68Ga-labeled TMTP1 radiotracer for PET imaging of cervical cancer.

Molecular imaging enables visualization and characterization of biological processes that influence tumor behavior and response to therapy. The TMTP1 (NVVRQ) peptide has shown remarkable affinity to highly metastatic tumors and and its potential receptor is aminopeptidase P2. In this study, we have designed and synthesized a 68Ga-labeled cyclic TMTP1 radiotracer (68Ga-DOTA-TMTP1), for PET imaging of cervical cancer. The goal of this study was to investigate the properties of this radiotracer and its tumor diagnostic potential. The radiochemical yield of 68Ga-DOTA-TMTP1 was high and the radiochemical purity was greater than 95%. The octanol-water partition coefficient for 68Ga-DOTA-TMTP1 was -2.76 ± 0.08 and 68Ga-DOTA-TMTP1 has showed excellent stability in in vitro studies. The cellular uptake and efflux of 68Ga-DOTA-TMTP1 in paired highly metastatic and lowly metastatic cervical cancer cell line HeLa and C-33A as well as normal cervical epithelial cell line End1 were measured in a γ counter. 68Ga-DOTA-TMTP1 exhibited higher uptake in HeLa cells than in C-33A cells. The binding to HeLa and C-33A cells could be blocked by excess TMTP1. On microPET images, HeLa tumors were clearly visualized within 60 min and the uptake of the radiotracer in HeLa tumors was higher than that of C-33A tumors. After blocking with TMTP1, HeLa tumors uptake was significantly reduced and the specificity 68Ga-DOTA-TMTP1 was thus validated. Overall, we have successfully synthesized 68Ga-DOTA-TMTP1 with high yield and high specific activity and have demonstrated its potential role for highly metastatic tumor-targeted diagnosis.

Gradient gyroid Ti6Al4V scaffolds with TiO2 surface modification: Promising approach for large bone defect repair.

Large bone defects, particularly those exceeding the critical size, present a clinical challenge due to the limited regenerative capacity of bone tissue. Traditional treatments like autografts and allografts are constrained by donor availability, immune rejection, and mechanical performance. This study aimed to develop an effective solution by designing gradient gyroid scaffolds with titania (TiO2) surface modification for the repair of large segmental bone defects. The scaffolds were engineered to balance mechanical strength with the necessary internal space to promote new bone formation and nutrient exchange. A gradient design of the scaffold was optimized through Finite Element Analysis (FEA) and Computational Fluid Dynamics (CFD) simulations to enhance fluid flow and cell adhesion. In vivo studies in rabbits demonstrated that the G@TiO2 scaffold, featuring a gradient structure and TiO2 surface modification, exhibited superior healing capabilities compared to the homogeneous structure and TiO2 surface modification (H@TiO2) and gradient structure (G) scaffolds. At 12 weeks post-operation, in a bone defect representing nearly 30 % of the total length of the radius, the implantation of the G@TiO2 scaffold achieved a 27 % bone volume to tissue volume (BV/TV) ratio, demonstrating excellent osseointegration. The TiO2 surface modification provided photothermal antibacterial effects, enhancing the scaffold's biocompatibility and potential for infection prevention. These findings suggest that the gradient gyroid scaffold with TiO2 surface modification is a promising candidate for treating large segmental bone defects, offering a combination of mechanical strength, bioactivity, and infection resistance.

Effects of foliar selenium, biochar, and pig manure on cadmium accumulation in rice grains and assessment of health risk.

