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Abstract Background Understanding the factors that contribute to variability in breast cancer-related lymphedema (BCRL) is an important first step in developing targeted interventions to improve quality of life in breast cancer patients. Although previous research studies have has identified many risk factors for BCRL, dietary habits and catheterization type have rarely been studied until the present. Aim This study aims to explore the effects of nursing factors such as dietary habits and catheterization type on breast cancer-related lymphedema (BCRL). Methods This retrospective cohort study included 1,476 breast cancer patients who underwent surgery between January 1, 2012, and September 1, 2020. Lymphedema was assessed with a validated self-report questionnaire. All research data were obtained from medical records and a follow-up database. Multivariate Cox regression was conducted to explore the effects of dietary habits and catheterization type on BCRL. Results The results showed an increased risk for BCRL among breast cancer patients who followed a high-fat diet prehospitalization (HR = 2.47; 95% CI = 1.55–3.94; P

Abstract To evaluate the genetic etiology of fetal dextrocardia, associated ultrasound anomalies, and perinatal outcomes, we investigated the utility of whole exome sequencing (WES) for prenatal diagnosis of dextrocardia. Fetuses with dextrocardia were prospectively collected between January 2016 and December 2022. Trio-WES was performed on fetuses with dextrocardia, following normal karyotyping and/or chromosomal microarray analysis (CMA) results. A total of 29 fetuses with dextrocardia were collected, including 27 (93.1%) diagnosed with situs inversus totalis and 2 (6.9%) with situs inversus partialis. Cardiac malformations were present in nine cases, extra-cardiac anomalies were found in seven cases, and both cardiac and extra-cardiac malformations were identified in one case. The fetal karyotypes and CMA results of 29 cases were normal. Of the 29 cases with dextrocardia, 15 underwent WES, and the other 14 cases refused. Of the 15 cases that underwent WES, clinically relevant variants were identified in 5/15 (33.3%) cases, including the diagnostic variants DNAH5, DNAH11, LRRC56, PEX10, and ZIC3, which were verified by Sanger sequencing. Of the 10 cases with non-diagnostic results via WES, eight (80%) chose to continue the pregnancies. Of the 29 fetuses with dextrocardia, 10 were terminated during pregnancy, and 19 were live born. Fetal dextrocardia is often accompanied by cardiac and extra-cardiac anomalies, and fetal dextrocardia accompanied by situs inversus is associated with a high risk of primary ciliary dyskinesia. Trio-WES is recommended following normal karyotyping and CMA results because it can improve the diagnostic utility of genetic variants of fetal dextrocardia, accurately predict fetal prognosis, and guide perinatal management and the reproductive decisions of affected families.

Objective: To evaluate the accuracy of expanded noninvasive prenatal testing (NIPT) for maternal copy number variations. Materials and methods: Expanded NIPT was used to detect CNVs ≥2 Mb at a whole-genome scale. The threshold of maternal deletion was copy numbers (CN) ≤ 1.6, and the threshold of maternal duplication was CN ≥ 2.4. Results: Of the 5440 pregnant women with successful expanded NIPT results, 28 maternal CNVs ≥2 Mb were detected in 27 pregnant women. Except for five cases reported as test failure, 23 CNVs ≥2 Mb were confirmed among the remaining 22 pregnant women by CNV-seq of maternal lymphocyte DNA. The genomic location, copy numbers and fragment size of maternal CNVs reported by expanded NIPT were consistent with the results of CNV-seq of maternal lymphocyte DNA. Conclusions: Maternal CNVs ≥2 Mb can be accurately evaluated according to the CN indicated by expanded NIPT results.

Objective: Intracerebral hemorrhage (ICH) is a severe stroke that can adversely affect patient outcomes due to the accompanying inflammatory response. As a result, there is a growing interest in studying inflammation in ICH. We systematically reviewed relevant articles using the Web of Science to understand the literature on this subject. This study aims to provide a comprehensive overview of the field through bibliometric analysis, highlight its current status, identify frontiers, and speculate on future directions. Methods: We conducted a bibliometric analysis of the global English literature on inflammation related to ICH research based on the Web of Science from 1993 to the present to address publication trends and research hotspots. Results: A total of 885 publications were included from 1993 to 2023. These articles were authored by 7375 researchers from 1639 organizations in 68 countries and published in 571 journals. Collectively, they cited 48,980 references from 5621 journals. The author who published the most articles was Dr. Zhang, John H. Interestingly, 6 of the top ten most published authors were from China. Regarding the countries that published the most articles, China was at the top of the list, followed by the United States. The most frequently used keywords were “Inflammation”, “Neuroinflammation”, and “Microglia”. Regarding journal publication and reference citations, Stroke was the most published and cited journal. Conclusions: Over the past 30 years, there has been considerable progress in scientific research concerning inflammation in the context of ICH. The pivotal themes of these studies have been immune cells and inflammatory mediators. It is worth noting, however, that most of the published literature on inflammation in ICH pertains to preclinical studies, with comparatively fewer clinical investigations. Several challenges must be addressed to translate these promising research achievements into clinical practice.

In recent years, micro-light-emitting diode (micro-LED) displays have attracted much attention due to their high brightness, low power consumption, long lifetime, and fast response. It is considered to have the potential to revolutionize the development direction of next-generation visual display technology. However, the development of micro-LED displays faces numerous issues, primarily due to etching processes for pixel array manufacturing, which cause sidewall damage and decreased photoelectric efficiency. Specifically, these issues are particularly serious when preparing small-sized high-resolution displays. In this work, we effectively overcame the above-mentioned problems by only etching the electron barrier during the preparation process of pixel arrays. The prepared micro-LED display exhibits excellent optoelectronic properties, with the highest brightness and current efficiency reaching 1.66 × 106 nits and 104 cd/A, respectively. The method provides a feasible idea for preparing high-performance micro-LED displays.

