Smooth Muscle Cell-Specific LKB1 Protects Against Sugen5416/Hypoxia-Induced Pulmonary Hypertension through Inhibition of BMP4.

Pulmonary hypertension (PH) is a life-threatening syndrome associated with hyperproliferation of pulmonary artery smooth muscle cells (PASMCs), which exhibit similar features to cancer cells. Currently, there is no curative treatment for PH. LKB1 is known as a tumor suppressor gene with an anti-proliferative effect on cancer cells. However, its role and mechanism in the development of PH remain unclear. Gain-and loss-of-function strategies were used to elucidate the mechanisms of LKB1 in regulating the occurrence and progression of PH. Sugen5416/Hypoxia (SuHx) PH model was utilized for in vivo study. We observed not only a decreased expression of LKB1 in the lung vessels of the SuHx mouse model, but also in human pulmonary artery smooth muscle cells (HPASMCs) exposed to hypoxia. Smooth muscle-specific LKB1 knockout significantly aggravated SuHx-induced PH in mice. RNA sequencing analysis revealed a substantial increase in bone morphogenetic protein-4 (BMP4) in the aortas of LKB1SMKO mice compared with controls, identifying BMP4 as a novel target of LKB1. LKB1 knockdown in HPASMCs cultured under hypoxic conditions increased BMP4 protein level and HPASMC proliferation and migration. The co-immunoprecipitation analysis revealed that LKB1 directly modulates BMP4 protein degradation through phosphorylation. Therapeutically, suppressing BMP4 expression in SMCs alleviates PH in LKB1SMKO mice. Our findings demonstrate that LKB1 attenuates PH by enhancing the lysosomal degradation of BMP4, thus suppressing the proliferation and migration of HPASMCs. Modulating LKB1-BMP4 axis in SMC could be a promising therapeutic strategy of PH.

Case report: heart failure related to intravitreal injection of anti-VEGF.

BACKGROUND: Intravitreal injection of anti-vascular endothelial growth factor is considered the first-line treatment for polypoidal choroidal vasculopathy. It has potential risks for circulatory system, which should be particularly carefully evaluated in older patients. In this case study, we aim to discuss the potential impact of this treatment regimen on cardiac health. CASE PRESENTATION: This case report describes an elderly patient with no prior history of heart disease who exhibited unexpected heart enlargement and dysfunction. Throughout the patient's hospital stay, various potential causes were investigated, leading to the hypothesis that a 10-year history of intravitreal injections of anti-vascular endothelial growth factor could be related to the observed clinical manifestations. The patient was advised to discontinue this treatment, and after a 2-month follow-up period, there was a gradual improvement in the patient's cardiac structure and function. CONCLUSION: This manuscript highlights the importance of conducting cardiac examinations before and after anti-vascular endothelial growth factor treatment, especially for individuals at risk of heart diseases like the elderly. It emphasizes the need to carefully weigh the benefits and risks of treatment regimens to ensure optimal therapeutic outcomes.

One-Pot Total Synthesis of Natural Products Nitramarine, Nitraridine, and Analogues via a Cascade Oxidation/Pictet-Spengler Condensation/Annulation Process.

A cascade oxidation/Pictet-Spengler condensation/annulation process has been developed for the one-pot total synthesis of nitramarine, nitraridine, and their analogues. The procedure proceeded with easily available quinolines and tryptophan derivatives. A simple and metal-free approach, wide substrate scope, and functional group tolerance make it applicable for the synthesis of diverse bioactive nitramarine, nitraridine, and their derivatives. Furthermore, the bioactivity evaluation has identified two promising leading compounds 5d and 5e with potent antitumor proliferative activity against breast cancer cells.

Reclaiming Selenium from Water Using Aluminum-Modified Biochar: Adsorption Behaviors, Mechanisms, and Effects on Growth of Wheat Seedlings.