Addressing cadmium (Cd) contamination in agricultural lands is crucial, given its health implications and accumulation in crops. This study used pot experiments to evaluate the impact of foliar selenium spray (Se) (0.40 mM), corn straw biochar (1%), and pig manure (1%) on the growth of rice plants, the accumulation of Cd in rice grain, and to examine their influence on health risk indices associated with Cd exposure. The treatments were designated as follows: a control group without any amendment (CK), biochar (T1), pig manure (T2), Se (T3), Se and biochar (T4), Se and pig manure (T5), and Se along with biochar and pig manure (T6). Our results indicated that the treatments affected soil pH and redox potential and improved growth and the nitrogen and phosphorus content in rice plants. The soil-plant analysis development (SPAD) meter readings of leaves during the tillering stage indicated a 5.27%-15.86% increase in treatments T2 to T6 compared to CK. The flag leaves of T2 exhibited increases of 12.06%-38.94% for electrolyte leakage and an 82.61%-91.60% decline in SOD compared to treatments T3 to T6. Treatments T1 to T6 increased protein content; however, amylose content was significantly reduced in T6. Treatment T6 recorded the lowest Cd concentration in rice grains (0.018 mg/kg), while T2 recorded the highest (0.051 mg/kg). The CK treatment group showed a grain Cd content reduction of 29.30% compared to T2. The assessment of acceptable daily intake, hazard quotient, and carcinogenic risk revealed an ascending order as follows: T6 < T3 < T5 < T4 < T1 < CK < T2. In conclusion, the application of treatment T6 demonstrates the potential to lower oxidative stress, enhance production, reduce cancer risk, and ensure the safe cultivation of rice in environments affected by Cd contamination.

Reactive oxygen species-scavenging nanomaterials for the prevention and treatment of age-related diseases.

With increasing proportion of the elderly in the population, age-related diseases (ARD) lead to a considerable healthcare burden to society. Prevention and treatment of ARD can decrease the negative impact of aging and the burden of disease. The aging rate is closely associated with the production of high levels of reactive oxygen species (ROS). ROS-mediated oxidative stress in aging triggers aging-related changes through lipid peroxidation, protein oxidation, and DNA oxidation. Antioxidants can control autoxidation by scavenging free radicals or inhibiting their formation, thereby reducing oxidative stress. Benefiting from significant advances in nanotechnology, a large number of nanomaterials with ROS-scavenging capabilities have been developed. ROS-scavenging nanomaterials can be divided into two categories: nanomaterials as carriers for delivering ROS-scavenging drugs, and nanomaterials themselves with ROS-scavenging activity. This study summarizes the current advances in ROS-scavenging nanomaterials for prevention and treatment of ARD, highlights the potential mechanisms of the nanomaterials used and discusses the challenges and prospects for their applications.

Dual-Activated H2O2-Responsive AIE Probes for Oocyte Quality Assessment.

Nonobstructive azoospermia (NOA) is an important cause of infertility, and intracytoplasmic sperm injection (ICSI) is the mainstay of treatment for these patients. In cases where a sufficient number of sperm (usually 1-2) is not available, the selection of oocytes for ICSI is a difficult problem that must be solved. Here, we constructed a dual-activated oxidative stress-responsive AIE probe, b-PyTPA. The strong donor-acceptor configuration of b-PyTPA leads to twisted intramolecular charge transfer (TICT) effect that quenches the fluorescence of the probe, however, H2O2 would specifically remove the boronatebenzyl unit and release a much weaker acceptor, which inhibits TICT and restores the fluorescence. In addition, the presence of a pyridine salt makes b-PyTPA more hydrophilic, whereas removal of the pyridine salt increases the hydrophobicity of PyTPA, which triggers aggregation and further enhances fluorescence. Thus, the higher the intracellular level of oxidative stress, the stronger the fluorescence. In vitro, this dual-activated fluorescent probe is capable of accurately detecting senescent cells (high oxidative stress). More importantly, b-PyTPA was able to characterize senescent oocytes, as assessed by the level of oxidative stress. It is also possible to identify high quality oocytes from those obtained for subsequent ICSI. In conclusion, this dual-activated oxidative stress-assessment probe enables the quality assessment of oocytes and has potential application in ICSI.

Connexin 43 Prevents Radiation-Induced Intestinal Damage via the Ca2+-Dependent PI3K/Akt Signaling Pathway.

