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Gardens not only provide people with a place for leisure and relaxation, they also contribute to improving urban ecological environments and promoting social interactions and cohesion. Additionally, from a psychological perspective, gardens play a role in alleviating stress, enhancing happiness, and improving the quality of life. Current research on gardens has primarily employed methods such as questionnaire surveys, environmental psychology analyses, and eye-tracking analyses; however, comprehensive studies on the relationships between multiple factors and levels in garden designs are lacking. Here, we propose a response surface analysis approach based on eye-tracking technology for the design and optimization of gardens. Firstly, the impacts of different garden elements on visitors’ psychology and fixation counts were analyzed using environmental psychology and eye-tracking analyses. Subsequently, the optimal range of each garden feature was determined through single-factor experiments, followed by response surface analysis to obtain the optimal value for each element. The results revealed that changes in garden elements such as the greenery ratio, number of buildings, and water saturation significantly affected visitors’ psychology. The greenery ratio had a greater impact than the number of buildings, which in turn had a greater impact than water saturation. This study is the first to analyze the relationships between multiple garden elements. A strong relationship was found between the greenery ratio and the number of buildings, as well as between the number of buildings and water saturation, while the relationship between the greenery ratio and water saturation was weaker. This approach can not only optimize garden designs but can also be widely applied in fields such as urban planning and public space transformation to enhance visitors’ comfort and satisfaction with the environment and promote sustainable urban development.

Purpose: The molecular etiology of atrial fibrillation (AF) and its treatment are poorly understood. AF involves both electrical and structural features. Vericiguat can ameliorate cardiac remodeling in heart failure. The effects of vericiguat on AF, however, are unclear. Here, the actions of vericiguat on atrial structural and electrical remodeling in AF and its possible mechanisms were investigated. Methods and Results: Thirty-six rabbits were randomly allocated to four groups, namely, sham, RAP (pacing with 600 beats/min over three weeks), vericiguat-treated (three weeks’ pacing plus daily oral dose of 1.5 mg/kg of vericiguat), and vericiguat-treated only. HL-1 cells received rapid pacing with or without vericiguat. Parameters including electrophysiology, echocardiography, histology, Ca 2+ levels, and I CaL density, as well as levels of TRPC6, CaN, NFAT4, p-NFAT4, Cav1.2, collagen I, collagen III, and ST2 were measured. Significant changes of above proteins expression level, circulating biochemical indices, Ca 2+ concentrations, and I CaL density in both animals and cell models, these effects were significantly restored by vericiguat. Vericiguat also reversed the enlarged atrium and significantly reduced myocardial fibrosis, together with preventing reduced atrial effective refractory periods (AERPs) and AF induction rate. Conclusion: Vericiguat thus ameliorated AF-associated structural and electrical remodeling. These findings suggest the potential of vericiguat for treating AF.

Abstract Increasingly intricate in their multilevel multiscale microarchitecture, metamaterials with unique physical properties are challenging the inherent constraints of natural materials. Their applicability in the nanomedicine field still suffers because nanomedicine requires a maximum size of tens to hundreds of nanometers; however, this size scale has not been achieved in metamaterials. Therefore, “nano‐metamaterials,” a novel class of metamaterials, are introduced, which are rationally designed materials with multilevel microarchitectures and both characteristic sizes and whole sizes at the nanoscale, investing in themselves remarkably unique and significantly enhanced material properties as compared with conventional nanomaterials. Microarchitectural regulation through conventional thermodynamic strategy is limited since the thermodynamic process relies on the frequency‐dependent effective temperature, Teff(ω), which limits the architectural regulation freedom degree. Here, a novel dual‐kinetic control strategy is designed to fabricate nano‐metamaterials by freezing a high‐free energy state in a Teff(ω)‐constant system, where two independent dynamic processes, non‐solvent induced block copolymer (BCP) self‐assembly and osmotically driven self‐emulsification, are regulated simultaneously. Fe3+‐“onion‐like core@porous corona” (Fe3+‐OCPCs) nanoparticles (the products) have not only architectural complexity, porous corona and an onion‐like core but also compositional complexity, Fe3+ chelating BCP assemblies. Furthermore, by using Fe3+‐OCPCs as a model material, a microstructure‐biological performance relationship is manifested in nano‐metamaterials.