Although selenium is an essential nutrient, its contamination in water poses serious risks to human health and ecosystems. In this study, aluminum-modified bamboo biochar (Al-BC) was developed to reclaim Se(VI) from water. Compared to pristine biochar (BC), Al-BC had a larger specific surface area (176 m2/g) and pore volume (0.180 cm³/g). The modification, achieved by loading AlOOH and Al2O3 particles onto the surface, enabled Al-BC to achieve a maximum adsorption capacity of 37.6 mg/g for Se(VI) within 2 hours and remove 99.6% of Se(VI) across a pH range of 3-10. The main adsorption mechanism of Se(VI) involved electrostatic attraction, forming outer-sphere complexes between Se(VI) and AlOOH sites on the biochar. The bioavailability of Se sorbed on the spent biochar (Al-BC-Se) was thus evaluated. It was discovered that Al-BC-Se successfully released Se(VI), which impacted the growth of wheat seedlings. The Se content reached 134 µg/g dry weight (DW) in wheat shoots and 638 µg/g DW in roots, significantly exceeding normal selenium content (<40 µg/g DW). By successfully applying the modified biochar to capture selenium from water through adsorption and then reusing it as an essential nutrient in soil, this study suggests the promising feasibility of the "removal-collection-reuse" approach for the circular economy of selenium in wastewater.

Identification of NR3C2 as a functional diagnostic and prognostic biomarker and potential therapeutic target in non-small cell lung cancer.

Background: Non-small cell lung cancer (NSCLC), including the lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) subtypes, is a malignant tumor type with a poor 5-year survival rate. The identification of new powerful diagnostic biomarkers, prognostic biomarkers, and potential therapeutic targets in NSCLC is urgently required. Methods: The UCSC Xena, UALCAN, and GEO databases were used to screen and analyze differentially expressed genes, regulatory modes, and genetic/epigenetic alterations in NSCLC. The UCSC Xena database, GEO database, tissue microarray, and immunohistochemistry staining analyses were used to evaluate the diagnostic and prognostic values. Gain-of-function assays were performed to examine the roles. The ESTIMATE, TIMER, Linked Omics, STRING, and DAVID algorithms were used to analyze potential molecular mechanisms. Results: NR3C2 was identified as a potentially important molecule in NSCLC. NR3C2 is expressed at low levels in NSCLC, LUAD, and LUSC tissues, which is significantly related to the clinical indexes of these patients. Receiver operating characteristic curve analysis suggests that the altered NR3C2 expression patterns have diagnostic value in NSCLC, LUAD, and especially LUSC patients. Decreased NR3C2 expression levels can help predict poor prognosis in NSCLC and LUAD patients but not in LUSC patients. These results have been confirmed both with database analysis and real-world clinical samples on a tissue microarray. Copy number variation contributes to low NR3C2 expression levels in NSCLC and LUAD, while promoter DNA methylation is involved in its downregulation in LUSC. Two NR3C2 promoter methylation sites have high sensitivity and specificity for LUSC diagnosis with clinical application potential. NR3C2 may be a key participant in NSCLC development and progression and is closely associated with the tumor microenvironment and immune cell infiltration. NR3C2 co-expressed genes are involved in many cancer-related signaling pathways, further supporting a potentially significant role of NR3C2 in NSCLC. Conclusions: NR3C2 is a novel potential diagnostic and prognostic biomarker and therapeutic target in NSCLC.

Intensive Surveillance of Porcine-Rhesus Kidney Xenotransplant Using Different Ultrasound Techniques.

BACKGROUND: Significant progress has been made in kidney xenotransplantation in the past few years, and this field is accelerating towards clinical translation. Therefore, surveillance of the xenograft with appropriate tools is of great importance. Ultrasonography has been widely used in kidney allotransplantation and served as an economical and non-invasive method to monitor the allograft. However, questions remain whether the ultrasonographic criteria established for human kidney allograft could also be applied in xenotransplantation. METHODS: In the current study, we established a porcine-rhesus life sustaining kidney xenotransplantation model. The xenograft underwent intensive surveillance using gray-scale, colorful Doppler ultrasound as well as 2D shear wave elastography. The kidney growth, blood perfusion, and cortical stiffness were measured twice a day. These parameters were compared with the clinical data including urine output, chemistry, and pathological findings. RESULTS: The observation continued for 16 days after transplantation. Decline of urine output and elevated serum creatinine were observed on POD9 and biopsy proven antibody-mediated rejection was seen on the same day. The xenograft underwent substantial growth, with the long axis length increased by 32% and the volume increased by threefold at the end of observation. The resistive index of the xenograft arteries elevated in response to rejection, together with impaired cortical perfusion, while the peak systolic velocity (PSV) was not compromised. The cortical stiffness also increased along with rejection. CONCLUSION: In summary, the ultrasound findings of kidney xenograft shared similarities with those in allograft but possessed some unique features. A modified criteria needs to be established for further application of ultrasound in kidney xenotransplantation.