Radiation-induced intestinal damage (RIID) is a common side effect of radiotherapy in patients with abdominopelvic malignancies. Gap junctions are special structures consisting of connexins (Cxs). This study aimed to investigate the expression and role of connexins in RIID and underlying mechanism. In this study, a calcein-AM fluorescence probe was used to detect changes in gap junctional intercellular communication in intestinal epithelial IEC-6 cells. Our results show that gap junctional intercellular communication of IEC-6 cells was reduced at 6, 12, 24, and 48 h after irradiation, with the most pronounced effect at 24 h. Western blotting and immunofluorescence results showed that the expression of Cx43, but not other connexins, was reduced in irradiated intestinal epithelial cells. Silencing of Cx43 reduced gap junctional intercellular communication between irradiated intestinal epithelial cells with increased ROS and intracellular Ca2+ levels. Furthermore, knockdown of Cx43 reduced the number of clonal clusters, decreased cell proliferation with increased cytotoxicity and apoptosis. Western blotting results showed that silencing of Cx43 resulted in changed γ-H2AX and PI3K/AKT pathway proteins in irradiated intestinal epithelial cells. Administration of the PI3K/AKT pathway inhibitor LY294002 inhibited the radioprotective effects in Cx43-overexpressing intestinal epithelial cells. Our study demonstrated that Cx43 expression is decreased by ionizing radiation, which facilitates the radioprotection of intestinal epithelial cells.

The relationship between red cell distribution width, serum calcium ratio, and in-hospital mortality among patients with acute respiratory failure: A retrospective cohort study of the MIMIC-IV database.

To investigate the impact of RDW/CA (the ratio of red cell distribution width to calcium) on in-hospital mortality in patients with acute respiratory failure (ARF). This retrospective cohort study analyzed the data of 6981 ARF patients from the Medical Information Mart for Intensive Care (MIMIC-IV) database 2.0. Critically ill participants between 2008 and 2019 at the Beth Israel Deaconess Medical Center in Boston. The primary outcome of interest was in-hospital mortality. A Cox proportional hazards regression model was used to determine whether the RDW/CA ratio independently correlated with in-hospital mortality. The Kaplan-Meier method was used to plot the survival curves of the RDW/CA. Subgroup analyses were performed to measure the mortality across various subgroups. After adjusting for potential covariates, we found that a higher RDW/CA was associated with an increased risk of in-hospital mortality (HR = 1.17, 95% CI: 1.01-1.35, P = .0365) in ARF patients. A nonlinear relationship was observed between RDW/CA and in-hospital mortality, with an inflection point of 1.97. When RDW/CA ≥ 1.97 was positively correlated with in-hospital mortality in patients with ARF (HR = 1.554, 95% CI: 1.183-2.042, P = .0015). The Kaplan-Meier curve indicated the higher survival rates for RDW/CA < 1.97 and the lower for RDW/CA ≥ 1.97 after adjustment for age, gender, body mass index, and ethnicity. RDW/CA is an independent predictor of in-hospital mortality in patients with ARF. Furthermore, a nonlinear relationship was observed between RDW/CA and in-hospital mortality in patients with ARF.

Formation, physicochemical properties, and biological activities of theabrownins.

Theabrownins (TBs) are heterogeneous mixtures of water-soluble brown tea pigments, and important constituents to evaluate the quality of dark tea. TBs have numerous hydroxyl and carboxyl groups and are formed by the oxidative polymerization of tea polyphenols. Many biological activities attributed to TBs, including antioxidant, anti-obesity, and lipid-regulating, have been demonstrated. This review summarizes the research progress made on the formation mechanism and physicochemical properties of TBs. It also discusses their protective effects against various diseases and associated potential molecular mechanisms. Additionally, it examines the signaling pathways mediating the bioactivities of TBs and highlights the difficulties and challenges of TBs research as well as their research prospects and applications.

Cellulose Nanofibrils of High Immunoaffinity for Efficient Enrichment of Small Extracellular Vesicles.

