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Abstract There are several gaps in the field of digital inequity in education because it is still in its initial stage. To fill the research gaps, this study has revealed a complex landscape of problems and solutions. The analysis highlights the urgent need to address digital inequity that prevents equal access to educational resources and opportunities. While the challenges are numerous, the solutions are also diverse. Addressing cultural norms and stereotypes that perpetuate gender-based inequity is crucial, along with investing in gender-sensitive technology and infrastructure. Promoting digital literacy among all learners is also essential to empower them in the digital age. By taking a comprehensive approach that combines policy changes, technological advancements, and educational strategies, we can hope to bridge the digital inequity and create a more equitable and inclusive education system. Future research could highlight cross-cultural and cross-contextual studies, longitudinal studies, and integration of multiple methodologies.

Bacillus paranthracis, a Gram-positive conditional pathogen of Bacillus cereus group species, is capable of causing foodborne and waterborne illnesses, leading to intestinal diseases in humans characterized by diarrhoea and vomiting. However, documented cases of B. paranthracis infection outbreaks are rare in the world, and the genomic background of outbreak strains is seldom characterized. This study retrospectively analyzed strains obtained from an outbreak in schools, as well as from water systems in peri-urban areas, China, in 2020. In total, 28 B. cereus group isolates were retrieved, comprising 6 from stool samples and 22 from water samples. Epidemiological and phylogenetic investigations indicated that the B. paranthracis isolate from drinking water as the causative agent of the outbreak. The genomic comparison revealed a high degree of consistency among 8 outbreak-related strains in terms of antimicrobial resistance gene profiles, virulence gene profiles, genomic content, and multilocus sequence typing (MLST). The strains related to the outbreak show highly similar genomic ring diagrams and close phylogenetic relationships. Additionally, this study shed light on the pathogenic potential and complexity of B. cereus group through its diversity in virulence genes and mice infection model. The findings highlight the usefulness of B. paranthracis genomes in understanding genetic diversity within specific environments and in tracing the source of pathogens during outbreak situations, thereby enabling targeted infection control interventions.

The antitumor activity of a fermented juice (called Shaduojin, SDJ) made from sea buckthorn, raspberry, etc. was investigated using CT26 bearing mice. The results showed a dose-dependent inhibition of tumor growth in the SDJ groups compared to the model group. The number of CD8+ T and dendritic cells were increased while the Treg cells and monocytes was decreased in both the tumor and spleen in the SDJ groups. The TNF-α and INF-γ increased and the IL-1β, IL-6, and IL-10 decreased in the SDJ groups. Additionally, there was an increase in the abundance of beneficial bacteria (Firmicutes, Coildextribacter, and Lachnospiraceae) which contribute to intestinal health and produce short-chain fatty acids (SCFAs). On the other hand, harmful bacteria (Muribaculaceae and uncultured Bacteroidales) decreased. The SCFA content in the intestine also increased in the SDJ groups. Therefore, it has been showed that SDJ may elicit its effect on preventing colorectal cancer by regulating the immune system and gut microbiota.

Background: Overweight and obese older adults have a high risk for developing cardiovascular disease. Aerobic exercise is a valuable strategy to improve vascular health, but the effects of aerobic exercise on vascular endothelial function in obese and overweight older adults remain controversial. The purpose of this meta-analysis was to investigate the effects of aerobic exercise on vascular function in obese and overweight older adults with or without comorbidity. Methods: A systematic literature search for related studies published in English was conducted between January 1989 and October 30, 2022, in the PubMed, Embase, and Cochrane Library databases. A random effects model was chosen for meta-analysis, which calculated the effect sizes of control and intervention groups after exercise intervention using standardized mean differences (SMDs) corrected for Hedges' g bias and 95% confidence intervals (95% CIs). Results: Twenty-six studies containing 1418 participants were included in the study. After excluding three studies contributing to higher heterogeneity by sensitivity analysis, there are small effects of regular aerobic exercise on vascular function of obese and overweight older adults, including flow-mediated dilation (FMD) [SMD = 0.21, 95% CI (0.02, 0.41), z = 2.16, df = 19, I2 = 52.2%, P = 0.031] and pulse wave velocity (PWV) [SMD = −0.24, 95% CI (−0.46, −0.02), z = 2.17, df = 10, I2 = 8.6%, P = 0.030], and no significant effect was observed on augmentation index (Aix). Subgroup analysis showed small effects of regular aerobic exercise on FMD [SMD = 0.37, 95% CI (0.13, 0.61), z = 3.05, df = 9, I2 = 52.6%, P = 0.002] in the overweight not obese subgroup (25 = BMI