The outbreak of nuclear power cooling water system (NPCS) disaster-causing organisms has become more frequent, causing huge economic losses. Therefore, it is necessary to understand the aggregation mechanism of disaster-causing organisms for the risk prevention and control of NPCS. Hence, this study applied the Lagrangian flow network (LFN) to analyze the aggregation mechanism of Acetes near NPCS, as such a complex network can describe the interconnections between massive nodes and has already been used for modeling complex nonlinear systems, revealing how the mechanisms of such novel processes emerge. In this study, the degree and probability paths in the network were used to reveal the transport pathway and aggregation area of Acetes. The experimental results highlighted that the sea area of the nuclear power plant is the key node with a large in-degree of the LFN, where the material easily accumulated. The Acetes near the NPCS mainly originated from the east along two critical paths. Overall, this study demonstrates that the LFN is a feasible approach to predicting the transport and the accumulation of the NPCS disaster-causing plankton.

BackgroundPulmonary arterial end-diastolic forward flow (EDFF) following repaired tetralogy of Fallot (rTOF) is recognized as right ventricular (RV) restrictive physiology, which is closely related to poor prognosis. This study sought to review mid-term experience and investigate the risk factors of EDFF in the rTOF patients.MethodsFrom September 2016 to January 2019, 100 patients (age < 18 years old) who underwent complete tetralogy of Fallot (TOF) repair were enrolled and were divided into EDFF group (n = 52) and non-EDFF group (n = 48) based on the presence of postoperative EDFF. Elastic net analysis was performed for variable selection. Univariate and multivariate logistic analyses were used to analyze the correlation between risk factors and EDFF.ResultsEnd-diastolic forward flow group had lower systolic blood pressure (P = 0.037), diastolic blood pressure (P = 0.027), and higher vasoactive-inotrope score within 24 h after surgery (P = 0.022) than non-EDFF group. Transannular patch (TAP) was an independent predictor of postoperative EDFF [P = 0.029, OR: 2.585 (1.102∼6.061)]. Patients were followed up for a median of 2.6 years [interquartile range (IQR) 1.6] after the first TOF repair. During follow-up, the prevalence of the EDFF was lower in those with pulmonary valve (PV) reconstructions than that in those undergoing patch enlargement without PV reconstructions in the primary TOF repair (P < 0.001).ConclusionEnd-diastolic forward flow was associated with TAP. Patients with EDFF might have a transient hemodynamic instability in the early postoperative period. PV reconstructions in the TOF repair might reduce the incidence of EDFF in the mid-term follow-up.

Material transport around the headland has received more attention. To reveal the material transport pattern and its response to the topography in the Yellow River Estuary (YRE), in this paper, three Lagrangian analysis methods, including Lagrangian residual current, particle tracking model, and Lagrangian coherent structures (LCSs), are used to analyze the material horizontal transport near the headland in the YRE. The results of the study show that the headland plays an important role in the hydrodynamic processes and material transport in the YRE. Due to the current shear induced by the topography, materials easily diffuse, forming a front around the headland. Due to the blocking and shading effects of the headland, the materials tend to accumulate on the right side of the headland (facing the sea). The above three Lagrangian methods can describe the characteristics of the material distribution, but the LCS method is superior in comparison. Due to their more stable spatial structure, LCSs can be used to analyze the transport of pollutants, larvae, microplastics, etc. in the YRE.

Marine fishes are sensitive to the environment during their early life stages. This study adopts a habitat suitability index (HSI) model to evaluate the environmental suitability for early stages of anchovy (Engraulis japonicus) in Laizhou Bay. Instead of calculating the suitability of spawning grounds and nursery grounds independently or the simple average of the two, an individual-based model is used to simulate the drifting trajectories of anchovy eggs to establish the link between a spawning ground and its corresponding nursery ground. The HSI of early life habitat is determined by averaging the HSI value of the paired two grounds. The model results suggest that a small patch at eastern Laizhou Bay (near 120.1 E°, 37.6 N°) is the most critical and suitable area for anchovy in early life stages. It can provide an appropriate habitat for anchovy eggs and allow the eggs to migrate to the inside of the bay with plenty of plankton, which would benefit the newly hatching larvae. The results indicate the significant impact of hydrodynamic transport on fishery recruitment process, which should not be neglected in habitat quality evaluation. The model adopted in this study is applied to anchovy as a case study, but it is also exportable to other species of commercial interest.