Pain sensitivity varies depending on both the state and age of an individual. For example, chronic pain is more common in older individuals, but the underlying mechanisms remain unknown. This study revealed that 18-month-old mice (aged) experienced more severe and long-lasting allodynia and hyperalgesia in the chronic constriction injury (CCI)-induced pain state compared to 2-month-old mice. Interestingly, the aged mice had a higher baseline mechanical pain threshold than the adult mice. The expression of spinal receptor-active modification protein 1 (RAMP1), as a key component and regulator of the calcitonin gene-related peptide (CGRP) receptor for nociceptive transmission from the periphery to the spinal cord, was reduced in the physiological state but significantly increased after CCI in the aged mice compared to the adult mice. Moreover, when RAMP1 was knocked down using shRNA, the pain sensitivity of adult mice decreased significantly, and CCI-induced allodynia in aged mice was reduced. These findings suggest that spinal RAMP1 is involved in regulating pain sensitivity in a state- and age-dependent manner. Additionally, interfering with RAMP1 could be a promising strategy for alleviating chronic pain in older individuals.

Abstract The occurrence of NAD+ as a non-canonical RNA cap has been demonstrated in diverse organisms. TIR domain-containing proteins present in all kingdoms of life act in defense responses and can have NADase activity that hydrolyzes NAD+. Here, we show that TIR domain-containing proteins from several bacterial and one archaeal species can remove the NAM moiety from NAD-capped RNAs (NAD-RNAs). We demonstrate that the deNAMing activity of AbTir (from Acinetobacter baumannii) on NAD-RNA specifically produces a cyclic ADPR-RNA, which can be further decapped in vitro by known decapping enzymes. Heterologous expression of the wild-type but not a catalytic mutant AbTir in E. coli suppressed cell propagation and reduced the levels of NAD-RNAs from a subset of genes before cellular NAD+ levels are impacted. Collectively, the in vitro and in vivo analyses demonstrate that TIR domain-containing proteins can function as a deNAMing enzyme of NAD-RNAs, raising the possibility of TIR domain proteins acting in gene expression regulation.

Abstract Background The pattern recognition receptor Dectin-1 was initially discovered to play a pivotal role in mediating pulmonary antifungal immunity and promoting neutrophil-driven inflammation. Recent studies have revealed that Dectin-1 is overexpressed in asthma, but the specific mechanism remains elusive. Additionally, Dectin-1 has been implicated in promoting pyroptosis, a hallmark of severe asthma airway inflammation. Nevertheless, the involvement of the non-classical pyroptosis signal caspase-11/4 and its upstream regulatory mechanisms in asthma has not been completely explored. Methods House dust mite (HDM)-induced mice was treated with Dectin-1 agonist Curdlan, Dectin-1 inhibitor Laminarin, and caspase-11 inhibitor wedelolactone separately. Subsequently, inflammatory cells in bronchoalveolar lavage fluid (BALF) were analyzed. Western blotting was performed to measure the protein expression of caspase-11 and gasdermin D (GSDMD). Cell pyroptosis and the expression of chemokine were detected in vitro. The correlation between Dectin-1 expression, pyroptosis factors and neutrophils in the induced sputum of asthma patients was analyzed. Results Curdlan appeared to exacerbate neutrophil airway inflammation in asthmatic mice, whereas wedelolactone effectively alleviated airway inflammation aggravated by Curdlan. Moreover, Curdlan enhanced the release of caspase-11 activation fragments and N-terminal fragments of gasdermin D (GSDMD-N) stimulated by HDM both in vivo or in vitro. In mouse alveolar macrophages (MH-S cells), Curdlan/HDM stimulation resulted in vacuolar degeneration and elevated lactate dehydrogenase (LDH) release. In addition, there was an upregulation of neutrophil chemokines CXCL1, CXCL3, CXCL5 and their receptor CXCR2, which was suppressed by wedelolactone. In asthma patients, a positive correlation was observed between the expression of Dectin-1 on macrophages and caspase-4 (the human homology of caspase-11), and the proportion of neutrophils in induced sputum. Conclusion Dectin-1 activation in asthma induced caspase-11/4 mediated macrophage pyroptosis, which subsequently stimulated the secretion of chemokines, leading to the exacerbation of airway neutrophil inflammation. Graphical Abstract

Abstract Recent evidence has shed light on the significant role of FANCD2 in cancer initiation, development, and progression. However, a comprehensive pan-cancer analysis of FANCD2 has been lacking. In this study, we have conducted a thorough investigation into the expression profiles and prognostic significance of FANCD2, as well as its correlation with clinicopathological parameters and immune cell infiltration, using advanced bioinformatic techniques. The results demonstrate that FANCD2 is significantly upregulated in various common cancers and is associated with prognosis. Notably, higher expression levels of FANCD2 are linked to poor overall survival, as indicated by Cox regression and Kaplan-Meier analyses. Additionally, we have observed a decrease in the methylation of FANCD2 DNA in some cancers, and this decrease is inversely correlated with FANCD2 expression. Genetic alterations in FANCD2 predominantly manifest as mutations, which are associated with overall survival, disease-specific survival, disease-free survival, and progression-free survival in certain tumor types. Moreover, FANCD2 exhibits a strong correlation with infiltrating cell levels, immune checkpoint genes, tumor mutation burden (TMB), and microsatellite instability (MSI). Enrichment analysis further highlights the potential impact of FANCD2 on Fanconi anemia (FA) pathway and cell cycle regulation. Through this comprehensive pan-cancer analysis, we have gained a deeper understanding of the functions of FANCD2 in oncogenesis and metastasis across different types of cancer.

ABSTRACT Aims/Introduction The coronary physiology and prognosis of patients with different hemoglobin A1c (HbA1c) levels after percutaneous coronary intervention (PCI) are currently unknown. The aim of this study was to assess the effect of different levels of HbA1c control on coronary physiology in patients who underwent PCI for coronary heart disease combined with type 2 diabetes mellitus by quantitative flow ratio (QFR). Materials and Methods Patients who successfully underwent PCI and completed 1‐year coronary angiographic follow up were enrolled, clinical data were collected, and QFR at immediate and 1‐year follow up after PCI was retrospectively analyzed. A total of 257 patients (361 vessels) were finally enrolled and divided into the hemoglobin A1c (HbA1c)‐compliance group (103 patients, 138 vessels) and non‐HbA1c‐compliance group (154 patients, 223 vessels) according to the HbA1c cut‐off value of 7%. We compared the results of QFR analysis and clinical outcomes between the two groups. Results At 1‐year follow up after PCI, the QFR was significantly higher (0.94 ± 0.07 vs 0.92 ± 0.10, P = 0.019) and declined less (0.014 ± 0.066 vs 0.033 ± 0.095, P = 0.029) in the HbA1c‐compliance group. Meanwhile, the incidence of physiological restenosis was lower in the HbA1c‐compliance group (2.9% vs 8.5%, P = 0.034). Additionally, the target vessel revascularization rate was lower in the HbA1c‐compliance group (6.8% vs 16.9%, P = 0.018). Furthermore, HbA1c ≥7% (OR 2.113, 95% confidence interval 1.081–4.128, P = 0.029) and QFR decline (OR 2.215, 95% confidence interval 1.147–4.277, P = 0.018) were independent risk factors for target vessel revascularization. Conclusion Patients with well‐controlled HbA1c levels have better coronary physiological benefits and the incidence of adverse clinical outcome events might be reduced.