In this paper, targeting the problem that it is difficult to deal with the time-varying sideslip angle of an underactuated unmanned surface vehicle (USV), a line–of–sight (LOS) guidance law based on an improved extended state observer (ESO) is proposed. A reduced-order ESO is introduced into the identification of the sideslip angle caused by the environmental disturbance, which ensures a fast and accurate estimation of the sideslip angle. This enables the USV to follow the reference path with high precision, despite external disturbances from wind, waves, and currents. These unknown disturbances are modeled as drift, which the modified ESO-based LOS guidance law compensates for using the ESO. In the guidance subsystem incorporating the reduced-order state observer, the observer estimation and track errors are proved uniformly ultimately bounded. Simulation and experimental results are presented to validate the effectiveness of the proposed method. The simulation and comparison results demonstrate that the proposed ELOS guidance can help a USV track different types of paths quickly and smoothly. Additionally, the experimental results confirm the feasibility of the method.

Urban greenspace has a profound impact on public health by purifying the air, blocking bacteria, and creating activity venues. Due to people’s different position, the greenspace exposure to different age groups changes at various times. In this study, we combined NDVI (normalized difference vegetation index) and GVI (green view index) green indices with mobile signaling big data to evaluate the greenspace exposure of 3 age groups in Shanghai at different times. A dynamic assessment model for greenspace exposure has been adopted in this study. April 2021 and April 2022 were selected as the study periods, representing the non-lockdown period and the lockdown period, respectively. The results indicate that greenspace exposure changes slightly during the lockdown period. During lockdown, the NDVI exposure in the age groups of 31 to 50, 51, and above was higher than that during non-lockdown. However, the NDVI exposure of people aged 0 to 30 during lockdown is lower than that during non-lockdown. The GVI exposure of people aged 51 and above is lower than that of the other age group. Whether it is under lockdown or not, from 8:00 to 17:00, the NDVI exposure showed a slightly higher value than at other hours. The value of GVI exposure fluctuates steadily during 6:00 to 24:00. This study enriches the evaluation dimensions of urban greenspace exposure.

Abstract Background Mitochondrial dysfunction in kidney cells has been implicated in the pathogenesis of chronic kidney disease (CKD). Estimation of mitochondrial DNA copy number (mtDNA-CN) is considered a convenient method for representing mitochondrial function in large samples. However, no study has investigated the association between mtDNA-CN and CKD in older adults with the highest prevalence. The objective is to examine cross-sectional and prospective associations between mtDNA-CN values and CKD risk in older adults to determine whether mtDNA-CN represents a novel potential biomarker for the recognition of CKD risk. Patients and methods In a Chinese community-based cohort of over 65-year-olds, we included 14,467 participants (52.6% females). CKD was defined by eGFR

