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BackgroundThe current exploration of the tumor immune microenvironment is enthusiastic, but few studies explored the impact of angiogenesis on the immune microenvironment. Immunotherapy combined with anti-angiogenesis therapy has become one of the first-line treatment for lung adenocarcinoma. Our study aimed to explore the reasons for resistance of immunotherapy, and explore markers for immunotherapy combined with anti-angiogenesis therapy.MethodsFirst, by unsupervised clustering of 36 angiogenesis-related genes in lung adenocarcinoma patients from TCGA database, AGS1 and AGS2 groups were distinguished with significantly different clinical outcomes. Secondly, the immune microenvironment and metabolic characteristics were analyzed. Next, we used the GDSC and GEO database to analyze therapeutic responses. Then, through multivariate Cox regression, the hub gene: JAG1, significantly related to prognosis was selected, and further verified by multi-omics data. Finally, we validated that patient with high JAG1 expression had a low immune-infiltrating tumor microenvironment through single-cell transcriptomic data.ResultsCompared with the AGS1 group, AGS2 showed an immune “cold” phenotype with lower lymphocyte infiltration, and was associated with worse prognoses. At the same time, the immunosuppressive TGF-β response was significantly higher in AGS2. Furthermore, the glycolysis ability of the AGS2 was stronger than AGS1. The expression of JAG1 was significantly higher in the AGS2, and was significantly negatively correlated with the degree of immune infiltration, accompanying with higher glycolytic capacity. The above results indicate that patients with high expression of JAG1 may lead to immunosuppressive phenotype due to its strong glycolytic capacity, thus making immunotherapy resistance.ConclusionPatients with high expression of JAG1 enhanced glycolytic capacity was likely to cause suppressed immune microenvironment. JAG1 may be a marker for resistance of immunotherapy. Combining anti-angiogenesis therapy could be considered to improve the prognosis of those patients.

In this paper, a symmetric training sequence-based (STSB) carrier frequency offset estimation (FOE) scheme for coherent free-space optical (CFSO) communication is proposed. In the proposed technique, we exploit the training-sequence-based (TSB) carrier FOE algorithm to the CFSO communication system in the quadrature phase-shift keying (QPSK) modulation format. A symmetric training sequence, tailored to the carrier FOE algorithm for atmospheric turbulence channel, is formulated to accurately identify the correct temporal position of a data frame from received signals. Unlike the 4th power algorithm, the proposed algorithm requires only the identified training sequence and the symmetric sequence of the original training sequence in the FOE stage, performing a single multiplication to accurately remove the signal modulation phase. In this way, the proposed technique significantly improves the estimation accuracy. Furthermore, by avoiding the time-consuming 4th power operation, the proposed method reduces the computational complexity while expanding the FOE range. Therefore, when compared with existing algorithms, our proposed technique can achieve more accurate timing, a wider estimation range, and lower complexity. A 10-Gbps QPSK CFSO communication transmission experiment with different turbulence channels was carried out to validate the proposed technique and the improvement in receiver sensitivity.

When using distributed storage systems to store gridded remote sensing data in large, distributed clusters, most solutions utilize big table index storage strategies. However, in practice, the performance of big table index storage strategies degrades as scenarios become more complex, and the reasons for this phenomenon are analyzed in this paper. To improve the read and write performance of distributed gridded data storage, this paper proposes a storage strategy based on Ceph software. The strategy encapsulates remote sensing images in the form of objects through a metadata management strategy to achieve the spatiotemporal retrieval of gridded data, finding the cluster location of gridded data through hash-like calculations. The method can effectively achieve spatial operation support in the clustered database and at the same time enable fast random read and write of the gridded data. Random write and spatial query experiments proved the feasibility, effectiveness, and stability of this strategy. The experiments prove that the method has higher stability than, and that the average query time is 38% lower than that for, the large table index storage strategy, which greatly improves the storage and query efficiency of gridded images.