End-stage renal disease is a worldwide health burden, but the pathogenesis of uremia-associated cognitive impairment (CI) is poorly recognized. We hypothesized that uremia brings about deficiency of thiamin and folic acid and causes CI by inducing oxidative stress. Therefore, 24 Sprague-Dawley rats were randomly divided into two groups: a 5/6 nephrectomy group (n = 12) and a sham-operated group (n = 12). The Morris water maze was used to assess the cognitive function eight weeks post-surgery, and serum levels of thiamin, folic acid and homocysteine were detected subsequently. Brain and kidney tissues were collected for pathological examination and 8-Hydroxy-2’-deoxyguanosine (8-OHdG) immunochemistry staining. Results showed that the escape latency on training days 1-2 was longer, and the time in quadrant IV on experimental day 6 was significantly shorter in 5/6 nephrectomy group. Meanwhile, the uremic rats showed decreased thiamin, folic acid and increased homocysteine. We also found the time in quadrant IV was positively correlated with thiamin and folic acid level, while negatively correlated with the blood urea nitrogen and 8-OHdG positive cell proportion. Furthermore, in 5/6 nephrectomy group, the hippocampal neuron count was significantly reduced, and a greater proportion of 8-OHdG positive cells were detected. Pretreating LPS-stimulated rat microglial cells with thiamin or folic acid in vitro alleviated the inflammatory impairment in terms of cell viability and oxidative stress. In summary, we applied a uremic rat model and proved that uremia causes serum thiamin and folic acid deficiency, homocysteine elevation, along with neuron reduction and severe oxidative stress in hippocampus, finally leading to CI.

Background Long noncoding RNA (lncRNA) and mRNA profiles in leukocytes have shown potential as biomarkers for acute ischemic stroke (AIS). This study aimed to identify altered lncRNA and target mRNA profiles in peripheral blood leukocytes as biomarkers and to assess the diagnostic value and association with AIS prognosis. Methods and Results Differentially expressed lncRNAs (DElncRNAs) and differentially expressed target mRNAs (DEmRNAs) were screened by RNA sequencing in the discovery set, which consisted of 10 patients with AIS and 20 controls. Validation sets consisted of a multicenter (311 AIS versus 303 controls) and a nested case–control study (351 AIS versus 352 controls). The discriminative value of DElncRNAs and DEmRNAs added to the traditional risk factors was estimated with the area under the curve. NAMPT‐AS, FARP1‐AS1, FTH1, and NAMPT were identified in the multicenter case–control study (P

Levulinic acid, a hydrolysis product of lignocellulose, can be metabolized into important compounds in the field of medicine and pesticides by engineered strains of Saccharomyces cerevisiae. Levulinic acid, as an intermediate product widely found in the conversion process of lignocellulosic biomass, has multiple applications. However, its toxicity to Saccharomyces cerevisiae reduces its conversion efficiency, so screening Saccharomyces cerevisiae genes that can tolerate levulinic acid becomes the key. By creating a whole-genome knockout library and bioinformatics analysis, this study used the phenotypic characteristics of cells as the basis for screening and found the HMX1 gene that is highly sensitive to levulinic acid in the oxidative stress pathway. After knocking out HMX1 and treating with levulinic acid, the omics data of the strain revealed that multiple affected pathways, especially the expression of 14 genes related to the cell wall and membrane system, were significantly downregulated. The levels of acetyl-CoA and riboflavin decreased by 1.02-fold and 1.44-fold, respectively, while the content of pantothenic acid increased. These findings indicate that the cell wall-membrane system, as well as the metabolism of acetyl-CoA and riboflavin, are important in improving the resistance of Saccharomyces cerevisiae to levulinic acid. They provide theoretical support for enhancing the tolerance of microorganisms to levulinic acid, which is significant for optimizing the conversion process of lignocellulosic biomass to levulinic acid.

Abstract Tumor‐infiltrating CD4+ T cells orchestrate the adaptive immune response through remarkable plasticity, and the expression patterns of exhaustion‐related inhibitory receptors in these cells differ significantly from those of CD8+ T cells. Thus, a better understanding of the molecular basis of CD4+ T cell exhaustion and their responses to immune checkpoint blockade (ICB) is required. Here, we integrated multiomics approaches to define the phenotypic and molecular profiles of exhausted CD4+ T cells in oropharyngeal squamous cell carcinoma (OPSCC). Two distinct immune‐promoting (Module 1) and immunosuppressive (Module 2) functional modules in tumor‐infiltrating CD4+ T cells were identified, and both the immune‐promoting function of Module 1 cells and immunosuppressive function of Module 2 cells were positively associated with their corresponding exhaustion states. Furthermore, the application of ICBs targeting effector CD4+ T cells in Module 1 (αPD‐1) and Treg cells in Module 2 (αCTLA‐4) in mouse models could help reinvigorate the effector function of Module 1‐exhausted CD4+ T cells and reduce the immunosuppressive function of Module 2‐exhausted CD4+ T cells, ultimately promoting OPSCC tumor regression. Taken together, our study provides a crucial cellular basis for the selection of optimal ICB in treating OPSCC.

Summary: Exhausted CD8+ T cells (Texs) are characterized by the expression of various inhibitory receptors (IRs), whereas the functional attributes of these co-expressed IRs remain limited. Here, we systematically characterized the diversity of IR co-expression patterns in Texs from both human oropharyngeal squamous cell carcinoma (OPSCC) tissues and syngeneic OPSCC model. Nearly 60% of the Texs population co-expressed two or more IRs, and the number of co-expressed IRs was positively associated with superior exhaustion and cytotoxicity phenotypes. In OPSCC patients, programmed cell death-1 (PD-1) blockade significantly enhanced PDCD1-based co-expression with other IR genes, whereas dual blockades of PD-1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) significantly upregulated CTLA4-based co-expression with other IR genes. Collectively, our findings demonstrate that highly diverse IR co-expression is a leading feature of Texs and represents their functional states, which might provide essential clues for the rational selection of immune checkpoint inhibitors in treating OPSCC.