Abstract Background Biological laboratories and companies involved in antibody development need convenient and versatile methods to detect highly active antibodies. Methods To develop a mammalian cell-based ZZ display system for antibody quantification, the eukaryotic ZZ-displayed plasmid was constructed and transfected into CHO cells. After screening by flow cytometric sorting, the stable ZZ display cells were incubated with reference IgG and samples with unknown IgG content for 40 min at 4℃, the relative fluorescence intensity of cells was analyzed and the concentration of IgG was calculated. Results By investigating the effects of different display-associated genetic elements, a eukaryotic ZZ-displaying plasmid with the highest display efficiency were constructed. After transfection and screening, almost 100% of the cells were able to display the ZZ peptide (designated CHO-ZZ cells). These stable CHO-ZZ cells were able to capture a variety of IgG, including human, rabbit, donkey and even mouse and goat. CHO-ZZ cells could be used to quantify human IgG in the range of approximately 12.5–1000 ng/mL, and to identify high-yielding engineered monoclonal cell lines. Conclusions We have established a highly efficient CHO-ZZ display system in this study, which enables the quantification of IgG from various species under physiological conditions. This system offers the advantage of eliminating the need for antibody purification and will contribute to antibody development.

Endothelial cells line all blood vessels, where they coordinate blood vessel formation and the blood-tissue barrier via regulation of cell-cell junctions. The nucleus also regulates endothelial cell behaviors, but it is unclear how the nucleus contributes to endothelial cell activities at the cell periphery. Here, we show that the nuclear-localized linker of the nucleoskeleton and cytoskeleton (LINC) complex protein SUN1 regulates vascular sprouting and endothelial cell-cell junction morphology and function. Loss of murine endothelial Sun1 impaired blood vessel formation and destabilized junctions, angiogenic sprouts formed but retracted in SUN1-depleted sprouts, and zebrafish vessels lacking Sun1b had aberrant junctions and defective cell-cell connections. At the cellular level, SUN1 stabilized endothelial cell-cell junctions, promoted junction function, and regulated contractility. Mechanistically, SUN1 depletion altered cell behaviors via the cytoskeleton without changing transcriptional profiles. Reduced peripheral microtubule density, fewer junction contacts, and increased catastrophes accompanied SUN1 loss, and microtubule depolymerization phenocopied effects on junctions. Depletion of GEF-H1, a microtubule-regulated Rho activator, or the LINC complex protein nesprin-1 rescued defective junctions of SUN1-depleted endothelial cells. Thus, endothelial SUN1 regulates peripheral cell-cell junctions from the nucleus via LINC complex-based microtubule interactions that affect peripheral microtubule dynamics and Rho-regulated contractility, and this long-range regulation is important for proper blood vessel sprouting and junction integrity.

This paper proposes a new type of small-sized I-shaped engineered cementitious composite (ECC)/ ultra-high performance concrete (UHPC) composite beam which has the potential to be suitable for corrosive environments. The lower tensile part of the beam was made of ECC material (2/3 of the height), and the top compressive part was made of UHPC material (1/3 of the height). Inner embedded steel bars and surface-bonded basalt fiber reinforced polymer (BFRP) sheets were adopted as the reinforcing materials in combination. A total of nine I-shaped beams were designed and tested under four-point bending test. The influence of parameters such as the ratio of the embedded tensile steel bars, the top UHPC flange, and the surface bonded tensile BFRP sheet on the behavior of the beams was investigated. The results showed that the I-shaped ECC/UHPC composite beams have excellent comprehensive performance, and thanks to the ultra-high durability of the component materials, they have ultra-high durability that ordinary I-steel beams do not have and thus have broad application prospects in corrosive environments. The shear resistance capacity of the thin-walled ECC web needs to be further improved, and UHPC is recommended for the web in the follow-up study.

