin-induced nuclear but not cytoplasmic AKT activation accompanied by elevated nuclear PTEN level. Co-immunoprecipitation, co-immunostaining, and proximity ligation assay show an interaction of MYO1B and PTEN resulting in reduced nuclear PTEN. Moreover, the elevated nuclear PTEN upon silencing MYO1B promotes apoptosis of MEFs and melanoma B16F10 cells. Taken together, we demonstrate that MYO1B, by interacting with PTEN, prevents nuclear localization of PTEN contributing to nuclear AKT activation and suppression of cell apoptosis. This may present a therapeutic approach for cancer treatment such as melanoma. : Biochemistry; Biological Sciences; Cell Biology; Molecular Biology Subject Areas: Biochemistry, Biological Sciences, Cell Biology, Molecular Biology

Hypoxia plays a crucial role in acute and chronic renal injury, which is attributable to renal tubular and glomerular cell damage. Some studies provide evidence that hypoxia-dependent upregulation of the mitochondrial enzyme arginase type-II (Arg-II) in tubular cells promotes renal tubular injury. It is, however, not known whether Arg-II is also expressed in glomerular cells, particularly podocytes under hypoxic conditions, contributing to hypoxia-induced podocyte injury. The effects of hypoxia on human podocyte cells (AB8/13) in cultures and on isolated kidneys from wild-type (wt) and arg-ii gene-deficient (arg-ii−/−) mice ex vivo, as well as on mice of the two genotypes in vivo, were investigated, respectively. We found that the Arg-II levels were enhanced in cultured podocytes in a time-dependent manner over 48 h, which was dependent on the stabilization of hypoxia-inducible factor 1α (HIF1α). Moreover, a hypoxia-induced derangement of cellular actin cytoskeletal fibers, a decrease in podocin, and an increase in mitochondrial ROS (mtROS) generation—as measured by MitoSOX—were inhibited by adenoviral-mediated arg-ii gene silencing. These effects of hypoxia on podocyte injury were mimicked by the HIFα stabilizing drug DMOG, which inhibits prolyl hydroxylases (PHD), the enzymes involved in HIFα degradation. The silencing of arg-ii prevented the detrimental effects of DMOG on podocytes. Furthermore, the inhibition of mtROS generation by rotenone—the inhibitor of respiration chain complex-I—recapitulated the protective effects of arg-ii silencing on podocytes under hypoxic conditions. Moreover, the ex vivo experiments with isolated kidney tissues and the in vivo experiments with mice exposed to hypoxic conditions showed increased Arg-II levels in podocytes and decreased podocyte markers regarding synaptopodin in wt mice but not in arg-ii−/− mice. While age-associated albuminuria was reduced in the arg-ii−/− mice, the hypoxia-induced increase in albuminuria was, however, not significantly affected in the arg-ii−/−. Our study demonstrates that Arg-II in podocytes promotes cell injury. Arg-ii ablation seems insufficient to protect mice in vivo against a hypoxia-induced increase in albuminuria, but it does reduce albuminuria in aging.

Sedimentary microorganisms play crucial roles in maintaining the functional stability of aquatic ecosystems. However, their taxonomic composition and assembly processes are not well known in estuarine–coastal margins because of their complex environment. We investigated microbial communities, co-occurrence relationships, and underlying mechanisms in 33 surface sediment samples collected in the Jiulong River Estuary and the Taiwan Strait to reveal their composition dynamics. The abundance, diversity, and composition of microorganisms demonstrated obvious spatial variables. Methanobacterium and Methanosarcina, as well as Candidatus_Nitrosopumilus and Nitrososphaeraceae were the main methanogenic and ammonia-oxidizing archaea, with an average abundance of more than 5.91% and 4.27%, respectively. Along with a salinity gradient increase, the relative abundance of methanogenic archaea (from 42.9% to 16.6%) contrasted with the trend of ammonia-oxidizing archaea (from 6.04% to 18.7%). The number of methanogenic archaea gradually decreased with increasing geographic distance (p < 0.05), whereas ammonia-oxidizing archaea showed no significant change (p > 0.05). In co-occurrence patterns, closer inter-taxa connections were observed among archaea–archaea and bacteria–bacteria than in archaea–bacteria, which indicated that coexistence within the same kingdom was greater than interaction between different kingdoms in shaping the community structure along the salinity gradient. Furthermore, null model analyses of the microbial community showed that undominated was the most prominent process, explaining over 44.9% of community variation, followed by heterogeneous selection and dispersal limitation, which contributed to 27.7% and 16.3%, respectively. We demonstrated that stochasticity, rather than determinism, regulates community assembly. These results further highlight that intra-kingdom co-occurrence and stochastic processes shape the structure and assembly of microbial communities in estuarine–coastal margins.