At present, guideline-directed medical therapy of heart failure (HF) has achieved certain results, but the evidence mostly focuses on HF with reduced ejection fraction, and there are some problems in the research on HF with preserved ejection fraction (HFpEF), such as inconsistent inclusion criteria and unconvincing results. Therefore, it may be more individualized and targeted to perform classification, typing, and treatment of HF from aspects such as pathogenesis, etiology, or pathophysiology, but not ejection fraction, especially HFpEF with strong heterogeneity. Ge's phenotyping of HFpEF is based on etiology and pathology, aiming at improving the outcome of HFpEF and exploring new approaches for the prognosis of HF.

Background and Purpose: Atrial metabolic remodeling plays a critical role in the pathogenesis of atrial fibrillation (AF). Sirtuin3 (Sirt3) plays an important role in energy homeostasis. However, the effect of Sirt3 agonist Honokiol (HL) on AF is unclear. Therefore, the aim of this study is to determine the effect of HL on atrial metabolic remodeling in AF and to explore possible mechanisms.Experimental Approach: irt3 and glycogen deposition in left atria of AF patients were examined. Twenty-one rabbits were divided into sham, P (pacing for 3 weeks), P + H treatment (honokiol injected with pacing for 3 weeks). The HL-1 cells were subjected to rapid pacing at 5 Hz for 24 h, in the presence or absence of HL and overexpression or siRNA of Sirt3 by transfection. Metabolic factors, circulating metabolites, atrial electrophysiology, ATP level, and glycogens deposition were detected. Acetylated protein and activity of its enzymes were detected.Key Results: Sirt3 was significantly down-regulated in AF patients and rabbit/HL-1cell model, resulting in the abnormal expression of its downstream metabolic key factors, which were significantly restored by HL. Meanwhile, AF induced an increase of the acetylation level in long-chain acyl-CoA dehydrogenase (LCAD), AceCS2 and GDH, following decreasing of activity of it enzymes, resulting in abnormal alterations of metabolites and reducing of ATP, which was inhibited by HL. The Sirt3 could regulate acetylated modification of key metabolic enzymes, and the increase of Sirt3 rescued AF induced atrial metabolic remodeling.Conclusion and Implications: HL inhibited atrial metabolic remodeling in AF via the Sirt3 pathway. The present study may provide a novel therapeutical strategy for AF.

BackgroundPostoperative recurrence is a significant obstacle in hepatocellular carcinoma (HCC) treatment. This study aimed to construct a blood index-based model to predict hepatitis B virus-associated HCC (HBV-HCC) recurrence after curative hepatectomy.MethodsA total of 370 patients who received initially curative hepatectomy for HBV-HCC were included in this study. A novel blood index signature (BIS) was identified and systematically analyzed for its recurrence predictive value. Following this, multivariate Cox regression analysis was performed to build a blood index-based nomogram.ResultsA BIS based on the aminotransferase-to-platelet ratio index and a systemic inflammatory response index was used to construct a nomogram. The model showed good clinical applicability and reliability. Notably, the patients in the high recurrence risk group tended to benefit from adjuvant transcatheter arterial chemoembolization (TACE).ConclusionA reliable model was constructed to predict the HBV-HCC recurrence after curative hepatectomy. This model can guide the surgeons in selecting patients with high recurrence risk patients who may benefit from adjuvant TACE.