Abstract Background Intractable postpartum hemorrhage (PPH) during cesarean section has been a significant concern for obstetricians. We aimed to explore the effectiveness and safety of a new type of uterine compression suture, the step-wise surgical technique of knapsack-like sutures for treating intractable PPH caused by uterine atony and placenta factors in cesarean section. Methods The step-wise surgical technique of knapsack-like sutures was established on the basis of the artful combination of vertical strap-like sutures and an annular suture-ligation technique. This novel surgical technique was applied to 34 patients diagnosed with PPH during cesarean section due to severe uterine atony and placental factors in our department. The hemostatic effects, clinical outcomes and follow-up visit results were all reviewed and analyzed. Results This new uterine compression suture successfully stopped bleeding in 33 patients, and the effective rate was 97.06%. Only 1 patient failed and was changed to use bilateral uterine arterial embolization and internal iliac artery embolization. The follow-up visits indicated that 33 patients restored menstruation except for 1 who was diagnosed with amenorrhea. The gynecological ultrasound tests of all the patients suggested good uterine involutions, and they had no obvious complaints such as hypogastralgia. Conclusions This step-wise surgical technique of knapsack-like uterine compression sutures can compress the uterus completely. It is a technique that can conserve the uterus and fertility function without special equipment in caesarean section for PPH, with the characteristics of being safe, simple and stable (3 S) with rapid surgery, reliable hemostasis and resident doctor to operation (3R).

Abstract The study explored the clinical significance of fetal loss of heterozygosity (LOH) identified by single-nucleotide polymorphism array (SNP array). We retrospectively reviewed data from pregnant women who underwent invasive diagnostic procedures at prenatal diagnosis centers in southeastern China from December 2016 to December 2021. SNP array was performed by the Affymetrix CytoScan 750 K array platform. Fetuses with LOH were further identified by parental verification, MS-MLPA, and/or trio whole-exome sequencing (trio-WES). The genetic results, fetal clinical manifestations, and perinatal outcome were analyzed. Of 11,062 fetuses, 106 (0.96%) had LOH exhibiting a neutral copy number, 88 (83.0%) had LOH in a single chromosome, whereas 18 (17.0%) had multiple LOHs on different chromosomes. Sixty-six fetuses had ultrasound anomalies (UAs), most frequently fetal growth restriction (18/66 (27.3%)). Parental SNP array verification was performed in 21 cases and trio-WES in 21 cases. Twelve cases had clinically relevant uniparental disomy, five had pathogenic variants, four had likely pathogenic variants, six had variants of unknown significance, and eight had identity by descent. The rate of adverse pregnancy outcomes in fetuses with LOH and UAs (24/66 (36.4%)) was higher than in those without UAs (6/40 (15.0%)) (p

Abstract Chromosomal abnormalities are the most common etiology of early spontaneous miscarriage. However, traditional karyotyping of chorionic villus samples (CVSs) is limited by cell culture and its low resolution. The objective of our study was to investigate the efficiency of molecular karyotyping technology for genetic diagnosis of early missed abortion tissues. Chromosome analysis of 1191 abortion CVSs in early pregnancy was conducted from August 2016 to June 2021; 463 cases were conducted via copy-number variations sequencing (CNV-seq)/quantitative fluorescent-polymerase chain reaction (QF-PCR) and 728 cases were conducted using SNP array. Clinically significant CNVs of CVSs were identified to clarify the cause of miscarriage and to guide the couples’ subsequent pregnancies. Among these, 31 cases with significant maternal cell contamination were removed from the study. Among the remaining 1160 samples, 751 cases (64.7%) with genetic abnormalities were identified, of which, 531 (45.8%) were single aneuploidies, 31 (2.7%) were multiple aneuploidies, 50 (4.3%) were polyploidies, 54 (4.7%) were partial aneuploidies, 77 (6.6%) had submicroscopic CNVs (including 25 with clinically significant CNVs and 52 had variants of uncertain significance), and 8 cases (0.7%) were uniparental disomies. Our study suggests that both SNP array and CNV-seq/QF-PCR are reliable, robust, and high-resolution technologies for genetic diagnosis of miscarriage.

This study delves into the effects of carbonation curing and autoclave–carbonation curing on the properties of calcium oxide–belite–calcium sulfoaluminate (CBSAC) cementitious material aerated concrete. The objective is to produce aerated concrete that adheres to the strength index in the Chinese standard GB/T 11968 while simultaneously mitigating CO2 emissions from cement factories. Results show that the compressive strength of CBSAC aerated concrete with different curing regimes (autoclave curing, carbonation curing, and autoclave–carbonation curing) can reach 4.3, 0.8, and 4.1 MPa, respectively. In autoclave–carbonation curing, delaying CO2 injection allows for better CO2 diffusion and reaction within the pores, increases the carbonation degree from 19.1% to 55.1%, and the bulk density from 603.7 kg/m3 to 640.2 kg/m3. Additionally, microstructural analysis reveals that delaying the injection of CO2 minimally disrupts internal hydrothermal synthesis, along with the formation of calcium carbonate clusters and needle-like silica gels, leading to a higher pore wall density. The industrial implementation of autoclavecarbonation curing results in CBSAC aerated concrete with a CO2 sequestration capacity ranging from 40 to 60 kg/m3 and a compressive strength spanning from 3.6 to 4.2 MPa. This innovative approach effectively mitigates the carbon emission pressures faced by CBSAC manufacturers.