We previously introduced a three-stage design and associated end-of-stage analyses for allergen immunotherapy (AIT) trials. End-of-stage differences alone may not provide a fuller picture of Stages 2 and 3 effects because they may depend upon stage-specific durations. Therefore, we introduce an additional trend analysis to evaluate the difference in progression curves of two groups over the entire stage. Results from such analysis are used to inform persistence of end-of-stage benefit and thus provide evidence for stagewise effects beyond the study periods. We jointly apply end-of-stage and trend analyses to support the enhanced three-stage design to determine treatment response over time and sustained response to AIT. A simulation study was performed to illustrate the statistical properties (bias and power) of trend analyses under varying statistical missing mechanisms and effect sizes. The extent of bias depended on the missing mechanism and magnitude. Powers were largely driven by effect and sample sizes as well as pre-specified success margins, particularly of relative trend. As an illustration, assuming relative treatment differences of 25-30%, stagewise dropout rate of 15%, and parallel outcome progressions, a sample size of 200 per group may achieve 97% power to demonstrate a treatment effect and 53% power to demonstrate a sustained effect post-treatment. Trend analysis supplements the end-of-stage analysis to enhance the statistical claims of stagewise effects. Inferential statistics support our proposed trend analysis for evaluating benefits of AIT over time and inform clinical understanding and decisions.

Abstract High-density lipoprotein (HDL) particles have multiple beneficial and cardioprotective roles, yet our understanding of their full structural and functional repertoire is limited due to challenges in separating HDL particles from contaminating plasma proteins and other lipid-carrying particles that overlap HDL in size and/or density. Here we describe a method for isolating HDL particles using a combination of sequential flotation density ultracentrifugation and fast protein liquid chromatography with a size exclusion column. Purity was visualized by polyacrylamide gel electrophoresis and verified by proteomics, while size and structural integrity were confirmed by transmission electron microscopy. This HDL isolation method can be used to isolate a high yield of purified HDL from a low starting plasma volume for functional analyses. This method also enables investigators to select their specific HDL fraction of interest: from the least inclusive but highest purity HDL fraction eluting in the middle of the HDL peak, to pooling all of the fractions to capture the breadth of HDL particles in the original plasma sample. We show that certain proteins such as lecithin cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), and clusterin (CLUS) are enriched in large HDL particles whereas proteins such as alpha-2HS-glycoprotein (A2HSG), alpha-1 antitrypsin (A1AT), and vitamin D binding protein (VDBP) are enriched or found exclusively in small HDL particles.

BackgroundFor elderly patients with breast cancer, the treatment strategy is still controversial. In China, preoperative axillary lymph node needle biopsy is not widely used, resulting in many patients receiving axillary lymph node dissection (ALND) directly. Our study aims to determine whether local and systemic therapy can be safely de-escalated in elderly breast cancer.MethodsPatients aged ≥70 years were retrospectively enrolled from our institution’s medical records between May 2013 and July 2021. Groups were assigned according to local and systemic treatment regimens, and stratified analysis was performed by molecular subtypes. Univariate and multivariate survival analyses were used to compare the effects of different regimens on relapse-free survival (RFS).ResultsA total of 653 patients were enrolled for preliminary data analysis, and 563 patients were screened for survival analysis. The mean follow-up was 19 months (range, 1–82 months). Axillary lymph node metastases were pathologically confirmed in only 2.1% of cN0 cases and up to 97.1% of cN+ cases. In the aspect of breast surgery, RFS showed no significant difference between mastectomy and BCS group (p = 0.3078). As for axillary surgery, patients in the ALND group showed significantly better RFS than those in the sentinel lymph node biopsy (SLNB) group among pN0 patients (p = 0.0128). Among these cases, the proportion of cN+ in ALND was significantly higher than that in SLNB (6.4% vs. 0.4%, p = 0.002), which meant axillary lymph nodes (ALNs) of ALND patients were larger in imaging and more likely to be misdiagnosed as metastatic. With regard to adjuvant therapy, univariate and multivariate analyses showed that RFS in different comprehensive adjuvant regimens were similar especially among hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)− subgroup where patients who did not receive any adjuvant therapy accounted for 15.7% (p > 0.05).ConclusionsIt is feasible to reduce some unnecessary local or systemic treatments for elderly breast cancer patients, especially in HR+/HER2− subtype. Multiple patient-related factors should be considered when making treatment plans.