Background. The aging population is increasingly susceptible to cardiovascular disease (CVD). Visit-to-visit variability in glucose and lipid levels both contributed to CVD risk independent of their mean values. However, whether variability in the triglyceride-glucose (TyG) index is a risk factor for CVD remains unknown. Research Design and Methods. In this retrospective study of electronic health records, 27,520 participants aged over 60 years were enrolled. The visit-to-visit variability of TyG index was calculated from annual health examination data and defined as average real variability (ARV), standard deviation (SD), or the coefficient of variability (CV). CVD events were identified from the chronic disease registry or follow-up database and included myocardial infarction, angina, coronary, and stroke. Multivariate Cox regression was used to examine the correlation between TyG variability and incident CVD. Results. Over a median follow-up of 6.2 years, there were 2,178 CVD events. When participants were divided into four quartiles according to their TyG variability, after adjusting for established CVD risk factors, subjects in the top quartile had (HR = 1.18, 95% CI 1.05–1.34, P=0.005) significantly higher CVD risk than those in the bottom quartile. The association remained significant in overweight individuals or those without diabetes (P

This paper presents mechanical properties of fast-growing poplar specimens reinforced with carbon fibers. A total of 90 specimens including 10 contrast specimens were tested to investigate the influence from the following parameters: (a) different carbon fiber ratios (0.167%, 0.251%, 0.334%, 0.401%, and 0.501%) and (b) different fiber locations. The failure mode, compressive strength, elastic modulus, and axial deformation of specimens were analyzed. The test results indicate the following: (1) The compressive strength, elastic modulus, and axial deformation of specimens reinforced with carbon fiber were significantly improved compared with that of fast-growing poplar specimens. The compressive strength, elastic modulus, and axial deformation increased by 54.1–76.03%, 11.58–22.89%, and 24.86–60.06%, respectively. (2) There was little effect on the compressive strength of the specimen with the increase of carbon fiber ratio. With the increase of carbon fiber ratio, the elastic modulus of specimens slightly decreased and the axial deformation increased. The elastic modulus decreased by 1.39–18.69%, and the axial deformation increased by 10%–48%. (3) The different locations of the carbon fiber distribution resulted in a large difference in the compressive strength of the specimens, while the effects on the modulus of elasticity and axial deformation were not significant. Finally, the compressive strength calculation formula was proposed.

Background: Little is known about how biomechanics govern the five fixtures such as DHS, MLS, DHS + LS, LP, and HA are accepted as common therapeutic techniques. Aims and objectives: A series of numerical models for a femoral neck fracture of Pauwels-I will be constructed by innovative approach of finite element in order to determine the most optimized option in comparison with biomechanical performance. Method: Twenty sets of computer tomography scanned femora were imported onto Mimics to extract 3 D models; these specimens were transferred to Geomagic-Studio for a simulative osteotomy and kyrtograph; then, they underwent UG to fit simulative solid models; 5 sorts of fixture were then expressed by Pro-Engineer virtually. After processing with HyperMesh, all compartments (fracture model + internal implant) were assembled onto 5 systems: “Dynamic Hip Screw (DHS), Multiple Lag screw (MLS), DHS + LS, femoral Locking Plate (LP) and HemiArthroplasty (HA).” Eventually, numerical models of the finite-elemental analysis were exported to AnSys to determine the solution. Result: Four models of fixation and a simulation of HA for Pauwels-I were established, validated, and analyzed with the following findings: In term of displacement, these 5 fixtures ranged between 0.3801 and 0.7536 mm have no significant difference; in term of stress, the averages of peaks for integral assemblage are b(MLS) = 43.5766 ≈< d(LP) = 43.6657 ≈< e(Ha) = 43.6657

Abstract Background The application of artificial intelligence techniques for processing electronic health records data plays increasingly significant role in advancing clinical decision support. This study conducts a quantitative comparison on the research of utilizing artificial intelligence on electronic health records between the USA and China to discovery their research similarities and differences. Methods Publications from both Web of Science and PubMed are retrieved to explore the research status and academic performances of the two countries quantitatively. Bibliometrics, geographic visualization, collaboration degree calculation, social network analysis, latent dirichlet allocation, and affinity propagation clustering are applied to analyze research quantity, collaboration relations, and hot research topics. Results There are 1031 publications from the USA and 173 publications from China during 2008–2017 period. The annual numbers of publications from the USA and China increase polynomially. JAMIA with 135 publications and JBI with 13 publications are the top prolific journals for the USA and China, respectively. Harvard University with 101 publications and Zhejiang University with 12 publications are the top prolific affiliations for the USA and China, respectively. Massachusetts is the most prolific region with 211 publications for the USA, while for China, Taiwan is the top 1 with 47 publications. China has relatively higher institutional and international collaborations. Nine main research areas for the USA are identified, differentiating 7 for China. Conclusions There is a steadily growing presence and increasing visibility of utilizing artificial intelligence on electronic health records for the USA and China over the years. The results of the study demonstrate the research similarities and differences, as well as strengths and weaknesses of the two countries.