Dendritic cells (DCs) serve as key regulators in tumor immunity, with activated DCs potentiating antitumor responses through the secretion of pro-inflammatory cytokines and the expression of co-stimulatory molecules. Most current studies focus on the relationship between DC subgroups and clear-cell renal-cell carcinoma (ccRCC), but there is limited research on the connection between DCs and ccRCC from the perspective of immune activation. In this study, activated DC genes were identified in both bulk and single-cell RNA-seq data. A prognostic model related to activated DCs was constructed using univariate, multivariate Cox regression and LASSO regression. The prognostic model was validated in three external validation sets: GSE167573, ICGC, and E-MTAB-1980. The prognostic model consists of five genes, PLCB2, XCR1, IFNG, HLA-DQB2, and SMIM24. The expression of these genes was validated in tissue samples using qRT-PCR. Stratified analysis revealed that the prognostic model was able to better predict outcomes in advanced ccRCC patients. The risk scores were associated with tumor progression, tumor mutation burden, immune cell infiltration, and adverse outcomes of immunotherapy. Notably, there was a strong correlation between the expression of the five genes and the sensitivity to JQ1, a BET inhibitor. Molecular docking indicated high-affinity binding of the proteins encoded by these genes with JQ1. In conclusion, our study reveals the crucial role of activated DCs in ccRCC, offering new insights into predicting immune response, targeted therapy effectiveness, and prognosis for ccRCC patients.

Proper feeding and nutrition are vital for maintaining the health of giant pandas (GPs), yet the impact of dietary changes and gut microbiota on their nutrient utilization remains unclear. To address these uncertainties, we investigated nutrient intake and apparent digestibility, as well as gut microbiota composition across different age groups of giant pandas: sub-adults (SGPs), adults (AGPs), and geriatrics (GGPs). Our findings revealed notable shifts in dietary patterns from SGPs to GGPs. As they aged, significantly more bamboo shoots and less bamboo were consumed. Consequently, GGPs showed significantly reduced crude fiber (CF) intake and digestibility, while crude protein (CP) did not alter significantly. In addition, 16S rRNA microbial sequencing results showed that unidentified_Enterobacteriaceae and Streptococcus were the dominant genera among all age groups. The relative abundance of the genus Enterococcus in GGPs was significantly higher than that in SGPs and AGPs (p < 0.05). Overall, our results indicated the importance of bamboo shoots as a major source of protein in GGPs’ diet, which can effectively compensate for the certain nutritional loss caused by the reduction in bamboo intake. Age-related changes in bacterial abundance have an effect on specific nutrient apparent digestibility in the gut of GPs. The data presented in this study serve as a useful reference for nutritional management in different ages of GPs under healthy conditions.

The hypervapotron structure was considered to be a feasible configuration to meet the high heat-dissipating requirement of divertors in nuclear fusion devices. In this work, symmetric CuCrZr-based transverse microchannels (TMHC) and longitudinal microchannels (LMHC) with an integrated hypervapotron channel were proposed and manufactured, and subcooled flow boiling experiments were conducted using deionized water at an inlet temperature of 20 °C with a traditional flat-type hypervapotron channel (FHC) for comparison. The LMHC and TMHC obtained lower wall temperatures than the FHC for all conditions, and the TMHC yielded the lowest temperatures. The heat transfer coefficients of the LMHC and TMHC outperformed the FHC due to the enlarged heat transfer area, and the TMHC had the greatest heat transfer coefficient (maximumly increased by 132% compared to the FHC) because the transverse-arranged microchannels were conductive, promoting the convection and liquid replenishment ability by introducing branch flow between fins; however, the microchannels of the LMHC were insensible to flow velocities due to the block effect of longitudinal microchannels. The LMHC obtained the largest pressure drop, and the pressure drop for the FHC and TMHC were comparable since the transverse-placed microchannels had little effect on frictional pressure loss. The TMHC attained the greatest comprehensive thermohydraulic performance which might bring significant insight to the structural design of hypervapotron devices.

Lentiviral vectors (LVs) have been widely used as a tool for gene therapies. However, tissue-selective transduction after systemic delivery remains a challenge. Inducible degrader of low-density lipoprotein receptor is an attractive target for treating hypercholesterolemia. Here, a liver-targeted LV, CS8-LV-shIDOL, is developed by incorporating a hepatocyte-targeted peptide derived from circumsporozoite protein (CSP) into the lentivirus envelope for liver-targeted delivery of IDOL-shRNA (short hairpin RNA) to alleviate hypercholesterolemia. Tail-vein injection of CS8-LV-shIDOL results in extremely high accumulation in liver and nearly undetectable levels in other organs in mice. In addition, it shows superior therapeutic efficacy in lowering serum low-density lipoprotein cholesterol (LDL-C) and reducing atherosclerotic lesions over unmodified LV-shIDOL in hyperlipidemic mice. Mechanically, the envelope-engineered CS8-LV-shIDOL can enter liver cells via low-density lipoprotein receptor-related protein (LRP). Thus, this study provides a novel approach for liver-targeted delivery of IDOL-shRNA to treat hypercholesterolemia by using an envelope-engineered LV, and this delivery system has great potential for liver-targeted transgene therapy.

It is well known that colorectal cancer (CRC) has a high morbidity rate, a poor prognosis when metastasized, and a greatly shortened 5-year survival rate. Therefore, understanding the mechanism of tumor metastasis is still important. Based on the ''seed and soil'' theory, the concept of '' premetastatic niche (PMN)'' was introduced by Kaplan et al. The complex interaction between primary tumors and the metastatic organ provides a beneficial microenvironment for tumor cells to colonize at a distance. With further exploration of the PMN, exosomes have gradually attracted interest from researchers. Exosomes are extracellular vesicles secreted from cells that include various biological information and are involved in communication between cells. As a key molecule in the PMN, exosomes are closely related to tumor metastasis. In this article, we obtained information by conducting a comprehensive search across academic databases including PubMed and Web of Science using relevant keywords. Only recent, peer-reviewed articles published in the English language were considered for inclusion. This study aims to explore in depth how exosomes promote the formation of pre-metastatic microenvironment (PMN) in colorectal cancer and its related mechanisms.