Objective: The aim of this study was to compare the early outcomes of the cone and Hetzer procedures for Ebstein's malformation.Methods: This retrospective study included patients who underwent either cone (n = 83) or Hetzer repair (n = 45) with Ebstein's malformation from January 2011 to December 2020.Results: One early death occurred in the cone group due to low cardiac output syndrome. Five cone and three Hetzer repair patients required reoperation before discharge. At discharge, the cone group had a better reduction in tricuspid valve regurgitation (TR) than the Hetzer group (74.7 vs. 51.1%, p = 0.009). Two patients in the cone group and seven patients in the Hetzer group required reoperation >30 days after their initial surgery. The cone group with no/mild TR was 75.6%, and the Hetzer group was 48.9% at the time of last follow-up (p = 0.010).Conclusion: Short-term outcomes of the cone repair are better than the Hetzer procedure. The cone repair should be the better option among patients with Ebstein's malformation who need surgical intervention.

Seru production can be used to enhance productivity, such as makespan reduction and manpower saving. Seru system operation includes two NP-hard problems, i.e., seru formation and seru scheduling. The exact solution cannot be obtained by solving only one of seru formation and seru scheduling. We develop a cooperative coevolution algorithm for the Seru production with minimizing makespan by solving the seru formation and seru scheduling simultaneously. The cooperative coevolution algorithm includes two evolution algorithms, i.e., the algorithm combining generic algorithm and local search, and the ant colony optimization algorithm. The former algorithm is used to deal with the evolution of seru formation. The latter is used to find a better seru scheduling. In the cooperative mechanism, the two algorithms cooperate to seek a better solution of seru system operation. Finally, extensive-tested experiments show that the proposed cooperative coevolution algorithm can obtain a better solution than all the existing algorithms and, even, can obtain the exact solution for some medium-and-small instances.

Bone marrow mesenchymal stem/stromal cells (BMSCs) can be transformed into tumor-associated MSCs (TA-MSCs) within the tumor microenvironment to facilitate tumor progression. However, the underline mechanism and potential therapeutic strategy remain unclear. Here, we explored that interleukin 17 (IL-17) cooperating with IFNγ transforms BMSCs into TA-MSCs, which promotes tumor progression by recruiting macrophages/monocytes and myeloid-derived suppressor cells (MDSCs) in murine melanoma. IL-17 and IFNγ transformed TA-MSCs have high expression levels of myelocyte-recruiting chemokines (CCL2, CCL5, CCL7, and CCL20) mediated by activated NF-κB signaling pathway. Furthermore, retinoic acid inhibits NF-κB signaling, decreases chemokine expression, and suppresses the tumor-promoting function of transformed TA-MSCs by prohibiting the recruitment of macrophages/monocytes and MDSCs in the tumor microenvironment. Overall, our findings demonstrate that IL-17 collaborating with IFNγ to induce TA-MSC transformation, which can be targeted by RA for melanoma treatment.

Bone marrow mesenchymal stem cells (MSCs) are widely used clinically due to their versatile roles in multipotency, immunomodulation, and hematopoietic stem cell (HSC) niche function. However, cellular heterogeneity limits MSCs in the consistency and efficacy of their clinical applications. Metabolism regulates stem cell function and fate decision; however, how metabolites regulate the functional heterogeneity of MSCs remains elusive. Here, using single-cell RNA sequencing, we discovered that fatty acid pathways are involved in the regulation of lineage commitment and functional heterogeneity of MSCs. Functional assays showed that a fatty acid metabolite, butyrate, suppressed the self-renewal, adipogenesis, and osteogenesis differentiation potential of MSCs with increased apoptosis. Conversely, butyrate supplement significantly promoted HSC niche factor expression in MSCs, which suggests that butyrate supplement may provide a therapeutic approach to enhance their HSC niche function. Overall, our work demonstrates that metabolites are essential to regulate the functional heterogeneity of MSCs.