Background. Triglyceride-glucose (TyG) index is a convenient indicator of insulin resistance. It has been shown to be associated with macrovascular and microvascular complications in nonhospitalized diabetic patients. However, whether TyG index is a risk factor of diabetes vascular complications in hospitalized type 2 diabetic patients is unclear. We sought to explore the association between TyG index and the risk of macrovascular and microvascular complications in a large Chinese cohort of hospitalized patients. Method. A total of 4,721 patients with type 2 diabetes (T2D) who were hospitalized in the Department of Endocrinology, Kunshan Hospital Affiliated to Jiangsu University were enrolled between January 2015 and November 2020. TyG index was calculated as lnfasting triglycerides mg/dL×fasting glucose mg/dL/2. Measures of macrovascular complications included brachial-ankle pulse wave velocity (ba-PWV) and ankle-brachial index (ABI), whilst urine microalbumin (MAU), chronic kidney disease (CKD), and diabetic retinopathy (DR) were evaluated for microvascular complications. Logistic regressions were used to examine the association between TyG index and diabetes complications. Results. In univariate logistic regressions, higher TyG index was significantly (p

Cryptococcal meningitis, mainly caused by Cryptococcus neoformans/gattii species complexes, is a lethal infection in both immunosuppressive and immunocompetent populations. We characterized 110 Cryptococcus strains collected from Xiangya Hospital of Central South University in China during the 6-year study period between 2013 and 2018, and performed their antifungal susceptibility testing. Furthermore, the clinical features, laboratory and imaging data, treatment strategies and outcomes of the subjects were retrospectively analyzed. Of 110 Cryptococcus strains, C. neoformans species complexes accounted for 96.4% (106/110), including C. neoformans sensu stricto (VNI molecular type, 95.5%, 105/110) and Cryptococcus deneoformans (VNIV molecular type, 0.9%, 1/110), and Cryptococcus deuterogattii (VGII molecular type) accounted for 3.6% (4/110). The strains were further classified into 17 individual sequence types (STs) by using multilocus sequence typing (MLST). 89.1% (98/110) were represented by ST5; seven C. deuterogattii strains and one Cryptococcus deneoformans strain were assigned as ST7 and ST260, respectively. Antifungal minimal inhibitory concentrations above the epidemiological cutoff values (ECVs) were found mainly in C. neoformans species complexes strains (nine for amphotericin B, nine for fluconazole and seven for 5-fluorocytosine). Furthermore, 60.9% (67/110) of the subjects were male, and 40.0% (44/110) did not have underlying diseases. Hepatic diseases (hepatitis/HBV carrier status and cirrhosis) were the most common underlying health conditions (11.8%, 13/110), followed by autoimmune disorders (10.9%, 12/110) and chronic kidney disease (6.36%, 7/110). Only 4.5% (5/110) of the patients were HIV/AIDS positives. For clinical presentation, headache (77.3%, 85/110), fever (47.3%, 52/110), and stiff neck (40.9%, 45/110) were commonly observed. The mortality rate was 35.0% (36/103). In conclusion, our data were characterized by a high prevalence of the Cryptococcal meningitis patients without HIV/AIDS and other underlying health conditions, a relatively high non-wild-type rate of fluconazole and amphotericin B resistance, and low genetic diversity in Cryptococcus strains. The present study will provide evidence for further improvement of the diagnosis and treatment of cryptococcosis in China.