Extracellular vesicles (EVs), crucial in facilitating the transport of diverse molecular cargoes for intercellular communication, have shown great potential in diagnostics, therapeutics, and drug delivery. The challenge of developing effective preparation methods for EVs is heightened by their intrinsic heterogeneity and complexity. Here, a novel strategy for high EV enrichment is developed by utilizing EV-affinitive-modified cellulose nanofibrils. Specifically, modified cellulose with rich carboxyl groups has outstanding dispersing properties, able to be dispersed into cellulose nanofibrils in solution. These cellulose nanofibrils are utilized as scaffolds for the immobilization of EV-affinitive antibody of CD63 by chemical conjugation. The CD63-modified nanofibrils demonstrate a superior EV capture efficiency of 86.4% compared with other reported methods. The high performance of this system is further validated by the efficient capture of EVs from biological blood plasma, allowing the detection of bioactive markers from EV-derived miRNAs and proteins. The authors envision that these modified cellulose nanofibrils of enhanced capability on EV enrichment will open new avenues in various biomedical applications.

Expanding the CRISPR Toolbox for Engineering Lycopene Biosynthesis in Corynebacterium glutamicum.

Lycopene represents one of the central compounds in the carotenoid pathway and it exhibits a potent antioxidant ability with wide potential applications in medicine, food, and cosmetics. The microbial production of lycopene has received increasing concern in recent years. Corynebacterium glutamicum (C. glutamicum) is considered to be a safe and beneficial industrial production platform, naturally endowed with the ability to produce lycopene. However, the scarcity of efficient genetic tools and the challenge of identifying crucial metabolic genes impede further research on C. glutamicum for achieving high-yield lycopene production. To address these challenges, a novel genetic editing toolkit, CRISPR/MAD7 system, was established and developed. By optimizing the promoter, ORI and PAM sequences, the CRISPR/MAD7 system facilitated highly efficient gene deletion and exhibited a broad spectrum of PAM sites. Notably, 25 kb of DNA from the genome was successfully deleted. In addition, the CRISPR/MAD7 system was effectively utilized in the metabolic engineering of C. glutamicum, allowing for the simultaneous knockout of crtEb and crtR genes in one step to enhance the accumulation of lycopene by blocking the branching pathway. Through screening crucial genes such as crtE, crtB, crtI, idsA, idi, and cg0722, an optimal carotenogenic gene combination was obtained. Particularly, cg0722, a membrane protein gene, was found to play a vital role in lycopene production. Therefore, the CBIEbR strain was obtained by overexpressing cg0722, crtB, and crtI while strategically blocking the by-products of the lycopene pathway. As a result, the final engineered strain produced lycopene at 405.02 mg/L (9.52 mg/g dry cell weight, DCW) in fed-batch fermentation, representing the highest reported lycopene yield in C. glutamicum to date. In this study, a powerful and precise genetic tool was used to engineer C. glutamicum for lycopene production. Through the modifications between the host cell and the carotenogenic pathway, the lycopene yield was stepwise improved by 102-fold as compared to the starting strain. This study highlights the usefulness of the CRISPR/MAD7 toolbox, demonstrating its practical applications in the metabolic engineering of industrially robust C. glutamicum.

Stability and integrity of self-assembled bovine parvovirus virus­like particles (BPV­VLPs) of VP2 and combination of VP1VP2 assisted by baculovirus-insect cell expression: a potential logistical platform for vaccine deployment.