SLC7A2-Mediated Lysine Catabolism Inhibits Immunosuppression in Triple Negative Breast Cancer.

Breast cancer is one of the most common malignant tumors worldwide. SLC7A2 is abnormally expressed in multiple cancers. However, its potential in triple negative breast cancer (TNBC) is still unclear. The purpose of this study was to investigate the roles of SLC7A2 and its underlying molecular mechanisms in TNBC. mRNA expression was detected by RT-qPCR. Protein expression was detected by western blot. Co-localization of ACOX1 and TCF1 was determined using FISH assay. Histone crotonylation was performed using in vitro histone crotonylation assay. Functional analysis was performed using CCK-8 and flow cytometry assays. Xenograft assay was conducted to further verify the role of SLC7A2 in TNBC. CD8A expression was detected using immunohistochemistry. We found that SLC7A2 is downregulated in TNBC tumors. Low levels are associated with advanced stages and lymph node metastasis. SLC7A2 expression is positively correlated with CD8A. SLC7A2-mediated lysine catabolism drives the activation of CD8+ T cells. Moreover, SLC7A2 promotes histone crotonylation via upregulating ACOX1. It also promotes interaction between ACOX1 and TCF1, thus promoting antitumor T cell immunity. Additionally, overexpression of SLC7A2 activates CD8+ T cells and enhances the chemosensitivity of anti-PD-1 therapies in vivo. In conclusion, SLC7A2 may function as an antitumor gene in TNBC by activating antitumor immunity, suggesting SLC7A2/ACOX1/TCF1 signaling as a promising therapeutic strategy.

NSUN2/YBX1 promotes the progression of breast cancer by enhancing HGH1 mRNA stability through m5C methylation.

BACKGROUND: RNA m5C methylation has been extensively implicated in the occurrence and development of tumors. As the main methyltransferase, NSUN2 plays a crucial regulatory role across diverse tumor types. However, the precise impact of NSUN2-mediated m5C modification on breast cancer (BC) remains unclear. Our study aims to elucidate the molecular mechanism underlying how NSUN2 regulates the target gene HGH1 (also known as FAM203) through m5C modification, thereby promoting BC progression. Additionally, this study targets at preliminarily clarifying the biological roles of NSUN2 and HGH1 in BC. METHODS: Tumor and adjacent tissues from 5 BC patients were collected, and the m5C modification target HGH1 in BC was screened through RNA sequencing (RNA-seq) and single-base resolution m5C methylation sequencing (RNA-BisSeq). Methylation RNA immunoprecipitation-qPCR (MeRIP-qPCR) and RNA-binding protein immunoprecipitation-qPCR (RIP-qPCR) confirmed that the methylation molecules NSUN2 and YBX1 specifically recognized and bound to HGH1 through m5C modification. In addition, proteomics, co-immunoprecipitation (co-IP), and Ribosome sequencing (Ribo-Seq) were used to explore the biological role of HGH1 in BC. RESULTS: As the main m5C methylation molecule, NSUN2 is abnormally overexpressed in BC and increases the overall level of RNA m5C. Knocking down NSUN2 can inhibit BC progression in vitro or in vivo. Combined RNA-seq and RNA-BisSeq analysis identified HGH1 as a potential target of abnormal m5C modifications. We clarified the mechanism by which NSUN2 regulates HGH1 expression through m5C modification, a process that involves interactions with the YBX1 protein, which collectively impacts mRNA stability and protein synthesis. Furthermore, this study is the first to reveal the binding interaction between HGH1 and the translation elongation factor EEF2, providing a comprehensive understanding of its ability to regulate transcript translation efficiency and protein synthesis in BC cells. CONCLUSIONS: This study preliminarily clarifies the regulatory role of the NSUN2-YBX1-m5C-HGH1 axis from post-transcriptional modification to protein translation, revealing the key role of abnormal RNA m5C modification in BC and suggesting that HGH1 may be a new epigenetic biomarker and potential therapeutic target for BC.

