Establishment and verification of a prediction model based on clinical characteristics and computed tomography radiomics parameters for distinguishing benign and malignant pulmonary nodules.

Background: The radiographic classification of pulmonary nodules into benign versus malignant categories is a pivotal component of early lung cancer diagnosis. The present study aimed to investigate clinical and computed tomography (CT) clinical-radiomics nomogram for preoperative differentiation of benign and malignant pulmonary nodules. Methods: This retrospective study included 342 patients with pulmonary nodules who underwent high-resolution CT (HRCT) examination. We assigned them to a training dataset (n=239) and a validation dataset (n=103). There are 1781 tumor characteristics quantified by extracted features from the lesion segmented from patients' CT images. The features with poor reproducibility and high redundancy were removed. Then a least absolute shrinkage and selection operator (LASSO) logistic regression model with 10-fold cross-validation was used to further select features and build radiomics signatures. The independent predictive factors were identified by multivariate logistic regression. A radiomics nomogram was developed to predict the malignant probability. The performance and clinical utility of the clinical-radiomics nomogram was evaluated by receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). Results: After dimension reduction by the LASSO algorithm and multivariate logistic regression, four radiomic features were selected, including original_shape_Sphericity, exponential_glcm_Maximum Probability, log_sigma_2_0_mm_3D_glcm_Maximum Probability, and ogarithm_firstorder_90Percentile. Multivariate logistic regression showed that carcinoembryonic antigen (CEA) [odds ratio (OR) 95% confidence interval (CI): 1.40 (1.09-1.88)], CT rad score [OR (95% CI): 2.74 (2.03-3.85)], and cytokeratin-19-fragment (CYFRA21-1) [OR (95% CI): 1.80 (1.14-2.94)] were independent influencing factors of malignant pulmonary nodule (all P<0.05). The clinical-radiomics nomogram combining CEA, CYFRA21-1 and radiomics features achieved an area of curve (AUC) of 0.85 and 0.76 in the training group and verification group for the prediction of malignant pulmonary nodules. The clinical-radiomics nomogram demonstrated excellent agreement and practicality, as evidenced by the calibration curve and DCA. Conclusions: The clinical-radiomics nomogram combined of CT-based radiomics signature, along with CYFRA21-1 and CEA, demonstrated strong predictive ability, calibration, and clinical usefulness in distinguishing between benign and malignant pulmonary nodules. The use of CT-based radiomics has the potential to assist clinicians in making informed decisions prior to biopsy or surgery while avoiding unnecessary treatment for non-cancerous lesions.

The Application of Drugs and Nano-Therapies Targeting Immune Cells in Hypoxic Inflammation.

Immune cells are pivotal in the dynamic interplay between hypoxia and inflammation. During hypoxic conditions, HIF-1α, a crucial transcription factor, facilitates the adaptation of immune cells to the hypoxic micro-environment. This adaptation includes regulating immune cell metabolism, significantly impacting inflammation development. Strategies for anti-inflammatory and hypoxic relief have been proposed, aiming to disrupt the hypoxia-inflammation nexus. Research extensively focuses on anti-inflammatory agents and materials that target immune cells. These primarily mitigate hypoxic inflammation by encouraging M2-macrophage polarization, restraining neutrophil proliferation and infiltration, and maintaining Treg/TH17 balance. Additionally, oxygen-releasing nano-materials play a significant role. By alleviating hypoxia and clearing reactive oxygen species (ROS), these nano-materials indirectly influence immune cell functions. This paper delves into the response of immune cells under hypoxic conditions and the resultant effects on inflammation. It provides a comprehensive overview of various therapies targeting specific immune cells for anti-inflammatory purposes and explores nano-materials that either carry or generate oxygen to alleviate anoxic micro-environments.

Highly stretchable graphene kirigami with tunable mechanical properties.

In recent years, kirigami techniques have inspired the design of graphene-based nanodevices with exceptional stretchability and ductility. Based on an I-shaped cutting pattern, here we propose a graphene kirigami that exhibits remarkable stretchability and ductility in two independent planar directions along with negative Poisson's ratios. The deformation mechanism underlying the high stretchability of the structure is the flipping and rotation of its cutting ligaments during elongation. Molecular dynamics simulations show that the yield and fracture strains of graphene kirigami can be enhanced by factors of 6 and 10 in the two planar directions. In addition, the mechanical properties of the graphene kirigami can be tuned by altering the cutting geometric parameters as well as incorporating distinct cutting patterns in series. We develop a numerical algorithm to predict the stress-strain response of the series-connected graphene kirigami, and verify its accuracy using appropriate simulations. On this basis, the stress-strain response of the series-connected graphene kirigami can be tuned by altering its geometric parameters and the number of building blocks. This graphene kirigami could be applied to the design and development of next-generation flexible electronics such as stretchable electrodes and strain sensors.