Abstract Background Natural language processing (NLP) has become an increasingly significant role in advancing medicine. Rich research achievements of NLP methods and applications for medical information processing are available. It is of great significance to conduct a deep analysis to understand the recent development of NLP-empowered medical research field. However, limited study examining the research status of this field could be found. Therefore, this study aims to quantitatively assess the academic output of NLP in medical research field. Methods We conducted a bibliometric analysis on NLP-empowered medical research publications retrieved from PubMed in the period 2007–2016. The analysis focused on three aspects. Firstly, the literature distribution characteristics were obtained with a statistics analysis method. Secondly, a network analysis method was used to reveal scientific collaboration relations. Finally, thematic discovery and evolution was reflected using an affinity propagation clustering method. Results There were 1405 NLP-empowered medical research publications published during the 10 years with an average annual growth rate of 18.39%. 10 most productive publication sources together contributed more than 50% of the total publications. The USA had the highest number of publications. A moderately significant correlation between country’s publications and GDP per capita was revealed. Denny, Joshua C was the most productive author. Mayo Clinic was the most productive affiliation. The annual co-affiliation and co-country rates reached 64.04% and 15.79% in 2016, respectively. 10 main great thematic areas were identified including Computational biology, Terminology mining, Information extraction, Text classification, Social medium as data source, Information retrieval, etc. Conclusions A bibliometric analysis of NLP-empowered medical research publications for uncovering the recent research status is presented. The results can assist relevant researchers, especially newcomers in understanding the research development systematically, seeking scientific cooperation partners, optimizing research topic choices and monitoring new scientific or technological activities.

The objective of this study is to examine and compare the impact of serious games and gamification on learning achievement and motivation. The results of the meta-analysis indicate that gamification has a more positive influence on learning achievement and motivation compared to serious games. The analysis reveals that gamification demonstrates a stronger impact on extrinsic motivation than on intrinsic motivation. Serious games have a more positive effect on intrinsic motivation in comparison to extrinsic motivation. The overall outcome suggests that gamification has relatively stronger effects than serious games. While the impact on extrinsic motivation is more significant with both approaches, serious games excel in fostering intrinsic motivation. However, further research is recommended to investigate the specific mechanisms that drive these effects and to identify optimal strategies for implementing serious games and gamification in diverse educational settings.

Cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) or directly reprogrammed from non-myocytes (induced cardiomyocytes [iCMs]) are promising sources for heart regeneration or disease modeling. However, the similarities and differences between iPSC-CMs and iCMs are still unknown. Here, we performed transcriptome analyses of beating iPSC-CMs and iCMs generated from cardiac fibroblasts (CFs) of the same origin. Although both iPSC-CMs and iCMs establish CM-like molecular features globally, iPSC-CMs exhibit a relatively hyperdynamic epigenetic status, whereas iCMs exhibit a maturation status that more closely resembles that of adult CMs. Based on gene expression of metabolic enzymes, iPSC-CMs primarily employ glycolysis, whereas iCMs utilize fatty acid oxidation as the main pathway. Importantly, iPSC-CMs and iCMs exhibit different cell-cycle status, alteration of which influenced their maturation. Therefore, our study provides a foundation for understanding the pros and cons of different reprogramming approaches.