Macrophage-derived CD36 + exosome subpopulations as novel biomarkers of Candida albicans infection.

Invasive candidiasis (IC) is a notable healthcare-associated fungal infection, characterized by high morbidity, mortality, and substantial treatment costs. Candida albicans emerges as a principal pathogen in this context. Recent academic advancements have shed light on the critical role of exosomes in key biological processes, such as immune responses and antigen presentation. This burgeoning body of research underscores the potential of exosomes in the realm of medical diagnostics and therapeutics, particularly in relation to fungal infections like IC. The exploration of exosomal functions in the pathophysiology of IC not only enhances our understanding of the disease but also opens new avenues for innovative therapeutic interventions. In this investigation, we focus on exosomes (Exos) secreted by macrophages, both uninfected and those infected with C. albicans. Our objective is to extract and analyze these exosomes, delving into the nuances of their protein compositions and subgroups. To achieve this, we employ an innovative technique known as Proximity Barcoding Assay (PBA). This methodology is pivotal in our quest to identify novel biological targets, which could significantly enhance the diagnostic and therapeutic approaches for C. albicans infection. The comparative analysis of exosomal contents from these two distinct cellular states promises to yield insightful data, potentially leading to breakthroughs in understanding and treating this invasive fungal infection. In our study, we analyzed differentially expressed proteins in exosomes from macrophages and C. albicans -infected macrophages, focusing on proteins such as ACE2, CD36, CAV1, LAMP2, CD27, and MPO. We also examined exosome subpopulations, finding a dominant expression of MPO in the most prevalent subgroup, and a distinct expression of CD36 in cluster14. These findings are crucial for understanding the host response to C. albicans and may inform targeted diagnostic and therapeutic approaches. Our study leads us to infer that MPO and CD36 proteins may play roles in the immune escape mechanisms of C. albicans. Additionally, the CD36 exosome subpopulations, identified through our analysis, could serve as potential biomarkers and therapeutic targets for C. albicans infection. This insight opens new avenues for understanding the infection's pathology and developing targeted treatments.

Aggregation-Augmented Magnetism of Lanthanide-Doped Nanoparticles and Enabling Magnetic Levitation-Based Exosome Sensing.

Due to the presence of unpaired electron orbitals in most lanthanide ions, lanthanide-doped nanoparticles (LnNPs) exhibit paramagnetism. However, as to biosensing applications, the magnetism of LnNPs is so weak that can hardly be employed in target separation. Herein, it is discovered that the magnetism of the LnNPs is highly associated with their concentration in a confined space, enabling aggregation-augmented magnetism to make them susceptive to a conventional magnet. Accordingly, a magnetic levitation (Maglev) sensing system is designed, in which the target exosomes can specifically introduce paramagnetic LnNPs to the microbeads' surface, allowing aggregation-augmented magnetism and further leverage the microbeads' levitation height in the Maglev device to indicate the target exosomes' content. It is demonstrated that this Maglev system can precisely distinguish healthy people's blood samples from those of breast cancer patients. This is the first work to report that LnNPs hold great promise in magnetic separation-based biological sample sorting, and the LnNP-permitted Maglev sensing system is proven to be promising for establishing a new generation of biosensing devices.

Amphiphilic Polymer Electrolyte Blocking Lattice Oxygen Evolution from High-Voltage Nickel-rich Cathodes for Ultra-Thermal Stabile Batteries.

