Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity.

Interferon-α (IFNα) signaling is essential for antiviral response via induction of IFN-stimulated genes (ISGs). Through a non-biased high-throughput RNAi screening of 711 known epigenetic modifiers in cellular models of IFNα-mediated inhibition of HBV replication, we identified methyltransferase SETD2 as a critical amplifier of IFNα-mediated antiviral immunity. Conditional knockout mice with hepatocyte-specific deletion of Setd2 exhibit enhanced HBV infection. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response. In addition, SETD2 selectively catalyzes the tri-methylation of H3K36 on promoters of some ISGs such as ISG15, leading to gene activation. Our study identifies STAT1 methylation on K525 catalyzed by the methyltransferase SETD2 as an essential signaling event for IFNα-dependent antiviral immunity and indicates potential of SETD2 in controlling viral infections.

Adult Connective Tissue-Resident Mast Cells Originate from Late Erythro-Myeloid Progenitors.

Tissue-resident mast cells are associated with many inflammatory and physiological processes. Although mast cells arise from the yolk sac, the exact ontogeny of adult mast cells remains unclear. Here we have investigated the hematopoietic origin of mast cells using fate-mapping systems. We have shown that early erythro-myeloid progenitors (EMPs), late EMPs, and definitive hematopoietic stem cells (HSCs) each gave rise to mast cells in succession via an intermediate integrin ß7+ progenitor. From late embryogenesis to adult, early EMP-derived mast cells were largely replaced by late EMP-derived cells in most connective tissues except adipose and pleural cavity. Thus, mast cells with distinct origin displayed tissue-location preferences: early EMP-derived cells were limited to adipose and pleural cavity and late EMP-derived cells dominated most connective tissues, while HSC-derived cells were a main group in mucosa. Therefore, embryonic origin shapes the heterogeneity of adult mast cells, with diverse functions in immunity and development.

IL-21 promoting angiogenesis contributes to the development of psoriasis.

BACKGROUND: Elevated IL-21 expression which can effectively induce Th17 cell differentiation has been implicated in the pathogenesis of psoriasis, but its role in angiogenesis remains poorly understood. METHODS: PASI and PSI score assessment was applied to evaluate the severity of psoriatic lesions. The expression of IL-21, IL-21 receptor (IL-21R), CD31, VEGFA, MMP-9, and ICAM-1 in skin was determined by immunohistochemistry or quantitative real-time polymerase chain reaction. The serum level of IL-21 was measured by enzyme-linked immunosorbent assay (ELISA). Then, their correlation was analyzed statistically. Human umbilical vein endothelial cells (HUVECs) cocultured with conditional medium from normal human epidermal keratinocytes (NHEKs) were treated with IL-21 and/or M5 cocktail (mixture of IL-1α, IL-17A, IL-22, TNF-α, and oncostatin M). The migration and tube formation of HUVECs were detected, and the levels of VEGFA, MMP-9, and ICAM-1 in NHEKs were measured by Western blotting or ELISA. RESULTS: Increased IL-21 and IL-21R expression was observed in psoriatic sera or skin specimens, with IL-21R mainly locating in keratinocytes and IL-21 in immune cells. Pearson analysis showed significantly positive correlation between IL-21/IL-21R and erythema scores/microvessel density in psoriatic lesions. Moreover, the expression of proangiogenic genes, VEGFA, ICAM-1, and MMP-9 was upregulated in skins of psoriasis. Additionally, in M5 microenvironment, migration and tube formation could be magnified in HUVECs using IL-21 pre-treated NHEK medium. Mechanically, the co-stimulation of IL-21 and M5 to NEHKs increased the expression of ICAM-1. CONCLUSION: IL-21 could regulate keratinocytes to secrete ICAM-1, thereby promoting angiogenesis in psoriasis.

Overcoming Intrinsic Quantum Confinement and Ultrafast Self-Trapping in Ag-Bi-I- and Cu-Bi-I-Based 2D Double Perovskites through Electroactive Cations.