Background: Hepatocellular carcinoma (HCC) is the most common histological type of liver cancer, with an unsatisfactory long-term survival rate. Despite immune checkpoint inhibitors for HCC have got glories in recent clinical trials, the relatively low response rate is still a thorny problem. Therefore, there is an urgent need to screen biomarkers of HCC to predict the prognosis and efficacy of immunotherapy.Methods: Gene expression profiles of HCC were retrieved from TCGA, GEO, and ICGC databases while the immune-related genes (IRGs) were retrieved from the ImmPort database. CIBERSORT and WGCNA algorithms were combined to identify the gene module most related to CD8+ T cells in the GEO cohort. Subsequently, the genes in hub modules were subjected to univariate, LASSO, and multivariate Cox regression analyses in the TCGA cohort to develop a risk signature. Afterward, the accuracy of the risk signature was validated by the ICGC cohort, and its relationships with CD8+ T cell infiltration and PDL1 expression were explored.Results: Nine IRGs were finally incorporated into a risk signature. Patients in the high-risk group had a poorer prognosis than those in the low-risk group. Confirmed by TCGA and ICGC cohorts, the risk signature possessed a relatively high accuracy. Additionally, the risk signature was demonstrated as an independent prognostic factor and closely related to the CD8+ T cell infiltration and PDL1 expression.Conclusion: A risk signature was constructed to predict the prognosis of HCC patients and detect patients who may have a higher positive response rate to immune checkpoint inhibitors.

Judicious use of lamps is of profound significance to improve the internal traffic safety of tunnels. This study evaluated the biological effects of spectrum on human visual and nonvisual under mesopic vision category. According to the difference of human eyes’ response to the visual and nonvisual biological effects of different wavelengths of light radiation, a method of applying the mesopic visual spectral luminous efficiency curve to the assessment of nonvisual biological effects and blue light hazards is proposed. The results show that, in theory, under mesopic vision category, the spectrum with high correlation color temperature (CCT) and high color rendering index (CRI) has higher blue light content Z-value and has greater impact on human nonvisual effects and blue light radiation damage, but it can also provide higher human perception luminance. The visual effect detection experiment of driving in the interior zones of the tunnel is simulated in the laboratory, and the critical flicker frequency and reaction time are taken as physiological indexes. The results show that the spectrum with high CCT and high CRI corresponds to lower critical flicker frequency drop value and faster reaction time, which has a positive effect on improving driving safety. Therefore, this paper suggests that the LED with high CCT and high CRI (CCT = 6500 K, CRI2012 = 95) should be used in the interior zones of the tunnel with relatively short lighting section, and the CCT and CRI should be appropriately reduced in other road environments with long lighting section to reduce the impact of spectrum on nonvisual photobiology, so as to improve road traffic safety.

The long reaction time of human eyes will increase the probability of traffic accidents in tunnels which can be reduced by improving lighting conditions. In recent years, light-emitting diodes (LEDs) have replaced the traditional lighting source in a tunnel. Colour rendering index 2012 (CRI2012, a colour rendering evaluation index) is the most suitable evaluation method for colour rendering of LEDs. In order to study the impact of colour rendering of LEDs on the reaction time of human eyes, a driving simulation environment was designed. First, three CCTs (correlated colour temperatures), four CRI2012s, and eight colours of targets were assessed using mesopic photometry model MES-2. The calculation results indicated that the contrast of targets had a positive correlation with CRI2012 and had a negative correlation with CCT. Then, reaction time experiment was conducted in simulated tunnel environments. There are 30 observers who participated. The results show that the LEDs with higher CRI2012 and lower CCT in tunnel is conducive to reducing the reaction time of human eyes. High CRI2012 enables drivers to accurately and quickly identify colours. This paper provides a reference for the design of light source parameters, roads, walls, and warning signs in the tunnel.

Background & Aims Aging is one of the risk factors of non-alcoholic fatty liver disease (NAFLD). Yet, the mechanism underlying the aging-associated NAFLD-like syndrome is not fully understood. Nicotinamide adenine dinucleotide (NAD), a ubiquitous coenzyme, has protective effects against aging. Here, we investigated the actions of NAD precursors nicotinamide riboside (NR) on the development of aging-induced NAFLD. Methods NR supplemented food (2.5 g/kg food) was applied to aged mice for three months while normal chow to the other groups. Body weight, food intake, liver weight and fat pat mass were measured. The serum concentrations of lipid content, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and NAD were determined by biochemical assays. Pathological assessment and immunohistochemistry analysis of hepatic tissues were used to evaluate the effect of NR on NAFLD development and inflammatory infiltration. Results NR repletion significantly reduced fat pat mass in aged mice, while not altered the body weight, food intake, and liver weight. NR repletion significantly rescued the NAD reduction in aged mice. The total cholesterol and triglyceride levels could be lowered by NR repletion in aged mice. The AST level was also significantly reduced by NR repletion in aged group, while the ALT level lowered but without significance. Notably, moderate NAFLD phenotypes, including steatosis and hepatic fibrosis could be markedly corrected by NR repletion. In addition, Kupffer cells accumulated and inflammatory infiltration could also be remarkably reversed by NR repletion in aged mice. Conclusion Aging was associated with NAFLD-like phenotypes in mice, which could be reversed by oral NR repletion. Therefore, oral NR uptake might be a promising strategy to halt the progression of NAFLD.