Plain-woven carbon fiber-reinforced plastic (PW-CFRP) exhibits high damage tolerance and is widely used in the aerospace field. To address the issue that single-scale drilling simulation is difficult to reflect the practical drilling force due to the change in material elastic properties in PW-CFRP drilling simulation, this paper studies the prediction of elastic properties of PW-CFRP and multi-scale three-dimensional drilling simulation. Based on the prediction model of elastic performance parameters with periodic boundary conditions, the three-dimensional drilling simulation of PW-CFRP is carried out using the predicted material elastic performance parameters and the multi-scale finite element method, with experimental verification. The results show that the finite element method based on periodic boundary conditions can accurately predict the elastic constants of braided composites. For the woven unit cell, its boundary surface changes from plane to surface under shear load, and convex-concave warping deformation occurs. The PW-CFRP three-dimensional drilling simulation model, based on the stiffness prediction model, can accurately predict the axial force and torque during the drilling process. Under the same process parameters, the maximum relative errors between the simulation prediction and the experimental results of the drilling thrust force and torque are 14.2% and 8.5%, respectively. The multi-scale drilling simulation of PW-CFRP, from microscopic to mesoscopic to macroscopic, is realized.

Abstract Esketamine provides an immediate and noticeable antidepressant effect, although the underlying molecular processes are yet unclear. Irisin induced by aerobic exercise has been implicated in the alleviation of depressive symptoms, whether irisin expression responds to the administration of esketamine remains unknown. In this study, we found that irisin was reduced in the hippocampus and peripheral blood of chronic unpredictable mild stress (CUMS) mice, whereas the irisin level was rescued by esketamine treatment. The reduction of PGC-1α expression (transcriptional regulator of irisin gene expression) in the CUMS mice was rescued by esketamine treatment, PGC-1α knockdown significantly reduced the irisin level induced by esketamine. Additionally, FNDC5/irisin-knockout mice developed more severe depressant-like behaviors than wild-type mice under CUMS stimulation, with an attenuated the antidepressant effect of esketamine. Further research indicated that irisin-mediated modulation of esketamine on depressive-like behaviors in CUMS mice involved the ERK1/2 pathway. Overall, the PGC-1α/irisin/ERK1/2 signaling activation may be a new mechanism underlying the antidepressant activity of esketamine, denoting that irisin may be a promising therapeutic target for the treatment of depression.

Abstract Although mRNA vaccines are known as potent activators of antigen-specific immune responses against infectious diseases, limited understanding of how they drive the functional commitment of CD8+ T cells in tumor microenvironment (TME) and secondary lymphoid organs hinders their broader application in cancer immunotherapy. Here, we systematically evaluated the immunological effects of a lipid nanoparticle (LNP)-encapsulated mRNA vaccine that encodes human papillomavirus E7 protein (HPV mRNA-LNP), a tumor-specific antigen of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). HPV mRNA-LNP vaccination activated overall and HPV-specific CD8+ T cells, as well as differentially drove the functional commitment of CD8+ T cells through distinct IFN-response and exhaustion trajectories in the spleen and TME, respectively. Combination therapies of HPV mRNA-LNP vaccination with immune checkpoint blockades boosted HPV-specific CD8+ T cells while maintaining their anti-tumor function, thus further promoting tumor regression. Our results showed that the HPV mRNA-LNP vaccination combined with immune checkpoint blockade is a promising approach for immunotherapy of HPV-positive OPSCC.

MicroRNAs (miRNAs) are short endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level in a broad range of eukaryotic species. In animals, it is estimated that more than 60% of mammalian genes are targets of miRNAs, with miRNAs regulating cellular processes such as differentiation and proliferation. In plants, miRNAs regulate gene expression and play essential roles in diverse biological processes, including growth, development, and stress responses. Arabidopsis mutants with defective miRNA biogenesis are embryo lethal, and abnormal expression of miRNAs can cause severe developmental phenotypes. It is therefore crucial that the homeostasis of miRNAs is tightly regulated. In this review, we summarize the key mechanisms of plant miRNA biogenesis and stabilization. We provide an update on nuclear proteins with functions in miRNA biogenesis and proteins linking miRNA biogenesis to environmental triggers.

The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, integrated DNA methylation and RNA-seq data were used to explore methylation-driven genes (MDGs). Immune scores were calculated using the ESTIMATE, which was employed to identify TME-related genes. A new signature connected with methylation-regulated TME using univariate, multivariate Cox regression and LASSO regression analyses was developed. This signature consists of four TME-MDGs, including AJAP1, HOXB9, MYH14, and SLC6A19, which exhibit high methylation and low expression in tumors. Validation was performed using qRT-PCR which confirmed their downregulation in ccRCC clinical samples. Additionally, the signature demonstrated stable predictive performance in different subtypes of ccRCC. Risk scores are positively correlated with TMN stages, immune cell infiltration, tumor mutation burden, and adverse outcomes of immunotherapy. Interestingly, the expression of four TME-MDGs are highly correlated with the sensitivity of first-line drugs in ccRCC treatment, especially pazopanib. Molecular docking indicates a high affinity binding between the proteins and pazopanib. In summary, our study elucidates the comprehensive role of methylation-driven TME in ccRCC, aiding in identifying patients sensitive to immunotherapy and targeted therapy, and providing new therapeutic targets for ccRCC treatment.

Abstract Background Two-dimensional ultrathin Ti3C2 nanosheets are increasingly being used in biomedical applications owing to their special physicochemical properties. But, the biological effects of its exposure on the reproductive system is still unclear. This study evaluated the reproductive toxicity of Ti3C2 nanosheets in the testes. Results Ti3C2 nanosheets at doses of 2.5 mg/kg bw and 5 mg/kg bw in mice caused defects in spermatogenic function, and we also clarified an underlying molecular mechanism of it in vivo and in vitro model. Ti3C2 nanosheets induced an increase of reactive oxygen species (ROS) in testicular and GC-1 cells, which in turn led to the imbalance in oxidative and antioxidant systems (also known as oxidative stress). Additionally, oxidative stress often induces cellular DNA strand damages via the oxidative DNA damages, which triggered cell cycle arrest in the G1/G0 phase, leading to cell proliferation inhibition and irreversible apoptosis. ATM/p53 signaling manifest key role in DNA damage repair (DDR), and we demonstrate that ATM/p53 signaling was activated, and mediated the toxic damage process caused by Ti3C2 nanosheet exposure. Conclusion Ti3C2 nanosheet-induced disruption of proliferation and apoptosis of spermatogonia perturbed normal spermatogenic function that was mediated by ATM/p53 signaling pathway. Our findings shed more light on the mechanisms of male reproductive toxicity induced by Ti3C2 nanosheets. Graphical abstract

Abstract How climate change in the middle to late Holocene has influenced the early human migrations in Central Asian Steppe remains poorly understood. To address this issue, we reconstructed a multiproxy-based Holocene climate history from the sediments of Kanas Lake and neighboring Tiewaike Lake in the southern Altai Mountains. The results show an exceptionally warm climate during ~6.5–3.6 kyr is indicated by the silicon isotope composition of diatom silica (δ30Sidiatom) and the biogenic silica (BSi) content. During 4.7-4.3 kyr, a peak in δ30Sidiatom reflects enhanced lake thermal stratification and periodic nutrient limitation as indicated by concomitant decreasing BSi content. Our geochemical results indicate a significantly warm and wet climate in the Altai Mountain region during 6.5–3.6 kyr, corresponding to the Altai Holocene Climatic Optimum (AHCO), which is critical for promoting prehistoric human population expansion and intensified cultural exchanges across the Central Asian steppe during the Bronze Age.