The impaired L-arginine/nitric oxide pathway is a well-recognized mechanism for cardiovascular and renal diseases with aging. Therefore, supplementation of L-arginine is widely proposed to boost health or as adjunct therapy for the patients. However, clinical data, show adverse effects and even enhanced mortality in patients receiving long-term L-arginine supplementation. The effects of long-term L-arginine supplementation on kidney aging and the underlying mechanisms remain elusive. Moreover, high protein and high amino acid diet has been thought detrimental for kidney. We therefore investigated effects of chronic dietary L-arginine supplementation on kidney aging. In both young (4 months) and old (18–24 months) mice, animals either receive standard chow containing 0.65% L-arginine or diet supplemented with L-arginine to 2.46% for 16 weeks. Inflammation and fibrosis markers and albuminuria are then analyzed. Age-associated increases in tnf-α, il-1β, and il-6, vcam-1, icam-1, mcp1, inos, and macrophage infiltration, collagen expression, and S6K1 activation are observed, which is not favorably affected, but rather further enhanced, by L-arginine supplementation. Importantly, L-arginine supplementation further enhances age-associated albuminuria and mortality particularly in females, accompanied by elevated renal arginase-II (Arg-II) levels. The enhanced albuminuria by L-arginine supplementation in aging is not protected in Arg-II−/− mice. In contrast, L-arginine supplementation increases ROS and decreases nitric oxide production in old mouse aortas, which is reduced in Arg-II−/− mice. The results do not support benefits of long-term L-arginine supplementation. It rather accelerates functional decline of kidney and vasculature in aging. Thus, the long-term dietary L-arginine supplementation should be avoided particularly in elderly population.

The increases in crop yield in China are linked to massive increases in fertilizer and water input, which have also accelerated the degradation of soil and environmental pollution. Nevertheless, the long-term changes in crop yield and water use efficiency (WUE) of three major cereals (maize, wheat and rice) in response to field management practices are rarely reported. This meta-analysis evaluated the effect of field management (nitrogen input (N), irrigation, fertilizer type, fertilization frequency, and irrigation method) on crop yield and WUE between 1990 and 2020 based on 3152 observations. We found that the N thresholds for maize, wheat, and rice were 150–200 kg ha−1, 140–210 kg ha−1, and 90–135 kg ha−1, respectively. N fertilization within the threshold levels increased the crop yield and WUE of maize (84% and 74%), wheat (47% and 41%), and rice (55% and 30%). The irrigation (mm) thresholds for maize and wheat were 180–240 mm and 300–400 mm and crop yield and WUE were increased by 37% and 13% for maize and by 84% and 41% for wheat. Agricultural management increased yield and WUE (% and %) through drip irrigation (23 and 13 maize; 31 and 14 wheat), alternate wetting and drying (AWD) (26 and 30 rice), split fertilization (31 and 21 maize; 64 and 40 wheat; 33 and 25 rice) and organic–inorganic fertilizer (43 and 39 maize; 68 and 66 wheat; 38 and 34 rice). With the increase in HI (humidity index) from 10 to 30, the contribution of irrigation to WUE decreased, but that of fertilization increased. This study concludes that N fertilizer and irrigation applications between threshold levels along with suitable field management is a win–win strategy to achieve climate-smart agricultural production with minimum damages to soil and environment and at lower dependence on fertilizer and irrigation.