Ni-rich cathodes have been intensively adopted in Li-ion batteries to pursuit high energy density, which still suffering irreversible degradation at high voltage. Some unstable lattice O2- species in Ni-rich cathodes would be oxidized to singlet oxygen 1O2 and released at high volt, which lead to irreversible phase transfer from the layered rhombohedral (R) phase to a spinel-like (S) phase. To overcome the issue, the amphiphilic copolymers (UMA-Fx) electrolyte were prepared by linking hydrophobic C-F side chains with hydrophilic subunits, which could self-assemble on Ni-rich cathode surface and convert to stable cathode-electrolyte interphase layer. Thereafter, the oxygen releasing of polymer coated cathode was obviously depressed and substituted by the Co oxidation (Co3+→Co4+) at high volt (>4.2 V), which could suppressed irreversible phase transfer and improve cycling stability. Moreover, the amphiphilic polymer electrolyte was also stable with Li anode and had high ion conductivity. Therefore, the NCM811//UMA-F6//Li pouch cell exhibited outstanding energy density (362.97 Wh/kg) and durability (cycled 200 times at 4.7 V), which could be stalely cycled even at 120°C without short circuits or explosions.

FGF1 attenuates sepsis-induced coagulation dysfunction and hepatic injury via IL6/STAT3 pathway inhibition.

BACKGROUND & AIMS: Sepsis, a globally prevalent and highly lethal condition, remains a critical medical challenge. This investigation aims to assess the relevance of FGF1 as a potential therapeutic target for sepsis. METHODS: Sepsis was induced in C57BL/6 mice through LPS administration to establish an in vivo animal model. Various in vitro assays were conducted using human umbilical vein endothelial cells to elucidate the role of FGF1 in the disruption of the coagulation system and liver injury associated with sepsis, as well as to explore its underlying molecular mechanisms. RESULTS: In in vivo experiments, FGF1 ameliorated coagulation system disruption in septic mice by reducing the levels of pro-inflammatory and coagulation-related factors in the bloodstream. FGF1 also enhanced liver function in septic mice, mitigating liver inflammation and cell apoptosis, fostering liver vascular regeneration, increasing liver blood perfusion, and improving mouse survival. In vitro experiments demonstrated that FGF1 could inhibit LPS-induced inflammatory responses and apoptosis in endothelial cells, fortify endothelial cell barrier function, decrease endothelial cell permeability, promote endothelial cell proliferation, and restore endothelial cell tube-forming ability. Both in vivo and in vitro experiments substantiated that FGF1 improved sepsis by inhibiting the IL-6/STAT3 signaling pathway. CONCLUSION: In summary, our study indicates that FGF1 mitigates excessive inflammatory responses in sepsis by suppressing the IL-6/STAT3 signaling pathway, thereby improving systemic blood circulation and ameliorating liver damage in septic organisms. Consequently, this research identifies FGF1 as a potential clinical target for the treatment of human sepsis.

Adipose mesenchymal stem cells-derived exosomes attenuated hyperoxia-induced lung injury in neonatal rats via inhibiting the NF-κB signaling pathway.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is the most common chronic morbidity in extremely preterm infants. Mesenchymal stem cells-derived exosomes (MSC-Exos) therapies have shown prospects in animal models of BPD. Our study aimed to evaluate the effect of adipose mesenchymal stem cells-derived exosomes (AMSC-Exos) on BPD and the role of the NF-κB signaling pathway in this process. METHODS: The AMSCs were extracted and AMSC-Exos were isolated by ultracentrifugation method. Newborn rats were exposed to hyperoxia (90% O2) continuously for 7 days to establish a BPD model. The rats were treated with AMSC-Exos by intratracheal administration on postnatal day 4 (P4). Pulmonary morphology, pulmonary vasculature, inflammatory factors, and NF-κB were assessed. Hyperoxia-induced primary type II alveolar epithelial cells (AECIIs) and AMSC-Exos treatment with or without a pan-NF-κB inhibitor (PDTC) were established to explore the potential mechanism. RESULTS: Hyperoxia-exposed rats showed alveolar simplification with decreased radial alveolar count and increased mean linear intercept, low CD31, and vascular endothelial growth factor expression, reduced microvessel density, increased the expression of TNF-α, IL-1ß, and IL-6 and decreased the expression of IL-10, and induced NF-κB phosphorylation. AMSC-Exos protected the neonatal lung from the hyperoxia-induced arrest of alveolar and vascular development, alleviated inflammation, and inhibited NF-κB phosphorylation. Hyperoxia decreased viability, increased apoptosis, enhanced inflammation, and induced NF-κB phosphorylation of AECIIs but improved by AMSC-Exos, PDTC, or AMSC-Exos+PDTC. The effect of AMSC-Exos+PDTC in AECIIs was the same as AMSC-Exos, but more notable than PDTC alone. CONCLUSION: AMSC-Exos attenuated the hyperoxia-induced lung injury in neonatal rats by inhibiting the NF-κB signaling pathway partly.