Purpose: This study aimed to demonstrate the correlations between the altered functional connectivity patterns in the triple-network model and cognitive impairment in patients with cerebral small vascular disease (CSVD). Methods: Resting-state functional magnetic resonance imaging data were obtained from 22 patients with CSVD and 20 healthy controls. The resting-state data were analyzed using independent component analysis and functional network connectivity (FNC) analysis to explore the functional alterations in the intrinsic triple-network model including the salience network (SN), default mode network (DMN), and central executive network (CEN), and their correlations with the cognitive deficits and clinical observations in the patients with CSVD. Results: Compared to the healthy controls, the patients with CSVD exhibited increased connectivity patterns in the CEN-DMN and decreased connectivity patterns in the DMN-SN, CEN-SN, intra-SN, and intra-DMN. Significant negative correlations were detected between the intra-DMN connectivity pattern and the Montreal Cognitive Assessment (MoCA) total scores (r = −0.460, p = 0.048) and MoCA abstraction scores (r = −0.565, p = 0.012), and a positive correlation was determined between the intra-SN connectivity pattern and the MoCA abstraction scores (r = 0.491, p = 0.033). Conclusions: Our study findings suggest that the functional alterations in the triple-network model are associated with the cognitive deficits in patients with CSVD and shed light on the importance of the triple-network model in the pathogenesis of CSVD.

Magnesium silicate hydrate (M-S-H) samples were prepared utilizing reactive magnesia and quartz with six various Mg/Si molar ratios by the autoclaved curing system. The characteristics and microstructure of M-S-H samples were examined using XRD, TGA, FTIR, SEM and 29Si MAS NMR. Additionally, silica fume was utilized as the siliceous raw material to prepare the M-S-H samples that served as controls. The results showed quartz can be utilized as siliceous raw material for preparing M-S-H. Compared with the samples employing silica fume, the M-S-H samples utilizing quartz as the siliceous material had a layered structure and a significant amount of silicate polymerization. Moreover, the SEM images of M-S-H utilizing quartz as the raw material exhibited a denser structure when compared to the microstructure of granular morphology of M-S-H with silica fume. Remarkably, the existence of quartz as a siliceous raw material led to the production of M-S-H with an antigorite structure. At the same time, the 29Si MAS NMR observations revealed that quartz as a siliceous raw material is favorable for the conversion of Q2 to Q3, resulting in improvement of polymerization degree of M-S-H silicone tetrahedron. The study demonstrated that it is the feasible to prepare M-S-H by replacing silica fume with quartz, which can provide a reference and choice for the preparation of green cementitious materials.

BackgroundSleep is an important biological process and has been linked to many diseases; however, very little is known about which and how genes control and regulate sleep. Although technology has seen significant development, this issue has still not been adequately resolved. Therefore, we conducted a bibliometric analysis to assess the progress in research on sleep quality and associated genes over the past 2 decades. Through our statistical data and discussions, we aimed to provide researchers with better research directions and ideas, thus promoting the advancement of this field.MethodsOn December 29, 2022, we utilized bibliometric techniques, such as co-cited and cluster analysis and keyword co-occurrence, using tools such as CiteSpace, VOSviewer, and the Online Analysis Platform of Literature Metrology (http://bibliometric.com/), to conduct a thorough examination of the relevant publications extracted from the Web of Science Core Collection (WoSCC). Our analysis aimed to identify the emerging trends and hot spots in this field while also predicting their potential development in future.ResultsCluster analysis of the co-cited literature revealed the most popular terms relating to sleep quality and associated genes in the manner of cluster labels; these included genome-wide association studies (GWAS), circadian rhythms, obstructive sleep apnea (OSA), DNA methylation, and depression. Keyword burst detection suggested that obstructive sleep apnea, circadian clock, circadian genes, and polygenic risk score were newly emergent research hot spots.ConclusionBased on this bibliometric analysis of the publications in the last 20 years, a comprehensive analysis of the literature clarified the contributions, changes in research hot spots, and evolution of research techniques regarding sleep quality and associated genes. This research can provide medical staff and researchers with revelations into future directions of the study on the pathological mechanisms of sleep-related diseases.

Abstract Background The biological effects of cerium dioxide nanoparticles (CeO2NPs), a novel material in the biomedical field, have attracted widespread attention. Our previous study confirmed that exposure to CeO2NPs during pregnancy led to abnormal trophoblast invasion during early placental development, thereby impairing placental development. The potential mechanisms may be related to low-quality decidualization triggered by CeO2NPs exposure, such as an imbalance in trophoblast invasion regulators secreted by decidual cells. However, the intermediate link mediating the “dialogue” between decidual cells and trophoblasts during this process remains unclear. As an important connection between cells, exosomes participate in the “dialogue” between endometrial cells and trophoblasts. Exosomes transfer bioactive microRNA into target cells, which can target and regulate the level of mRNA in target cells. Results Here, we constructed a mice primary uterine stromal cell-induced decidualization model in vitro, and detected the effect of CeO2NPs exposure on the expression of decidual-derived exosomal miRNAs by high-throughput sequencing. Bioinformatics analysis and dual-luciferase reporter assays were performed to identify target genes of the screened key miRNAs in regulating trophoblast invasion. Finally, the role of the screened miRNAs and their target genes in regulating trophoblast (HTR-8/SVneo cells) invasion was confirmed. The results showed that CeO2NPs exposure inhibited trophoblast invasion by promoting miR-99a-5p expression in decidual-derived exosomes, and Ppp2r5a is a potential target gene for miR-99a-5p to inhibit trophoblast invasion. Conclusions This study revealed the molecular mechanism by which CeO2NPs exposure inhibits trophoblast invasion from the perspective of decidual derived exosomal miRNAs. These results will provide an experimental basis for screening potential therapeutic targets for the negative biological effects of CeO2NPs exposure and new ideas for studying the mechanism of damage to trophoblast cells at the decidual-foetal interface by harmful environmental or occupational factors.