Dietary fiber, a nutrient derived mainly from whole grains, vegetables, fruits, and legumes, is known to confer a number of health benefits, yet most Americans consume less than half of the daily recommended amount. Convenience and affordability are key factors determining the ability of individuals to incorporate fiber-rich foods into their diet, and many Americans struggle to access, afford, and prepare foods rich in fiber. The objective of this clinical study was to test the changes in microbial community composition, human metabolomics, and general health markers of a convenient, easy to use prebiotic supplement in generally healthy young participants consuming a diet low in fiber. Twenty healthy adults participated in this randomized, placebo-controlled, double-blind, crossover study which was registered at clinicaltrials.gov as NCT03785860. During the study participants consumed 12 g of a prebiotic fiber supplement and 12 g of placebo daily as a powder mixed with water as part of their habitual diet in randomized order for 4 weeks, with a 4-week washout between treatment arms. Fecal microbial DNA was extracted and sequenced by shallow shotgun sequencing on an Illumina NovaSeq. Plasma metabolites were detected using liquid chromatography–mass spectrometry with untargeted analysis. The phylum Actinobacteria, genus Bifidobacterium, and several Bifidobacterium species (B. bifidum, B. adolescentis, B. breve, B. catenulatum, and B. longum) significantly increased after prebiotic supplementation when compared to the placebo. The abundance of genes associated with the utilization of the prebiotic fiber ingredients (sacA, xfp, xpk) and the production of acetate (poxB, ackA) significantly changed with prebiotic supplementation. Additionally, the abundance of genes associated with the prebiotic utilization (xfp, xpk), acetate production (ackA), and choline to betaine oxidation (gbsB) were significantly correlated with changes in the abundance of the genus Bifidobacterium in the prebiotic group. Plasma concentrations of the bacterially produced metabolite indolepropionate significantly increased. The results of this study demonstrate that an easy to consume, low dose (12 g) of a prebiotic powder taken daily increases the abundance of beneficial bifidobacteria and the production of health-promoting bacteria-derived metabolites in healthy individuals with a habitual low-fiber diet.Clinical Trial Registrationwww.clinicaltrials.gov/, identifier: NCT03785860

Abstract Minimally invasive thermal therapies have been attempted in the treatment of breast cancer, and the immune response induced by these therapies has not been fully reported. A clinical trial is performed to determine the effect of microwave ablation (MWA) in the treatment of early‐stage breast cancer. The authors perform single‐cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) from six patients before and after ablation. NK and CD8+T cells are activated by MWA of breast cancer, with the increased inhibitory signature of CD8+T cells but not dysfunctional. Enhanced co‐stimulatory signature of CD4+ T cells is observed and increased frequency of ICOS+CD4+ T cells after MWA is confirmed by flow cytometric analysis. After ablation, T‐cell clones expand with increased T‐cell receptor diversities. Activated antigen receptor‐mediated signaling pathways are found in B cells. Enhanced interactions between B cells and CD4+ T cells are found, indicating that B cells are important antigen‐presenting cells that initiate CD4+T cells in MWA‐induced immune response. Blockade of CTLA‐4 or PD‐1 of post‐MWA PBMCs show higher T‐cell activity than that of pre‐MWA PBMCs. This study provide global characteristics of MWA‐induced systemic immune response and pave a way for the identification of potential targets to improve the immune response.