Successful recovery from hepatectomy is partially contingent upon the rate of residual liver regeneration. The traditional Chinese medicines known as Periplaneta americana extracts (PAEs) positively influence wound healing by promoting tissue repair. However, the effect of PAEs on liver regeneration is unknown. We used a mouse liver regeneration model after 70% partial hepatectomy (PH) and a hepatocyte culture to determine whether PAEs can promote liver regeneration as effectively as skin regeneration and establish their modes of action. L02 cells were divided into serum-starved control (NC) and three PAEs (serum starvation + 0.1 mg/ml, 0.5 mg/ml, or 1 mg/ml PAEs) groups. L02 cell proliferation was assessed at 24 h, 48 h, and 72 h by CCK-8 assay. Forty male C57 mice were randomly divided into control (NC), normal saline (NS), PAEs400 (400 mg/kg/d), and PAEs800 (800 mg/kg/d) groups (n = 10 per group). The NS and both PAEs groups were administered normal saline and PAEs, respectively, by gavage for 10 days. Two hours after the tenth gavage, the NS and both PAEs groups were subjected to 70% PH and the residual liver was harvested after 48 h. The hepatic regeneration rate was evaluated and hepatocyte proliferation was estimated by immunohistochemical (IHC) staining for Ki-67. Twelve DEG libraries (three samples per group) were prepared and sequencing was performed in an Illumina HiSeq 2000 (Mus_musculus) at the Beijing Genomics Institute. The genes expressed in the liver tissues and their expression profiles were analyzed by bioinformatics. KEGG was used to annotate, enrich, and analyze the pathways. PAEs promoted hepatocyte proliferation in vitro and in vivo and accelerated mouse liver regeneration after 70% PH. The screening criteria were fold change (FC) ≥ 2 and q-value < 0.001. We identified 1,092 known DEGs in PAEs400 and PAEs800. Of these, 153 were categorized in cellular processes. The KEGG analysis revealed that the aforementioned DEGs participated in several signaling pathways closely associated with cell proliferation including PI3K-Akt, MAPK, Apelin, Wnt, FoxO, mTOR, Ras, VEGF, ErbB, Hippo, and AMPK. It was concluded that PAEs can effectively improve liver regeneration via the synergistic activation of different signaling pathways.

Identification of the target genes of microRNAs (miRNAs), trans-acting small interfering RNAs (ta-siRNAs), and small interfering RNAs (siRNAs) is an important step for understanding their regulatory roles in plants. In recent years, many bioinformatics software packages based on small RNA (sRNA) high-throughput sequencing (HTS) and degradome sequencing data analysis have provided strong technical support for large-scale mining of sRNA-target pairs. However, sRNA-target regulation is achieved using a complex network of interactions since one transcript might be co-regulated by multiple sRNAs and one sRNA may also affect multiple targets. Currently used mining software can realize the mining of multiple unknown targets using known sRNA, but it cannot rule out the possibility of co-regulation of the same target by other unknown sRNAs. Hence, the obtained regulatory network may be incomplete. We have developed a new mining software, sRNATargetDigger, that includes two function modules, "Forward Digger" and "Reverse Digger", which can identify regulatory sRNA-target pairs bidirectionally. Moreover, it has the ability to identify unknown sRNAs co-regulating the same target, in order to obtain a more authentic and reliable sRNA-target regulatory network. Upon re-examination of the published sRNA-target pairs in Arabidopsis thaliana, sRNATargetDigger found 170 novel co-regulatory sRNA-target pairs. This software can be downloaded from http://www.bioinfolab.cn/sRNATD.html.

MicroRNAs are small non-coding RNAs that range in length from 18 to 24 nucleotides. As one of the most extensively studied microRNAs, microRNA-21 (miR-21) is highly expressed in many mammalian cell types. It regulates multiple biological functions such as proliferation, differentiation, migration, and apoptosis. In this review, we summarized the mechanism of miR-21 in the pathogenesis of various liver diseases. While it is clear that miR-21 plays an important role in different types of liver diseases, its use as a diagnostic marker for specific liver disease or its therapeutic implication are not ready for prime time due to significant variability and heterogeneity in the expression of miR-21 in different types of liver diseases depending on the studies. Additional studies to further define miR-21 functions and its mechanism in association with each type of chronic liver diseases are needed before we can translate the bedside observations into clinical settings.