Abstract Cloning of multiple genes in a single vector has greatly facilitated both basic and translational studies that require co-expression of multiple factors or multi-units of complex protein. Many strategies have been adopted, among which 2A “self-cleaving” peptides have garnered increased interest for their polycistronic nature, small size and high “cleavage” efficiency. However, broad application of 2 A peptides is limited by the lack of systematic comparison of different 2As alone or in combination. Here we characterized the effect of varying gene position and 2As on the expression of proteins encoded in bi-, tri-, or quad-cistronic constructs. Using direct cardiac reprogramming as an example, we further determined the effect of varied 2As on the efficiency of fluorescent cell labeling and cell fate conversion. We found that the expression of fluorophores decreased as it was moved towards the end of the construct while reprogramming was most efficient with the fluorophore at the second position. Moreover, quad-cistronic TPE2A constructs resulted in more efficient reprogramming than 3P2A or PTE2A constructs. We expect that the bi-, tri-, and quad-cistronic vectors constructed here and our results on protein expression ratios from different 2A constructs could serve to guide future utilization of 2A peptides in basic research and clinical applications.

Direct conversion of fibroblasts into induced cardiomyocytes (iCMs) offers an alternative strategy for cardiac disease modeling and regeneration. During iCM reprogramming, the starting fibroblasts must overcome existing epigenetic barriers to acquire the CM-like chromatin pattern. However, epigenetic dynamics along this reprogramming process have not been studied. Here, we took advantage of our recently generated polycistronic system and determined the dynamics of two critical histone marks, H3K27me3 and H3K4me3, in parallel with gene expression at a set of carefully selected cardiac and fibroblast loci during iCM reprogramming. We observed reduced H3K27me3 and increased H3K4me3 at cardiac promoters as early as day 3, paralleled by a rapid significant increase in their mRNA expression. In contrast, H3K27me3 at loci encoding fibroblast marker genes did not increase until day 10 and H3K4me3 progressively decreased along the reprogramming process; these changes were accompanied by a gradual decrease in the mRNA expression of fibroblast marker genes. Further analyses of fibroblast-enriched transcription factors revealed a similarly late deposition of H3K27me3 and decreased mRNA expression of Sox9, Twist1 and Twist2, three important players in epithelial−mesenchymal transition. Our data suggest early rapid activation of the cardiac program and later progressive suppression of fibroblast fate at both epigenetic and transcriptional levels. Additionally, we determined the DNA methylation states of representative cardiac promoters and found that not every single CpG was equally demethylated during early stages of iCM reprogramming. Rather, there are specific CpGs, whose demethylation states correlated tightly with transcription activation, that we propose are the major contributing CpGs. Our work thus reveals a differential re-patterning of H3K27me3, H3K4me3 at cardiac and fibroblast loci during iCM reprogramming and could provide future genome-wide epigenetic studies with important guidance such as the appropriate time window and loci to be utilized as positive and negative controls.

Direct reprogramming of cardiac fibroblasts (CFs) to induced cardiomyocytes (iCMs) is a newly emerged promising approach for cardiac regeneration, disease modeling, and drug discovery. However, its potential has been drastically limited due to the low reprogramming efficiency and largely unknown underlying molecular mechanisms. We have previously screened and identified epigenetic factors related to histone modification during iCM reprogramming. Here, we used shRNAs targeting an additional battery of epigenetic factors involved in chromatin remodeling and RNA splicing factors to further identify inhibitors and facilitators of direct cardiac reprogramming. Knockdown of RNA splicing factors Sf3a1 or Sf3b1 significantly reduced the percentage and total number of cardiac marker positive iCMs accompanied with generally repressed gene expression. Removal of another RNA splicing factor Zrsr2 promoted the acquisition of CM molecular features in CFs and mouse embryonic fibroblasts (MEFs) at both protein and mRNA levels. Moreover, a consistent increase of reprogramming efficiency was observed in CFs and MEFs treated with shRNAs targeting Bcor (component of BCOR complex superfamily) or Stag2 (component of cohesin complex). Our work thus reveals several additional epigenetic and splicing factors that are either inhibitory to or required for iCM reprogramming and highlights the importance of epigenetic regulation and RNA splicing process during cell fate conversion.