BACKGROUND: Bovine parvovirus (BPV) is an autonomous DNA virus with a smaller molecular size and subtle differences in its structural proteins, unlike other animal parvoviruses. More importantly, this virus has the potential to produce visible to silent economic catastrophes in the livestock business, despite receiving very little attention. Parvoviral virus-like particles (VLPs) as vaccines and as logistical platforms for vaccine deployment are well studied. However, no single experimental report on the role of VP1 in the assembly and stability of BPV-VLPs is available. Furthermore, the self-assembly, integrity and stability of the VLPs of recombinant BPV VP2 in comparison to VP1 VP2 Cap proteins using any expression method has not been studied previously. In this study, we experimentally evaluated the self-assembling ability with which BPV virus-like particles (VLPs) could be synthesized from a single structural protein (VP2) and by integrating both VP2 and VP1 amino acid sequences. METHODS: In silico and experimental cloning methods were carried out. His-tagged and without-His-tag VP2 and V1VP2-encoding amino acid sequences were cloned and inserted into pFastbacdual, and insect cell-generated recombinant protein was evaluated by SDS‒PAGE and western blot. Period of infectivity and expression level were determined by IFA. The integrity and stability of the BPV VLPs were evaluated by transmission electron microscopy. The secondary structure of the BPV VLPs from both VP2 and V1VP2 was analyzed by circular dichroism. RESULTS: Our findings show that VP2 alone was equally expressed and purified into detectable proteins, and the stability at different temperatures and pH values was not appreciably different between the two kinds of VLPs. Furthermore, BPV-VP2 VLPs were praised for their greater purity and integrity than BPV-VP1VP2 VLPs, as indicated by SDS‒PAGE. Therefore, our research demonstrates that the function of VP1 has no bearing on the stability or integrity of BPV-VLPs. CONCLUSIONS: In summary, incredible physiochemically stable BPV VP2-derived VLPs have been found to be promising candidates for the development of multivalent vaccines and immunodiagnostic kits against enteric viruses and to carry heterogeneous epitopes for various economically important livestock diseases.

Cadmium Exposure was Associated with Sex-Specific Thyroid Dysfunction: Consistent Evidence from Two Independent Cross-Sectional Studies Based on Urinary and Blood Cadmium Measurements.

Population-based studies on the association between cadmium (Cd) exposure and thyroid function are limited and have shown conflicting results. Two independent cross-sectional studies using different Cd biomarkers were carried out in six rural areas with different soil Cd levels in China. Thyroid dysfunction was defined based on levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4). Multivariable linear regression, multiple logistic regression, and restrictive cubic splines models were used to estimate the association between Cd and thyroid dysfunction. For both of the two independent studies, higher Cd levels were observed to be associated with lower TSH levels and higher risk of thyroid dysfunction. The negative relationship between urinary Cd and TSH was found in both total participants (ß = - 0.072, p = 0.008) and males (ß = - 0.119, p = 0.020) but not in females; however, the negative relationship between blood Cd and TSH was only found in females (ß = - 0.104, p = 0.024). Higher urinary Cd was associated with higher risk of thyroid dysfunction (OR = 1.77, p = 0.031), while higher blood Cd was associated with higher risk of thyroid dysfunction (OR = 1.95, p = 0.011). Results from the two independent cross-sectional studies consistently suggested that higher Cd levels were associated with sex-specific thyroid dysfunction.

Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1.

Limited understanding exists regarding how aging impacts the cellular and molecular aspects of the human ovary. This study combines single-cell RNA sequencing and spatial transcriptomics to systematically characterize human ovarian aging. Spatiotemporal molecular signatures of the eight types of ovarian cells during aging are observed. An analysis of age-associated changes in gene expression reveals that DNA damage response may be a key biological pathway in oocyte aging. Three granulosa cells subtypes and five theca and stromal cells subtypes, as well as their spatiotemporal transcriptomics changes during aging, are identified. FOXP1 emerges as a regulator of ovarian aging, declining with age and inhibiting CDKN1A transcription. Silencing FOXP1 results in premature ovarian insufficiency in mice. These findings offer a comprehensive understanding of spatiotemporal variability in human ovarian aging, aiding the prioritization of potential diagnostic biomarkers and therapeutic strategies.

Characterization and expression profiles of the ZmLBD gene family in Zea mays.