Foxq1 Promotes Alveolar Epithelial Cell Death through Tle1-mediated Inhibition of the NFκB Signaling Pathway.

Acute lung injury is a common respiratory disease characterized by diffuse alveolar injury and interstitial edema, as well as a hyperinflammatory response, lung cell damage and oxidative stress. Foxq1, a member of the FOX family of transcription factors, is expressed in various tissues, such as the lungs, liver, and kidneys, and contributes to various biological processes, such as stress, metabolism, cell cycle arrest, and aging-related apoptosis. However, the role of Foxq1 in acute lung injury is unknown. We constructed ex vivo and in vivo acute lung injury models by lipopolysaccharide tracheal perfusion of ICR mice and conditioned medium stimulation of injured MLE-12 cells. Foxq1 expression was increased, and its localization was altered in our acute lung injury model. In normal or injured MLE-12 cells, knockdown of Foxq1 promoted cell survival, and overexpression had the opposite effect. This regulatory effect was likely mediated by Tle1 and the NFκB/Bcl2/Bax signaling pathway. These data suggest a potential link between Foxq1 and acute lung injury, indicating that Foxq1 can be used as a biomarker for the diagnosis of acute lung injury. Targeted inhibition of Foxq1 expression could promote alveolar epithelial cell survival and may provide a strategy for mitigating acute lung injury.

CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia.

Resistance to glucocorticoids (GCs), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-of-function experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GCresistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GCs against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

Systemic immune-inflammation index as a novel predictor of major adverse cardiovascular events in patients undergoing percutaneous coronary intervention: a meta-analysis of cohort studies.

BACKGROUND: The Systemic Immune-Inflammation Index (SII), a novel marker of inflammation based on neutrophil, platelet, and lymphocyte counts, has demonstrated potential prognostic value in patients undergoing percutaneous coronary intervention (PCI). Our aim was to assess the correlation between the SII and major adverse cardiovascular events following percutaneous coronary intervention. METHODS: We searched PubMed, Web of Science, Embase, and The Cochrane Library from inception to November 20, 2023, for cohort studies investigating the association between SII and the occurrence of MACEs after PCI. Statistical analysis was performed using Revman 5.3, with risk ratios (RRs) and 95% confidence intervals (CIs) as relevant parameters. RESULTS: In our analysis, we incorporated a total of 8 studies involving 11,117 participants. Our findings revealed that a high SII is independently linked to a increased risk of MACEs in PCI patients (RR: 2.08,95%CI: 1.87-2.32, I2 = 42%, p < 0.00001). Additionally, we demonstrated the prognostic value of SII in all-cause mortality, heart failure, and non-fatal myocardial infarction. CONCLUSIONS: Elevated SII may serve as a potential predictor for subsequent occurrence of MACEs in patients undergoing PCI. TRIAL REGISTRATION: Our protocol was registered in PROSPERO (registration number: CRD42024499676).

Large-scale whole-exome sequencing of neuropsychiatric diseases and traits in 350,770 adults.

While numerous genomic loci have been identified for neuropsychiatric conditions, the contribution of protein-coding variants has yet to be determined. Here we conducted a large-scale whole-exome-sequencing study to interrogate the impact of protein-coding variants on 46 neuropsychiatric diseases and 23 traits in 350,770 adults from the UK Biobank. Twenty new genes were associated with neuropsychiatric diseases through coding variants, among which 16 genes had impacts on the longitudinal risks of diseases. Thirty new genes were associated with neuropsychiatric traits, with SYNGAP1 showing pleiotropic effects across cognitive function domains. Pairwise estimation of genetic correlations at the coding-variant level highlighted shared genetic associations among pairs of neurodegenerative diseases and mental disorders. Lastly, a comprehensive multi-omics analysis suggested that alterations in brain structures, blood proteins and inflammation potentially contribute to the gene-phenotype linkages. Overall, our findings characterized a compendium of protein-coding variants for future research on the biology and therapeutics of neuropsychiatric phenotypes.

Impaired meningeal lymphatic drainage in Listeria monocytogenes infection.