The purpose of this study was to provide a new concept and technical method for the large-scale identification of industrial land and analyze the distribution characteristics of industrial land in China. The following research methods are employed using the point of interest data and random forest model based on data accessibility, this study selected 2015 data on Wuhan and Luoyang as training samples to identify the industrial land of China. Then, the proportion of industrial land in all 334 prefecture-level cities on the Chinese mainland was calculated, and the spatial pattern was analyzed. The results show that: 1) by comparing multiple experiments and robustness analysis, the optimal parameter setting of the random forest model is obtained. According to the test of actual industrial land distribution in Wuhan city and Luoyang city, the identification of industrial land in different scale cities by random forest model is accurate and effective. 2) From the perspective of spatial patterns, industrial land shows a “large aggregation and small scattering” distribution. 3) From the perspective of spatial distribution, the proportion of industrial land in these cities shows spatial aggregation. High–high aggregation areas were mainly distributed in North and Northeast China, and low–low aggregation areas were mainly located in West China. 4) From the perspective of related factors, industrial land was close to rivers, highways, and railway stations and had a relatively low correlation with the distribution of airports. Industrial land was located within approximately 10–60 km distance from the municipal government office. In terms of the proportion of industrial land, the proportion of industrial land is higher in the cities where the industrial land was closer to railway stations. However, when the industrial land in cities was closer to four other types of related factors (waters and lakes, major highways, airports, and municipal government stations), the share of industrial land is lower. In conclusion, the method based on the point of interest data and random forest model can accurately and effectively identify large-scale industrial land.

In recent decades, significant progress has been made in liver tissue engineering through the use of 3D bioprinting technology. This technology offers the ability to create personalized biological structures with precise geometric design capabilities. The complex and multifaceted nature of liver diseases underscores the need for advanced technologies to accurately mimic the physiological and mechanical characteristics, as well as organ-level functions, of liver tissue in vitro. Bioprinting stands out as a superior option over traditional two-dimensional cell culture models and animal models due to its stronger biomimetic advantages. Through the use of bioprinting, it is possible to create liver tissue with a level of structural and functional complexity that more closely resembles the real organ, allowing for more accurate disease modeling and drug testing. As a result, it is a promising tool for restoring and replacing damaged tissue and organs in the field of liver tissue engineering and drug research. This article aims to present a comprehensive overview of the progress made in liver tissue engineering using bioprinting technology to provide valuable insights for researchers. The paper provides a detailed account of the history of liver tissue engineering, highlights the current 3D bioprinting methods and bioinks that are widely used, and accentuates the importance of existing in vitro liver tissue models based on 3D bioprinting and their biomedical applications. Additionally, the article explores the challenges faced by 3D bioprinting and predicts future trends in the field. The progress of 3D bioprinting technology is poised to bring new approaches to printing liver tissue in vitro, while offering powerful tools for drug development, testing, liver disease modeling, transplantation, and regeneration, which hold great academic and practical significance.

In this paper, a low-complexity joint compensation scheme of carrier recovery (JCSCR) for coherent free-space optical (CFSO) communication is proposed. We applied the carrier recovery joint compensation approach to a CFSO communication system in the quadrature phase shift keying (QPSK) modulation format. A signal-preprocessing stage, which effectively avoided the repetitive operations found in traditional carrier recovery schemes, was proposed. Unlike in existing carrier recovery algorithms, the modulated phase of the received signal could be accurately removed using only the sum and subtraction of real absolute values in the signal-preprocessing stage, greatly reducing the complexity of the operation. Since this algorithm avoids the traditional fourth operation, the system’s complexity is reduced while additional noise generated by fourth cross-terms would be prevented and system noise immunity would be greatly enhanced. In addition, this algorithm uses joint compensation of phase errors in the final compensation stage, further reducing the complexity of the computation of the whole algorithmic scheme. A 10 Gbps QPSK CFSO communication transmission experiment was conducted in an atmospheric turbulence channel to verify the proposed technique and improvement in receiver sensitivity.