BACKGROUND: The Lateral Organ Boundaries Domain (LBD) gene family is a family of plant-specific transcription factors (TFs) that are widely involved in processes such as lateral organ formation, stress response, and nutrient metabolism. However, the function of LBD genes in maize remains poorly understood. METHODS AND RESULTS: In this study, a total of 49 ZmLBD genes were identified at the genome-wide level of maize, they were classified into nine branches based on phylogenetic relationships, and all of them were predicted to be nuclear localized. The 49 ZmLBD genes formed eight pairs of segmental duplicates, and members of the same branches' members had similar gene structure and conserved motif composition. The promoters of ZmLBD genes contain multiple types of cis-acting elements. In addition, by constructing the regulatory network of ZmLBD and other genes and miRNAs, 12 and 22 ZmLBDs were found to be involved in the gene regulatory network and miRNA regulatory network, respectively. The expression pattern analysis suggests that ZmLBD genes may be involved in different biological pathways, and drought stress induced the expressions of two inbred lines. CONCLUSIONS: The findings enhance our comprehension of the potential roles of the ZmLBD gene family in maize growth and development, which is pivotal for genetic enhancement and breeding efforts pertaining to this significant crop.

Identification of diagnostic signature, molecular subtypes, and potential drugs in allergic rhinitis based on an inflammatory response gene set.

Background: Rhinitis is a complex condition characterized by various subtypes, including allergic rhinitis (AR), which involves inflammatory reactions. The objective of this research was to identify crucial genes associated with inflammatory response that are relevant for the treatment and diagnosis of AR. Methods: We acquired the AR-related expression datasets (GSE75011 and GSE50223) from the Gene Expression Omnibus (GEO) database. In GSE75011, we compared the gene expression profiles between the HC and AR groups and identified differentially expressed genes (DEGs). By intersecting these DEGs with inflammatory response-related genes (IRGGs), resulting in the identification of differentially expressed inflammatory response-related genes (DIRRGs). Afterwards, we utilized the protein-protein interaction (PPI) network, machine learning algorithms, namely least absolute shrinkage and selection operator (LASSO) regression and random forest, to identify the signature markers. We employed a nomogram to evaluate the diagnostic effectiveness of the method, which has been confirmed through validation using GSE50223. qRT-PCR was used to confirm the expression of diagnostic genes in clinical samples. In addition, a consensus clustering method was employed to categorize patients with AR. Subsequently, extensive investigation was conducted to explore the discrepancies in gene expression, enriched functions and pathways, as well as potential therapeutic drugs among these distinct subtypes. Results: A total of 22 DIRRGs were acquired, which participated in pathways including chemokine and TNF signaling pathway. Additionally, machine learning algorithms identified NFKBIA, HIF1A, MYC, and CCRL2 as signature genes associated with AR's inflammatory response, indicating their potential as AR biomarkers. The nomogram based on feature genes could offer clinical benefits to AR patients. We discovered two molecular subtypes, C1 and C2, and observed that the C2 subtype exhibited activation of immune- and inflammation-related pathways. Conclusions: NFKBIA, HIF1A, MYC, and CCRL2 are the key genes involved in the inflammatory response and have the strongest association with the advancement of disease in AR. The proposed molecular subgroups could provide fresh insights for personalized treatment of AR.

Geriatric nutrition risk index: a more powerful index identifying muscle mass loss in patients with rheumatoid arthritis.