Hepatitis C virus (HCV) RNA replication involves complex interactions among the 3'x RNA element within the HCV 3' untranslated region, viral and host proteins. However, many of the host proteins remain unknown. In this study, we devised an RNA affinity chromatography /2D/MASS proteomics strategy and identified nine putative 3' X-associated host proteins; among them is oxysterol-binding protein-related protein 4 (ORP4), a cytoplasmic receptor for oxysterols. We determined the relationship between ORP4 expression and HCV replication. A very low level of constitutive ORP4 expression was detected in hepatocytes. Ectopically expressed ORP4 was detected in the endoplasmic reticulum and inhibited luciferase reporter gene expression in HCV subgenomic replicon cells and HCV core expression in JFH-1-infected cells. Expression of ORP4S, an ORP4 variant that lacked the N-terminal pleckstrin-homology domain but contained the C-terminal oxysterol-binding domain also inhibited HCV replication, pointing to an important role of the oxysterol-binding domain in ORP4-mediated inhibition of HCV replication. ORP4 was found to associate with HCV NS5B and its expression led to inhibition of the NS5B activity. ORP4 expression had little effect on intracellular lipid synthesis and secretion, but it induced lipid droplet formation in the context of HCV replication. Taken together, these results demonstrate that ORP4 is a negative regulator of HCV replication, likely via interaction with HCV NS5B in the replication complex and regulation of intracellular lipid homeostasis. This work supports the important role of lipids and their metabolism in HCV replication and pathogenesis.

One limit on developing complex synthetic gene circuits is the lack of basic components such as transcriptional logic gates that can process combinatorial inputs. Here, we propose a strategy to construct such components based on reusable designs and convergent reengineering of well‐studied natural systems. We demonstrated the strategy using variants of the transcription factor (TF) LacI and operator Olac that form specifically interacting pairs. Guided by a mathematical model derived from existing quantitative knowledge, rational designs of transcriptional NAND, NOR and NOT gates have been realized. The NAND gates have been designed based on direct protein–protein interactions in coupling with DNA looping. We demonstrated that the designs are reusable: a multiplex of logic devices can be readily created using the same designs but different combinations of sequence variants. The designed logic gates are combinable to form compound circuits: a demonstration logic circuit containing all three types of designed logic gates has been synthesized, and the circuit truthfully reproduces the pre‐designed input–output logic relations.

Voice portrait technology has explored and established the relationship between speakers' voices and their facial features, aiming to generate corresponding facial characteristics by providing the voice of an unknown speaker. Due to its powerful advantages in image generation, Generative Adversarial Networks (GANs) have now been widely applied across various fields. The existing Voice2Face methods for voice portraits are primarily based on GANs trained on voice-face paired datasets. However, voice portrait models solely constructed on GANs face limitations in image generation quality and struggle to maintain facial similarity. Additionally, the training process is relatively unstable, thereby affecting the overall generative performance of the model. To overcome the above challenges, we propose a novel deepGenerativeAdversarialNetworkmodel for audio-visual synthesis, namedAVPGAN (Attention-enhanced Voice Portrait Model using Generative Adversarial Network). This model is based on a convolutional attention mechanism and is capable of generating corresponding facial images from the voice of an unknown speaker. Firstly, to address the issue of training instability, we integrate convolutional neural networks with deep GANs. In the network architecture, we apply spectral normalization to constrain the variation of the discriminator, preventing issues such as mode collapse. Secondly, to enhance the model's ability to extract relevant features between the two modalities, we propose a voice portrait model based on convolutional attention. This model learns the mapping relationship between voice and facial features in a common space from both channel and spatial dimensions independently. Thirdly, to enhance the quality of generated faces, we have incorporated a degradation removal module and utilized pretrained facial GANs as facial priors to repair and enhance the clarity of the generated facial images. Experimental results demonstrate that our AVP-GAN achieved a cosine similarity of 0.511, outperforming the performance of our comparison model, and effectively achieved the generation of highquality facial images corresponding to a speaker's voice. [ABSTRACT FROM AUTHOR]