Performance and application of the total-body PET/CT scanner: a literature review.

BACKGROUND: The total-body positron emission tomography/computed tomography (PET/CT) system, with a long axial field of view, represents the state-of-the-art PET imaging technique. Recently, the total-body PET/CT system has been commercially available. The total-body PET/CT system enables high-resolution whole-body imaging, even under extreme conditions such as ultra-low dose, extremely fast imaging speed, delayed imaging more than 10 h after tracer injection, and total-body dynamic scan. The total-body PET/CT system provides a real-time picture of the tracers of all organs across the body, which not only helps to explain normal human physiological process, but also facilitates the comprehensive assessment of systemic diseases. In addition, the total-body PET/CT system may play critical roles in other medical fields, including cancer imaging, drug development and immunology. MAIN BODY: Therefore, it is of significance to summarize the existing studies of the total-body PET/CT systems and point out its future direction. This review collected research literatures from the PubMed database since the advent of commercially available total-body PET/CT systems to the present, and was divided into the following sections: Firstly, a brief introduction to the total-body PET/CT system was presented, followed by a summary of the literature on the performance evaluation of the total-body PET/CT. Then, the research and clinical applications of the total-body PET/CT were discussed. Fourthly, deep learning studies based on total-body PET imaging was reviewed. At last, the shortcomings of existing research and future directions for the total-body PET/CT were discussed. CONCLUSION: Due to its technical advantages, the total-body PET/CT system is bound to play a greater role in clinical practice in the future.

Unique immunohistochemical profiles of MUC5AC, MUC6, P53, and Ki67 in gastric atypical hyperplasia and dysplasia.

OBJECTIVES: Differentiating gastric atypical hyperplasia (AH) from dysplasia, including low-grade dysplasia (LGD) and high-grade dysplasia (HGD), poses significant challenges in small biopsies and specimens with technical artifacts. This study aims to establish objective diagnostic criteria for these conditions through combined morphologic and immunohistochemical (IHC) analyses. METHODS: Between January 2018 and September 2020, a total of 123 gastric mucosa biopsy specimens were collected at Anyang Tumor Hospital. According to the WHO Classification of Digestive System Tumors (5th edition), specimens were categorized into three groups: AH (n=48), LGD (n=30), and HGD (n=45). Morphologic characteristics were assessed, and IHC staining for MUC5AC, MUC6, MUC2, CD10, P53, and Ki67 was performed, followed by statistical analysis. RESULTS: Histologically, AH was predominantly marked by a pronounced inflammatory background (60.42%), intestinal metaplasia (64.58%), indistinct boundaries (83.33%), and a distinct maturation gradient (97.72%). AH nuclei were typically circular (97.92%), with a high nucleus-to-cytoplasm ratio (64.58%), prominent nucleoli (47.92%), and preserved polarity (89.58%). In contrast, LGD and HGD typically exhibited well-defined boundaries with an absent maturation gradient. LGD nuclei were rod-shaped (96.67%), with a low nucleus-to-cytoplasm ratio (96.67%) and preserved polarity (100%), whereas HGD demonstrated a loss of cellular polarity (77.78%). IHC findings revealed a consistent maturation gradient in AH, with polarized MUC5AC and MUC6 expression, significantly reduced in LGD (86.67%), and absent in HGD. P53 expression in HGD showed a predominant 'mutation-type pattern' (66.67%), contrasting with 'wild-type pattern' expression in AH and LGD (100%, 93.33%). Ki67 expression patterns varied from a 'pit neck pattern' in AH (95.83%) to a 'polarity pattern' in LGD (76.67%) and a 'diffuse pattern' in HGD (57.78%). The expression patterns of MUC5AC, MUC6, CD10, P53, and Ki67 varied significantly across the three groups (P<0.001). CONCLUSIONS: The integration of histomorphological features and expression profiles of MUC5AC, MUC6, P53, and Ki67 is instrumental in diagnosing gastric atypical hyperplasia and dysplasia.