To solve the fault diagnosis difficulty of bearings with small data samples, a novel multi-information fusion vision transformer (ViT) model based on time–frequency representation (TFR) maps is proposed in this paper. The original vibration signal is decomposed into different scale sub-signals by the discrete wavelet transforms (DWTs), and the continuous wavelet transforms (CWTs) are used to transform these different scale sub-signals into time–frequency representation (TFR) maps, which are concatenated to input to the ViT model to diagnose the bearing fault. Through the multifaceted experiment analysis on the fault diagnosis of bearings with small data samples, the diagnosis results demonstrate that the proposed multi-information fusion ViT model can diagnose the fault of bearings with small data samples, with strong generalization and robustness; its average diagnosis accuracy achieved 99.85%, and it was superior to the other fault diagnosis methods, such as the multi-information fusion CNN, ViT model based on one-dimensional vibration signal, and ViT model based on the TFR of the original vibration signal.

Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways.

High-density lipoproteins (HDL) play a critical role in cholesterol homeostasis. Apolipoprotein E (APOE), particularly the E4 allele, is a significant risk factor for Alzheimer’s disease but is also a key HDL-associated protein involved in lipid transport in both the periphery and central nervous systems. The objective was to determine the influence of the APOE genotype on HDL function and size in the context of Alzheimer’s disease. HDL from 194 participants (non-demented controls, mild cognitive impairment, and Alzheimer’s disease dementia) were isolated from the plasma. The HDL cholesterol efflux capacity (CEC), lecithin-cholesterol acyltransferase (LCAT) activity, and particle diameter were measured. Neuropsychological test scores, clinical dementia rating, and magnetic resonance imaging scores were used to determine if cognition is associated with HDL function and size. HDL CEC and LCAT activity were reduced in APOE3E4 carriers compared to APOE3E3 carriers, regardless of diagnosis. In APOE3E3 carriers, CEC and LCAT activity were lower in patients. In APOE3E4 patients, the average particle size was lower. HDL LCAT activity and particle size were positively correlated with the neuropsychological scores and negatively correlated with the clinical dementia rating. We provide evidence for the first time of APOE genotype-specific alterations in HDL particles in Alzheimer’s disease and an association between HDL function, size, and cognitive function.

In order to improve the diagnosis accuracy and generalization of bearing faults, an integrated vision transformer (ViT) model based on wavelet transform and the soft voting method is proposed in this paper. Firstly, the discrete wavelet transform (DWT) was utilized to decompose the vibration signal into the subsignals in the different frequency bands, and then these different subsignals were transformed into a time–frequency representation (TFR) map by the continuous wavelet transform (CWT) method. Secondly, the TFR maps were input with respective to the multiple individual ViT models for preliminary diagnosis analysis. Finally, the final diagnosis decision was obtained by using the soft voting method to fuse all the preliminary diagnosis results. Through multifaceted diagnosis tests of rolling bearings on different datasets, the diagnosis results demonstrate that the proposed integrated ViT model based on the soft voting method can diagnose the different fault categories and fault severities of bearings accurately, and has a higher diagnostic accuracy and generalization ability by comparison analysis with integrated CNN and individual ViT.

The architecture model of the Internet of thing system is the primary foundation for the design and implementation of the Internet of thing system. This article discusses the method and practice of time automaton modeling and model checking for the architecture of the Internet of thing system from the state and time dimensions. This article introduces the theory and method of modeling using time automata. And then, combined with the actual need of the elderly health cabin Internet of thing system, a dynamic and fault-tolerant time automaton model is established through a relatively complete architecture modeling. The model checking method verifies that the designed Internet of thing system has no deadlock system activity, service correctness, and timeliness correctness. The results of modeling experiments and model validation show that the reference model of time automata Internet of thing architecture established in this article can better reflect the nature of interaction with the physical world, heterogeneity and large-scale, dynamic, and incompleteness of the Internet of thing system.