OBJECTIVE: To explore the association of geriatric nutrition risk index (GNRI), a traditional albumin-body weight calculation, with myopenia in patients with rheumatoid arthritis (RA) and compare its ability to identify myopenia with protein indicators. METHODS: This cross-sectional study was carried out based on a Chinese RA cohort. Clinical data and protein indicators (including albumin, globulin, albumin to globulin ratio, prealbumin, hemoglobin) were collected. GNRI was estimated by serum albumin and body weight. Myopenia was indicated as muscle mass loss measured by bioelectric impedance analysis. RESULTS: There were 789 RA patients included with mean age 52.6 ± 12.6 years and 77.6% female. There were 41.3%, 18.0%, 27.5%, 13.2% patients with no (GNRI > 98), low (GNRI 92 to ≤ 98), moderate (GNRI 82 to < 92), and major nutrition-related risk (GNRI < 82). There were 406 (51.5%) RA patients with myopenia, RA patients with major nutrition-related risk had the highest prevalence of myopenia (87.5% vs. 73.3% vs. 50.0% vs. 26.1%). Multivariate logistic analysis showed that compared with no risk, RA patients with low (OR = 3.23, 95% CI: 1.86-5.61), moderate (OR = 9.56, 95% CI: 5.70-16.01), and major nutrition-related risk (OR = 28.91, 95% CI: 13.54-61.71) were associated with higher prevalence of myopenia. Receiver operating characteristic curves showed that GNRI (AUC = 0.79) performed a better identifiable ability toward myopenia than serum albumin (AUC = 0.66) or others indicators (AUC range 0.59 to 0.65), respectively. CONCLUSION: GNRI, an objective and convenient albumin-weight index, may be preferable for identifying myopenia in RA patients. Key Points • We firstly elucidated the association of GNRI with muscle mass loss among RA patients, and compared its ability to identify muscle mass loss with serum albumin or other protein indicators. • Major nutrition-related risk identified by GNRI showed the highest risk of muscle mass loss, GNRI demonstrated a greater ability to identify myopenia in RA patients. which indicated GNRI was an objective and convenient albumin-weight index to identify myopenia in RA patients.

Association of serum concentrations of remnant cholesterol with incident cardiovascular disease in patients with rheumatoid arthritis: A real-world data from 2001 to 2022.

BACKGROUND: Remnant cholesterol (RC) promotes cardiovascular disease (CVD) in the general population, but its role among rheumatoid arthritis (RA) patients remains unknown. We aimed to investigate circulating RC levels associated with incident CVD among Chinese patients with RA. METHODS: A total of 1018 RA patients free of baseline CVD were included and followed up in a prospective RA CVD cohort from 2001 to 2022. Fasting serum levels of triglycerides, total cholesterol (TC), low-density (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured, while RC and Non-HDL-C levels were calculated. The primary exposure was RC levels. A LASSO Cox model was used to select covariates. The Fine-Gray competing risk model was used to estimate hazard ratios (HRs). RESULTS: RA patients had a mean age of 53.9 years, and 802 (78.8%) were females. After a median follow-up of 5.54 years, 131 patients developed CVD with an incidence rate of 21.6 per 1000 person-years. Continuous and quartile-categorized RC levels were associated with incident CVD before and after multivariate adjustment and Bonferroni correction (all P < 0.001). There were no robust associations of other lipids with incident CVD. The fully adjusted HRs for RC were 2.30 (95% CI 1.58-3.35) per 1 mmol/L increase, and 2.40 (1.36-4.25) and 2.81 (1.60-4.94) for patients in the 3rd and 4th versus the 1st quartile, respectively. CONCLUSIONS: Circulating RC levels are positively associated with incident CVD among Chinese RA patients independent of known risk factors, implying its clinically preferable use for improving the stratification of CVD risk in RA patients.

Radar Micro-Doppler Signature Generation Based on Time-Domain Digital Coding Metasurface.

Micro-Doppler effect is a vital feature of a target that reflects its oscillatory motions apart from bulk motion and provides an important evidence for target recognition with radars. However, establishing the micro-Doppler database poses a great challenge, since plenty of experiments are required to get the micro-Doppler signatures of different targets for the purpose of analyses and interpretations with radars, which are dramatically limited by high cost and time-consuming. Aiming to overcome these limits, a low-cost and powerful simulation platform of the micro-Doppler effects is proposed based on time-domain digital coding metasurface (TDCM). Owing to the outstanding capabilities of TDCM in generating and manipulating nonlinear harmonics during wave-matter interactions, it enables to supply rich and high-precision electromagnetic signals with multiple micro-Doppler frequencies to describe the micro-motions of different objects, which are especially favored for the training of artificial intelligence algorithms in automatic target recognition and benefit a host of applications like imaging and biosensing.