Iron Metabolic Biomarkers and the Mortality Risk in the General Population: A Nationwide Population-Based Cohort Study.

Context: Iron is an essential element in the human body and plays a critical role in many physiological and cellular processes. However, the association between iron status and the risk of all-cause or cause-specific mortality has not been well-investigated. And it is unclear whether the association between iron metabolic biomarkers and the risk of mortality differs between people with and without diabetes mellitus (DM). Objective: This work aimed to investigate associations between iron metabolic biomarkers and all-cause and cause-specific mortality risk in the general population, and heterogeneities in the associations among population with and without DM.. Methods: A total of 29 166 adults from the National Health and Nutrition Examination Survey (NHANES) III and NHANES 1999 to 2010 were included, with linkage to the National Death Index to December 31, 2019. Cox proportional-hazard models and Fine-Gray subdistribution hazard models were used to estimate associations between iron metabolic biomarkers and outcomes. Results: During a median follow-up of 18.83 years, 9378 deaths were observed, including 3420 cardiovascular disease (CVD) deaths and 1969 cancer deaths. A significant linear association between serum ferritin (SF) and all-cause mortality was observed among the overall population and those without DM. J-shaped associations between transferrin saturation (TSAT) and all-cause and CVD mortality were observed among all populations. In the overall population, compared to the first quartile (Q1) group, the adjusted hazard ratio (HR) (95% CI) for all-cause mortality was 1.07 (1.00-1.15), 1.05 (0.98-1.12), 1.13 (1.05-1.21) in Q2, Q3, and Q4 groups for SF, while the HR was 0.94 (0.88-0.99), 0.92 (0.86-0.97), and 0.93 (0.88-0.99) for TSAT. In individuals without DM, the adjusted HR of the Q4 of SF were 1.19 (1.03-1.37) for CVD mortality and 1.25 (1.05-1.48) for cancer mortality. In individuals with DM, the adjusted HRs of the Q4 of TSAT were 0.76 (0.62-0.93) for CVD mortality and 1.47 (1.07-2.03) for cancer mortality. Conclusion: Iron metabolism abnormalities increase mortality risk in the general population. The associations of iron status with mortality were significantly different between individuals with and without DM, which indicated tailored strategies for iron homeostasis are needed.

CircALMS1 Alleviates Pulmonary Microvascular Endothelial Cell Dysfunction in Pulmonary Hypertension.

BACKGROUND: Circular RNAs can serve as regulators influencing the development of pulmonary hypertension (PH). However, their function in pulmonary vascular intimal injury remains undefined. Thus, we aimed to identify specifically expressed circular RNAs in pulmonary microvascular endothelial cells (PMECs) under hypoxia and PH. METHODS AND RESULTS: Deep RNA sequencing and quantitative real-time polymerase chain reaction revealed that circALMS1 (circular RNA Alstrom syndrome protein 1) was reduced in human PMECs under hypoxia (P<0.0001). Molecular biology and histopathology experiments were used to elucidate the roles of circALMS1 in regulating PMEC dysfunction among patients with PH. The circALMS1 expression was decreased in the plasma of patients with PH (P=0.0315). Patients with lower circALMS1 levels had higher risk of death (P=0.0006). Moreover, the circALMS1 overexpression of adeno-associated viruses improved right ventricular function and reduced pulmonary vascular remodeling in monocrotaline-PH and sugen/hypoxia-PH rats (P<0.05). Furthermore, circALMS1 overexpression promoted apoptosis and inhibited PMEC proliferation and migration under hypoxia by directly downregulating miR-17-3p (P<0.05). Dual luciferase assay confirmed the direct binding of circALMS1 to miR-17-3p and miR-17-3p binding to its target gene YT521-B homology domain-containing family protein 2 (YTHDF2) (P<0.05). The YTHDF2 levels were also downregulated in hypoxic PMECs (P<0.01). The small interfering RNA YTHDF2 reversed the effects of miR-17-3p inhibitors on PMEC proliferation, migration, and apoptosis. Finally, the results indicated that, although YTHDF2, as an N(6)-methyladenosine reader protein, contributes to the degradation of many circular RNAs, it could not regulate the circALMS1 levels in PMECs (P=0.9721). CONCLUSIONS: Our study sheds new light on circALMS1-regulated dysfunction of PMECs by the miR-17-3p/YTHDF2 pathway under hypoxia and provides insights into the underlying pathogenesis of PH.