Abstract Background Interspecific hybridization plays vital roles in enriching animal diversity, while male hybrid sterility (MHS) of the offspring commonly suffered from spermatogenic arrest constitutes the postzygotic reproductive isolation. Cattle-yak, the hybrid offspring of cattle (Bos taurus) and yak (Bos grunniens) can serve as an ideal MHS animal model. Although meiotic arrest was found to contribute to MHS of cattle-yak, yet the cellular characteristics and developmental potentials of male germline cell in pubertal cattle-yak remain to be systematically investigated. Results Single-cell RNA-seq analysis of germline and niche cell types in pubertal testis of cattle-yak and yak indicated that dynamic gene expression of developmental germ cells was terminated at late primary spermatocyte (meiotic arrest) and abnormal components of niche cell in pubertal cattle-yak. Further in vitro proliferation and differentially expressed gene (DEG) analysis of specific type of cells revealed that undifferentiated spermatogonia of cattle-yak exhibited defects in viability and proliferation/differentiation potentials. Conclusion Comparative scRNA-seq and in vitro proliferation analysis of testicular cells indicated that not only meiotic arrest contributed to MHS of cattle-yak. Spermatogenic arrest of cattle-yak may originate from the differentiation stage of undifferentiated spermatogonia and niche cells of cattle-yak may provide an adverse microenvironment for spermatogenesis.

Plants respond to light and temperature changes via the photoreceptor phytochrome B and the phytohormone auxin. Here the authors reveal microRNA156 as a previously uncharacterized developmental signal that gates environmentally regulated plant growth by licensing auxin sensitivity.

Severe ozone (O3) pollution has been recorded in China in recent years. The key precursor, volatile organic compounds (VOCs), is still not well understood in Nanning, which is a less developed city compared to other megacities in China. In this study, a year-long measurement of VOCs was conducted from 1 October 2020 to 30 September 2021, to characterize the ambient variations and apportion the source contributions of VOCs. The daily-averaged concentration of VOCs was measured to be 26.4 ppb, ranging from 3.2 ppb to 136.2 ppb across the whole year. Alkanes and oxygenated VOCs (OVOCs) were major species, contributing 46.9% and 25.2% of total VOC concentrations, respectively. Propane, ethane, and ethanol were the most abundant in Nanning, which differed from the other significant species, such as toluene (3.7 ppb) in Guangzhou, ethylene (3.8 ppb) in Nanjing, and isopentane (5.5 ppb), in Chengdu. The positive matrix factorization (PMF) model resolved six source factors, including vehicular emission (contributing 33% of total VOCs), NG and LPG combustion (19%), fuel burning (17%), solvent use (16%), industry emission (10%), and biogenic emission (5%). This indicated that Nanning was less affected by industrial emission compared with other megacities of China, with industry contributing 12–50%. Ethylene, m/p-xylene, butane, propylene, and isoprene were key species determined by ozone formation potential (OFP) analysis, which should be priority-controlled. The variations in estimated OFP and observed O3 concentrations were significantly different, suggesting that VOC reactivity-based strategies as well as meteorological and NOx effects should be considered collectively in controlling O3 pollution. This study presents a year-long dataset of VOC measurements in Nanning, which gives valuable implications for VOC control in terms of key sources and reactive species and is also beneficial to the formulation of effective ozone control strategies in other less developed regions of China.

The integration of micro-electro-mechanical system–inertial navigation systems (MEMS-INSs) with other autonomous navigation sensors, such as polarization compasses (PCs) and geomagnetic compasses, has been widely used to improve the navigation accuracy and reliability of vehicles in Internet of Things (IoT) applications. However, a MEMS-INS/PC integrated navigation system suffers from cumulative errors and time-varying measurement noise covariance in unknown, complex occlusion, and dynamic environments. To overcome these problems and improve the integrated navigation system’s performance, a dual data- and model-driven MEMS-INS/PC seamless navigation method is proposed. This system uses a nonlinear autoregressive neural network (NARX) based on the Gauss–Newton Bayesian regularization training algorithm to model the relationship between the MEMS-INS outputs composed of the specific force and angular velocity data and the PC heading’s angular increment, and to fit the integrated navigation system’s dynamic characteristics, thus realizing data-driven operation. In the model-driven part, a nonlinear MEMS-INS/PC loosely coupled navigation model is established, the variational Bayesian method is used to estimate the time-varying measurement noise covariance, and the cubature Kalman filter method is then used to solve the nonlinear problem in the model. The robustness and effectiveness of the proposed method are verified experimentally. The experimental results show that the proposed method can provide high-precision heading information stably in complex, occluded, and dynamic environments.

The present work aimed to study the feasibility of Angelica sinensis polysaccharide (ASP) as an instinctive liver targeting drug delivery carrier for oridonin (ORI) in the treatment of hepatocellular carcinoma (HCC). ASP was reacted with deoxycholic acid (DOCA) via an esterification reaction to form an ASP-DOCA conjugate. ORI-loaded ASP-DOCA nanoparticles (ORI/ASP-DOCA NPs) were prepared by the thin-film water method, and their size was about 195 nm in aqueous solution. ORI/ASP-DOCA NPs had a drug loading capacity of up to 9.2%. The release of ORI in ORI/ASP-DOCA NPs was pH-dependent, resulting in rapid decomposition and accelerated drug release at acidic pH. ORI/ASP-DOCA NPs significantly enhanced the accumulation of ORI in liver tumors through ASGPR-mediated endocytosis. In vitro results showed that ORI/ASP-DOCA NPs increased cell uptake and apoptosis in HepG2 cells, and in vivo results showed that ORI/ASP-DOCA NPs caused effective tumor suppression in H22 tumor-bearing mice compared with free ORI. In short, ORI/ASP-DOCA NPs might be a simple, feasible, safe and effective ORI nano-drug delivery system that could be used for the targeted delivery and treatment of liver tumors.