Unfolded Protein-Based Sandwich AIE Probe Imparts High Fluorescent Contrast for Pan-Cancer Surgical Navigation.

Fluorescence imaging-guided navigation for cancer surgery has a promising clinical application. However, pan-cancer encompasses a wide variety of cancer types with significant heterogeneity, resulting in the lack of universal and highly contrasted fluorescent probes for surgical navigation. Here, we developed an aggregation-induced emission (AIE) probe (MI-AIE-TsG, MAT) with dual activation for pan-cancer surgical navigation. MAT weakly activates fluorescence by targeting the SUR1 protein on the endoplasmic reticulum (ER) through the TsG group. Subsequently, the sulfhydryl groups on the unfolded proteins, which are highly enriched in cancer ER, react with the maleimide (MI) of MAT through the thiol-ene click reaction, further enhancing the fluorescence. The formation of a SUR1-MAT-unfolded protein sandwich complex reinforces the restriction of intramolecular motion and eliminates photoinduced electron transfer of MAT, leading to high signal-to-noise (9.2) fluorescence imaging and use for surgical navigation of pan-cancer. The generally high content of unfolded proteins in cancer cells makes MAT imaging generalizable, and it currently has proven feasibility in ovarian, cervical, and breast cancers. Meanwhile, MAT promotes cellular autophagy by hindering protein folding, thereby inhibiting cancer cell proliferation. This generalizable, high-contrast AIE fluorescent probe spans the heterogeneity of pancreatic cancer, enabling precise pancreatic cancer surgery navigation and treatment.

HIF1A transcriptional regulation of COX4I2 impacts angiogenesis in pheochromocytoma.

BACKGROUND: Pheochromocytoma (PCC) is a rare neuroendocrine tumor. Angiogenesis is primary contributing factor for tumorigenesis. Cytochrome c oxidase 4I2 (COX4I2) has been confirmed to take part in the progression of cancer. Hypoxia-inducible factor 1A (HIF1A) is the main regulatory factor for the steady-state response of hypoxia, involved in metabolism and angiogenesis. In this study, we intended to explore the functions of COX4I2 in PCC and the effect mechanism between HIF1A and COX4I2. MATERIALS AND METHODS: The RNA-sequencing and immunohistochemistry tested COX4I2 expression in highly vascular PCC. Small interfering RNA (siRNA) was used to reduce the mRNA expression of COX4I2, and a small molecule inhibitor was utilized to reduce the protein expression of HIF1A. Culturing cells in 1% O2environment was performed to activate HIF1A. Western blot was applied to quantify the expression of target genes at the protein levels. The supernatant from PCC cells and fibroblasts acted as the conditioned medium. We conducted the tube formation and transwell assays in human vascular endothelial cells (HUVECs) to determine angiogenesis, the binding of COX4I2 promoter and HIF1A was evaluated by the dual luciferase reporter assay. RESULTS: COX4I2 had been rigorously shown to be overexpressed in highly vascular PCC. Knockdown of COX4I2 in PCC cells (MPC) did not significantly impact angiogenesis, while knockdown of COX4I2 in fibroblast (3T3) notably inhibited angiogenesis. RNA sequencing suggested that the expression of 11 vascular markers, such as CD34 and angiogenesis associated pathways in 3T3, decreased with knockdown of COX4I2. HIF1A had been shown to enhance the mRNA expression of COX4I2 through transcriptional regulation. Activation and inhibition of HIF1A resulted in upregulation and downregulation of COX4I2, respectively. The HIF1A inhibitor demonstrated a reduction in angiogenesis. CONCLUSION: COX4I2 is overexpressed in highly vascular PCC and contributes to angiogenesis in fibroblasts. Mechanistically, HIF1A transcriptional regulation enhances COX4I2 and its effects on angiogenesis in PCC. COX4I2 might serve as a vascular marker and represent a potential target for vascular therapy.