Previous studies have demonstrated an association between lymphatic vessels and diseases caused by bacterial infections. Listeria monocytogenes (LM) bacterial infection can affect multiple organs, including the intestine, brain, liver and spleen, which can be fatal. However, the impacts of LM infection on morphological and functional changes of lymphatic vessels remain unexplored. In this study, we found that LM infection not only induces meningeal and mesenteric lymphangiogenesis in mice, but also impairs meningeal lymphatic vessels (MLVs)-mediated macromolecules drainage. Interestingly, we found that the genes associated with lymphatic vessel development and function, such as Gata2 and Foxc2, were downregulated, suggesting that LM infection may affect cellular polarization and valve development. On the other hand, photodynamic ablation of MLVs exacerbated inflammation and bacterial load in the brain of mice with LM infection. Overall, our findings indicate that LM infection induces lymphangiogenesis and may affect cell polarization, cavity formation, and valve development during lymphangiogenesis, ultimately impairing MLVs drainage.

Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease.

INTRODUCTION: Although glymphatic function is involved in Alzheimer's disease (AD), its potential for predicting the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood. METHODS: Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS) in participants with AD dementia (n = 47), mild cognitive impairment (MCI; n = 137), and normal controls (n = 235) from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: ALPS index was significantly lower in AD dementia than in MCI or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy. DISCUSSION: Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD. HIGHLIGHTS: The analysis along the perivascular space (ALPS) index is reduced in patients with Alzheimer's disease (AD) dementia, prodromal AD, and preclinical AD. Lower ALPS index predicted accelerated amyloid beta (Aß) positron emission tomography (PET) burden and Aß-positive transition. The decrease in the ALPS index occurs before cerebrospinal fluid Aß42 reaches the positive threshold. ALPS index predicted brain atrophy, clinical progression, and cognitive decline. Aß PET and brain atrophy mediated the link of ALPS index with cognitive decline.

Identification and validation of prognostic and immunotherapeutic responses in esophageal squamous carcinoma based on hypoxia phenotype-related genes.

The study aimed to investigate the clinical significance of the interaction between hypoxia and the immune system in esophageal squamous cell carcinoma (ESCC) microenvironment. A comprehensive evaluation of 13 hypoxia phenotype-related genes (HPRs) was conducted using data from TCGA-ESCC and two GEO cohorts. Three distinct HPRclusters were identified, and the HPRscore was established as an independent prognostic factor (p = 0.001), with higher scores indicating poorer prognosis. The HPRscore was validated in various immunotherapy cohorts, demonstrating its efficacy in evaluating immunotherapy and chemotherapy outcomes. Additionally, phenome-wide association study (PheWAS) analysis showed that PKP1 had no significant correlation with other traits at the gene level. PKP1 was identified as a potential prognostic marker for ESCC, with upregulated expression observed in ESCC patients. In vitro experiments showed that the knockdown of PKP1 inhibited ESCC cell proliferation and migration. These findings suggest that the novel HPRscore and PKP1 may serve as prognostic tools and therapeutic targets for ESCC patients.

Overexpression of transcription factor FaMYB63 enhances salt tolerance by directly binding to the SOS1 promoter in Arabidopsis thaliana.

Salinity is a pivotal abiotic stress factor with far-reaching consequences on global crop growth, yield, and quality and which includes strawberries. R2R3-MYB transcription factors encompass a range of roles in plant development and responses to abiotic stress. In this study, we identified that strawberry transcription factor FaMYB63 exhibited a significant upregulation in its expression under salt stress conditions. An analysis using yeast assay demonstrated that FaMYB63 exhibited the ability to activate transcriptional activity. Compared with those in the wild-type (WT) plants, the seed germination rate, root length, contents of chlorophyll and proline, and antioxidant activities (SOD, CAT, and POD) were significantly higher in FaMYB63-overexpressing Arabidopsis plants exposed to salt stress. Conversely, the levels of malondialdehyde (MDA) were considerably lower. Additionally, the FaMYB63-overexpressed Arabidopsis plants displayed a substantially improved capacity to scavenge active oxygen. Furthermore, the activation of stress-related genes by FaMYB63 bolstered the tolerance of transgenic Arabidopsis to salt stress. It was also established that FaMYB63 binds directly to the promoter of the salt overly sensitive gene SOS1, thereby activating its expression. These findings identified FaMYB63 as a possible and important regulator of salt stress tolerance in strawberries.

Case Report: A case report of myocardial fibrosis activation assessment after unstable angina using 68Ga-FAPI-04 PET/CT.