Ultrasensitive protein and exosome analysis based on a rolling circle amplification assisted-CRISPR/Cas12a strategy.

CRISPR/Cas12a system has attracted extensive concern in biosensing due to its high specificity and programmability. Nevertheless, existing Cas12a-based assays mainly focus on nucleic acid detection and have limitations in non-nucleic acid biomarker analysis. To broaden the application prospect of the CRISPR/Cas technology, a cascade Cas12a biosensing platform is reported by combining dual-functionalized gold nanoparticles (FGNPs)-assisted rolling circle amplification (RCA) and Cas12a trans-cleavage activity (GAR-Cas) for ultrasensitive protein and exosome analysis. FGNPs serve as a critical component in the transduction of protein or exosome recognition information into nucleic acid amplification events to produce Cas12a activators. In the GAR-Cas assay, by integrating the triple cascade amplification of FGNPs-assisted transduction, RCA, and Cas12a signal amplification, ultralow abundance of target molecules can arouse numerous concatemers to activate Cas12a trans-cleavage activity to release intense fluorescence, allowing the ultrasensitive detection of as low as 1 fg/mL (∼41 aM) cTnI and 5 exosomes per µL. Furthermore, the presented strategy can be applied to detect exosome levels from clinical samples, showing excellent performance in distinguishing cancer patients from healthy individuals. The GAR-Cas sensing platform exhibits great potential in clinical diagnosis and enlarges biosensing toolboxes based on CRISPR/Cas technology for non-nucleic acid target analysis.

FDG Uptake Caused by Right Varicocele.

ABSTRACT: A 67-year-old man underwent 18 F-FDG PET/CT for lung cancer staging. Interestingly, the PET scan revealed strip-shaped FDG uptake in the right inguinal contoured area, which was later confirmed as a right varicocele through ultrasound imaging.

Ultrasound contrast agent assisted ultrasonography guidance percutaneous nephrostomy for non-hydronephrotic kidney.

BACKGROUND: Given the limited success rate and considerable challenges associated with conventional ultrasonography (US) guidance for percutaneous nephrostomy (PCN) in non-hydronephrotic kidneys, this study proposed a solution with ultrasound contrast agent to enhance the success rate and mitigate the difficulties. MATERIALS AND METHODS: From January 2017 to August 2023, a total of thirteen patients diagnosed with non-hydronephrotic kidney were included in the study. Following routine ultrasonography examination, no significant dilatation of the renal collecting system was observed. US-guided percutaneous nephrostomy PCN was performed with the assistance of ultrasound contrast agent (UCA). The patients were subsequently monitored to assess the improvement of symptoms and postoperative recovery. RESULTS: The success rate was found to be 100% for all patients (13/13) and kidneys (20/20). The average volume of UCA solution used was 19 ± 6.7 mL (range, 11-35 mL), while the mean duration of the operation was 18.92 ± 8.96 min (range, 7-36 min). A majority of the patients (12/13) underwent a single puncture procedure. Throughout the follow-up period, no serious complications were observed, and surgery resulted in significant alleviation of symptoms in all patients. CONCLUSION: The use of UCA-assisted US guidance PCN has been shown to be effective in achieving urinary diversion and alleviating associated clinical symptoms in non-hydronephrotic kidneys. In comparison to traditional methods, this approach demonstrates a high success rate and safety profile, while also offering a simplified operative procedure. Consequently, it presents a novel method and concept for managing non-hydronephrotic kidneys afflicted by urine leakage.