The human induced pluripotent stem cell (iPSC) line ZJUCHi002-A was established from renal epithelial cells present in urine (urinary cells) collected from an 8-year-old Charcot-Marie-Tooth disease type 2A (CMT2A) patient carrying point mutation in MFN2 (c.752C > T). Urinary cells were reprogrammed by retrovirus vectors containing reprogramming factors: OCT4, SOX2, KLF4 and c-MYC. The pluripotency, capacity of differentiation into 3 germ layers, silence of reprogramming factors and normal karyotype were all confirmed in this study.

The human iPSC cell line ZJUCHi001-A was established from renal epithelial cells present in urine (urinary cells) harvested from a 2-year-old Charcot-Marie-Tooth disease type 1B (CMT1B) patient carrying point mutation in MPZ (c.292C>T). Urinary cells were reprogrammed by retrovirus vectors containing reprogramming factors: OCT4, SOX2, KLF4 and c-MYC. The pluripotency, capacity of differentiation into 3 germ layers, silence of reprogramming factors and normal karyotype for this cell line were all confirmed in this study.

Microwave-assisted and ultrasound-assisted extraction assays were used to isolate total flavonoids (TF) from Osmanthus fragrans flowers. The effects of the solid-liquid ratio, ethanol concentration, microwave power, microwave extraction time, ultrasonic power and ultrasonic extraction time on the yield of TF were studied. A sequential combination of microwave- and ultrasound-assisted extraction (SC-MUAE) methods was developed, which was subsequently optimized by Box-Behnken design-response surface methodology (BBD-RSM). The interaction effects of the ethanol concentration (40–60%), microwave extraction time (5–7 min), ultrasonic extraction time (8–12 min) and ultrasonic power (210–430 W) on the yield of TF were investigated. The optimum operating parameters for the extraction of TF were determined to be as follows: ethanol concentration (48.15%), microwave extraction time (6.43 min), ultrasonic extraction time (10.09 min) and ultrasonic power (370.9 W). Under these conditions, the extraction yield of TF was 7.86 mg/g.

A fundamental challenge for developing an effective and safe HIV-1 vaccine is to identify vaccine immunogens that can initiate and maintain immune responses leading to elicitation of broadly neutralizing HIV-1 antibodies (bnAbs) through complex maturation pathways. We have previously found that HIV-1 envelope glycoproteins (Env) lack measurable binding to putative germline predecessors of known bnAbs and proposed to search for non-HIV immunogens that could initiate their somatic maturation. Using bnAb b12 as a model bnAb and yeast display technology, we isolated five (poly)peptides from plant leaves, insects, E. coli strains, and sea water microbes that bind to b12 putative germline and intermediate antibodies. Rabbit immunization with the (poly)peptides alone induced high titers of cross-reactive antibodies that neutralized HIV-1 isolates SF162 and JRFL. Priming rabbits with the (poly)peptides followed by boosts with trimeric gp140SF162 and then resurfaced Env (RSC3) induced antibodies that competed with mature b12 and neutralized tier 1 and 2 viruses from clade B, C and E, while control rabbits without (poly)peptide priming induced antibodies that did not compete with mature b12 and neutralized fewer isolates. The degree of competition with mature b12 for binding to gp140SF162 correlated with the neutralizing activity of the rabbit IgG. Reversing the order of the two boosting immunogens significantly affected the binding profile and neutralization potency of the rabbit IgG. Our study is the first to provide evidence that appears to support the concept that non-HIV immunogens may initiate immune responses leading to elicitation of cross-clade neutralizing antibodies.