Objective: Glucose is the major energy substrate of the brain and crucial for normal brain function. In diabetes, the brain is subject to episodes of hypo- and hyperglycemia resulting in acute outcomes ranging from confusion to seizures, while chronic metabolic dysregulation puts patients at increased risk for depression and Alzheimer's disease. In the present study, we aimed to determine how glucose is metabolized in different regions of the brain using imaging mass spectrometry (IMS). Methods: To examine the relative abundance of glucose and other metabolites in the brain, mouse brain sections were subjected to imaging mass spectrometry at a resolution of 100 μm. This was correlated with immunohistochemistry, qPCR, western blotting and enzyme assays of dissected brain regions to determine the relative contributions of the glycolytic and pentose phosphate pathways to regional glucose metabolism. Results: In brain, there are significant regional differences in glucose metabolism, with low levels of hexose bisphosphate (a glycolytic intermediate) and high levels of the pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) and PPP metabolite hexose phosphate in thalamus compared to cortex. The ratio of ATP to ADP is significantly higher in white matter tracts, such as corpus callosum, compared to less myelinated areas. While the brain is able to maintain normal ratios of hexose phosphate, hexose bisphosphate, ATP, and ADP during fasting, fasting causes a large increase in cortical and hippocampal lactate. Conclusion: These data demonstrate the importance of direct measurement of metabolic intermediates to determine regional differences in brain glucose metabolism and illustrate the strength of imaging mass spectrometry for investigating the impact of changing metabolic states on brain function at a regional level with high resolution. Keywords: Brain imaging, Glucose metabolism, Pentose phosphate pathway, Glycolysis, ATP, Mass spectrometry

High‐mobility‐group protein 2 (HMGB2) expression is up‐regulated in human liver cancer; however, little is known about its regulatory function. Here, we establish HMGB2 as a new modulator of the pluripotency of mouse embryonic stem cells. Similar to octamer‐binding transcription factor 4 (OCT4) and sex‐determining region Y‐box 2 (SOX2), HMGB2 protein is highly expressed in undifferentiated CGR8 cells, whereas it undergoes rapid decline during embryonic body formation. HMGB2 interacts with OCT4, increases protein expression of OCT4 and SOX2, and enhances their transcriptional activities. We also show that microRNA (miRNA)‐127 is a translational repressor of HMGB2 protein expression by targeting its 3′ untranslated region. We further elucidate a transcriptional mechanism controlling HMGB2 messenger RNA expression by the nuclear receptor small heterodimer partner (SHP) and transcription factor E2F1. Diminishing HMGB2 expression by ectopic expression of miR‐127 or SHP or treatment with the small molecule inhibitor inflachromene decreases OCT4 and SOX2 expression and facilitates CGR8 differentiation. In addition, HMGB2 is markedly induced in liver tumor initiating cells. Diminishing HMGB2 expression by short hairpin RNA for HMGB2 (shHMGB2), miR‐127, or SHP impairs spheroid formation. Importantly, HMGB2 expression is elevated in various human cancers. Conclusion: HMGB2 acts upstream of OCT4/SOX2 signaling to control embryonic stem cell pluripotency. Diminishing HMGB2 expression by miR‐127 or SHP may provide a potential means to decrease the pluripotency of tumor initiating cells. (Hepatology Communications 2017;1:816–830)

Hypoxia plays a crucial role in the pathogenesis of cardiovascular diseases. Mitochondrial enzyme arginase type II (Arg-II) is reported to lead to endothelial dysfunction and enhance the expression of endothelial inflammatory adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). In this study, we investigate the role of Arg-II in hypoxia-induced endothelial activation and the potential underlying mechanisms. Exposure of the human endothelial cells to hypoxia induced a time-dependent increase in Arg-II, HIF1α, HIF2α, and ICAM-1 protein level, whereas no change in the protein level of VCAM-1 and E-selectin was observed. Similar effects were obtained in cells treated with a hypoxia mimetic Dimethyloxaloylglycine (DMOG). Silencing HIF1α, but not HIF2α, reversed hypoxia-induced upregulation of Arg-II. Moreover, silencing Arg-II prevented the ICAM-1 upregulation induced by hypoxia or DMOG. Furthermore, the endothelial cells incubated under hypoxic condition or treated with DMOG or hypoxia enhanced monocyte adhesion, which was inhibited by silencing Arg-II. Lastly, silencing Arg-II prevented hypoxia-induced mitochondrial superoxide production in endothelial cells, and hypoxia-induced ICAM-1 upregulation was reversed by mitochondrial electron transport inhibitor rotenone. These data demonstrate that hypoxia enhances ICAM-1 protein level and monocyte-endothelial interaction through HIF1α-mediated increase in Arg-II protein level on leading to increased mitochondrial reactive oxygen species production. These effects of hypoxia on endothelial cells may play a key role in cardiovascular diseases. Our results suggest that Arg-II could be a promising therapeutic target to prevent hypoxia-induced vascular damage/dysfunction.