Myocardial ischemia may induce myocardial fibrosis, a condition that progressively leads to ventricular remodeling, heightening the risk of heart failure. The timely detection of myocardial fibrosis is crucial for intervention and improved outcomes. 68Ga-FAPI-04 PET/CT shows promise in assessing fibroblast activation in patients with early myocardial infarction characterized by prolonged myocardial ischemia. However, there is a notable absence of data regarding patients with short-term myocardial ischemia, such as those experiencing unstable angina (UA). In this report, we evaluated a 49-year-old male with UA and severe stenosis in multiple coronary arteries using 68Ga-FAPI-04 PET/CT. The results demonstrated tracer-specific uptake (SUVmax = 4.6) in the left anterior descending artery (LAD) territory, consistent with myocardial anterior wall ischemia indicated by the electrocardiogram. Following vascular recanalization therapy and regular medication treatment, the patient remained free of angina recurrence. A subsequent review at 2 months revealed a significant reduction in myocardial tracer uptake (SUVmax = 1.8). This case illustrates the validity of 68Ga-FAPI-04 PET/CT in assessing the extent of early myocardial fibroblast activation in patients with UA. This approach offers valuable insights for early detection and visual evidence, providing information on disease progression and treatment response.

TiN as Radical Scavenger in Fe─N─C Aerogel Oxygen Reduction Catalyst for Durable Fuel Cell.

Fe─N─C is the most promising alternative to platinum-based catalysts to lower the cost of proton-exchange-membrane fuel cell (PEMFC). However, the deficient durability of Fe─N─C has hindered their application. Herein, a TiN-doped Fe─N─C (Fe─N─C/TiN) is elaborately synthesized via the sol-gel method for the oxygen-reduction reaction (ORR) in PEMFC. The interpenetrating network composed by Fe─N─C and TiN can simultaneously eliminate the free radical intermediates while maintaining the high ORR activity. As a result, the H2 O2 yields of Fe─N─C/TiN are suppressed below 4%, ≈4 times lower than the Fe─N─C, and the half-wave potential only lost 15 mV after 30 kilo-cycle accelerated durability test (ADT). In a H2 ─O2 fuel cell assembled with Fe─N─C/TiN, it presents 980 mA cm-2 current density at 0.6 V, 880 mW cm-2 peak power density, and only 17 mV voltage loss at 0.80 A cm-2 after 10 kilo-cycle ADT. The experiment and calculation results prove that the TiN has a strong adsorption interaction for the free radical intermediates (such as *OH, *OOH, etc.), and the radicals are scavenged subsequently. The rational integration of Fe single-atom, TiN radical scavenger, and highly porous network adequately utilize the intrinsic advantages of composite structure, enabling a durable and active Pt-metal-free catalyst for PEMFC.

TGR5 signalling in heart and brain injuries: focus on metabolic and ischaemic mechanisms.

The heart and brain are the core organs of the circulation and central nervous system, respectively, and play an important role in maintaining normal physiological functions. Early neuronal and cardiac damage affects organ function. The relationship between the heart and brain is being continuously investigated. Evidence-based medicine has revealed the concept of the "heart- brain axis," which may provide new therapeutic strategies for certain diseases. Takeda protein-coupled receptor 5 (TGR5) is a metabolic regulator involved in energy homeostasis, bile acid homeostasis, and glucose and lipid metabolism. Inflammation is critical for the development and regeneration of the heart and brain during metabolic diseases. Herein, we discuss the role of TGR5 as a metabolic regulator of heart and brain development and injury to facilitate new therapeutic strategies for metabolic and ischemic diseases of the heart and brain.

Theoretical Investigation of a Coumarin Fluorescent Probe for Distinguishing the Detection of Small-Molecule Biothiols.

Monitoring the level of biothiols in organisms would be beneficial for health inspections. Recently, 3-(2'-nitro vinyl)-4-phenylselenyl coumarin as a fluorescent probe for distinguishing the detection of the small-molecule biothiols cysteine/homocysteine (Cys/Hcy) and glutathione (GSH) was developed. By introducing 4-phenyselenium as the active site, the probe CouSeNO2/CouSNO2 was capable of detecting Cys/Hcy and GSH in dual fluorescence channels. Theoretical insights into the fluorescence sensing mechanism of the probe were provided in this work. The details of the electron excitation process in the probe and sensing products under optical excitation and the fluorescent character were analyzed using the quantum mechanical method. All these theoretical results would provide insight and pave the way for the molecular design of fluorescent probes for the detection of biothiols.

Construction of a g-C3N4/Bi(OH)3 Heterojunction for the Enhancement of Visible Light Photocatalytic Antibacterial Activity.

Photocatalytic technology has been recently conducted to remove microbial contamination due to its unique features of nontoxic by-products, low cost, negligible microbial resistance and broad-spectrum elimination capacity. Herein, a novel two dimensional (2D) g-C3N4/Bi(OH)3 (CNB) heterojunction was fabricated byincorporating Bi(OH)3 (BOH) nanoparticles with g-C3N4 (CN) nanosheets. This CNB heterojunction exhibited high photocatalytic antibacterial efficiency (99.3%) against Escherichia coli (E. coli) under visible light irradiation, which was 4.3 and 3.4 times that of BOH (23.0%) and CN (28.0%), respectively. The increase in specific surface area, ultra-thin layered structure, construction of a heterojunction and enhancement of visible light absorption were conducive to facilitating the separation and transfer of photoinduced charge carriers. Live/dead cell staining, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) assays and scanning electron microscopy (SEM) have been implemented to investigate the damage to the cell membrane and the leakage of the intracellular protein in the photocatalytic antibacterial process. The e-, h+ and O2•- were the active species involved in this process. This study proposed an appropriate photocatalyst for efficient treatment of bacterial contamination.

Plasma proteomic profiles predict future dementia in healthy adults.

The advent of proteomics offers an unprecedented opportunity to predict dementia onset. We examined this in data from 52,645 adults without dementia in the UK Biobank, with 1,417 incident cases and a follow-up time of 14.1 years. Of 1,463 plasma proteins, GFAP, NEFL, GDF15 and LTBP2 consistently associated most with incident all-cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VaD), and ranked high in protein importance ordering. Combining GFAP (or GDF15) with demographics produced desirable predictions for ACD (area under the curve (AUC) = 0.891) and AD (AUC = 0.872) (or VaD (AUC = 0.912)). This was also true when predicting over 10-year ACD, AD and VaD. Individuals with higher GFAP levels were 2.32 times more likely to develop dementia. Notably, GFAP and LTBP2 were highly specific for dementia prediction. GFAP and NEFL began to change at least 10 years before dementia diagnosis. Our findings strongly highlight GFAP as an optimal biomarker for dementia prediction, even more than 10 years before the diagnosis, with implications for screening people at high risk for dementia and for early intervention.

The genetic architecture of the human hypothalamus and its involvement in neuropsychiatric behaviours and disorders.

Despite its crucial role in the regulation of vital metabolic and neurological functions, the genetic architecture of the hypothalamus remains unknown. Here we conducted multivariate genome-wide association studies (GWAS) using hypothalamic imaging data from 32,956 individuals to uncover the genetic underpinnings of the hypothalamus and its involvement in neuropsychiatric traits. There were 23 significant loci associated with the whole hypothalamus and its subunits, with functional enrichment for genes involved in intracellular trafficking systems and metabolic processes of steroid-related compounds. The hypothalamus exhibited substantial genetic associations with limbic system structures and neuropsychiatric traits including chronotype, risky behaviour, cognition, satiety and sympathetic-parasympathetic activity. The strongest signal in the primary GWAS, the ADAMTS8 locus, was replicated in three independent datasets (N = 1,685-4,321) and was strengthened after meta-analysis. Exome-wide association analyses added evidence to the association for ADAMTS8, and Mendelian randomization showed lower ADAMTS8 expression with larger hypothalamic volumes. The current study advances our understanding of complex structure-function relationships of the hypothalamus and provides insights into the molecular mechanisms that underlie hypothalamic formation.

Mapping of individual sensory nerve axons from digits to spinal cord with the transparent embedding solvent system.

Achieving uniform optical resolution for a large tissue sample is a major challenge for deep imaging. For conventional tissue clearing methods, loss of resolution and quality in deep regions is inevitable due to limited transparency. Here we describe the Transparent Embedding Solvent System (TESOS) method, which combines tissue clearing, transparent embedding, sectioning and block-face imaging. We used TESOS to acquire volumetric images of uniform resolution for an adult mouse whole-body sample. The TESOS method is highly versatile and can be combined with different microscopy systems to achieve uniformly high resolution. With a light sheet microscope, we imaged the whole body of an adult mouse, including skin, at a uniform 0.8 × 0.8 × 3.5 µm3 voxel resolution within 120 h. With a confocal microscope and a 40×/1.3 numerical aperture objective, we achieved a uniform sub-micron resolution in the whole sample to reveal a complete projection of individual nerve axons within the central or peripheral nervous system. Furthermore, TESOS allowed the first mesoscale connectome mapping of individual sensory neuron axons spanning 5 cm from adult mouse digits to the spinal cord at a uniform sub-micron resolution.