The possibility to combine organic semiconducting materials with inorganic halide perovskites opens exciting pathways toward tuning optoelectronic properties. Exploring stable and nontoxic, double perovskites as a host for electroactive organic cations to form two-dimensional (2D) hybrid materials is an emerging opportunity to create both functional and lead-free materials for optoelectronic applications. By introducing naphthalene and pyrene moieties into Ag-Bi-I and Cu-Bi-I double perovskite lattices, intrinsic electronic challenges of double perovskites are addressed and the electronic anisotropy of 2D perovskites can be modulated. (POE)4AgBiI8 containing pyrene moieties in the 2D layers was selected from a total of eight new 2D double perovskites, exhibiting a favorable electronic band structure with a type IIb multiple quantum well system based on a layer architecture suitable for out-of-plane conductivity and leading to a photocurrent response ratio of almost 3 orders of magnitude under AM1.5G illumination. Finally, an exclusively parallelly oriented thin film of (POE)4AgBiI8 was integrated into a device to construct the first pure n = 1 Ruddlesden-Popper 2D double perovskite solar cell.

Neoadjuvant radiation target volume definition in esophageal squamous cell cancer: a multicenter recommendations from Chinese experts.

BACKGROUND: This study aimed to establish a consensus on the delineation of target volumes for neoadjuvant radiation therapy (nRT) in esophageal squamous cell carcinoma (ESCC) within China. METHODS: From February 2020 to June 2021, nine ESCC patients who received nRT were retrospectively selected from Sun Yat-sen University Cancer Center and Shandong Cancer Hospital. A panel from eight cancer radiotherapy centers performed two rounds of nRT target volume delineation for these patients: the first round for cases 1-6 and the second for cases 7-9. Online meetings were held after each delineation round to discuss findings. The consistency of delineations across centers was compared using mean undirected Hausdorff distances (Hmean), dice similarity coefficients (DSC), and total volumes, analyzed with the Mann-Whitney U test. RESULTS: The second round of delineations showed improved consistency across centers (total clinical target volume (CTVtotal): mean DSC = 0.76-0.81; mean Hmean = 2.11-3.14 cm) compared to the first round (CTVtotal: mean DSC = 0.63-0.64; mean Hmean = 5.66-7.34 cm; DSC and Hmean: P < 0.050 between rounds), leading to the formation of a consensus and an atlas for ESCC nRT target volume delineation. A proposal was reached through evaluating target volume delineations, analyzing questionnaire survey outcomes, and reviewing pertinent literature. CONCLUSIONS: We have developed guidelines and an atlas for target volume delineation in nRT therapy for ESCC in China. These resources are designed to facilitate more consistent delineation of target volumes in both clinical practice and clinical trials.

MRI Assessment of Brain Frailty and Clinical Outcome in Patients With Acute Posterior Perforating Artery Infarction.

BACKGROUND: Global brain health has gained increasing attention recently. Imaging markers of brain frailty have been related to functional outcomes in previous studies on anterior circulation; however, little data are available on imaging markers and posterior circulation. PURPOSE: To investigate the impact of brain frailty on functional outcomes in patients with acute perforating artery infarction (PAI) of the posterior circulation. STUDY TYPE: Prospective. POPULATION: One hundred patients (60.78 ± 9.51 years, 72% men) with acute posterior circulation PAI (determined by diffusion-weighted magnetic resonance imaging (MRI)/time-of-flight MR angiography). FIELD STRENGTH/SEQUENCE: T1- and T2-weighted fast spin echo, T2-weighted fluid-attenuated inversion recovery, diffusion-weighted echo planar, gradient echo (susceptibility-weight imaging), and 3D time-of-flight MR angiography sequences at 3.0 T. ASSESSMENT: Periventricular and deep white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS) in the basal ganglia and centrum semiovale area, lacunes, cerebral microbleeds (CMB), and total brain frailty score by calculating the above imaging characters were rated visually by three radiologists with 9, 10, and 11 years of experience and one neuroradiologist with 12. Infarction volume was assessed using baseline diffusion-weighted imaging (DWI) data obtained within 24 hours of symptom onset. A modified Rankin Scale (mRS) score >1 on day 90 defined an adverse functional outcome. Associations between the imaging markers of brain frailty and functional outcomes were assessed. STATISTICAL TESTS: Fisher's exact test, Mann-Whitney U test, and multivariable binary logistic regression. A P value <0.05 was considered statistically significant. RESULTS: Adverse prognoses (mRS > 1) were observed in 34 (34%) patients. Infarction volume, periventricular WMH, deep WMH, basal ganglia EPVS, CMB, and the brain frailty score were significantly associated with adverse functional outcomes. An increased brain frailty score was significantly associated with unfavorable mRS score on day 90 (odds ratio 1.773, 95% confidence interval 1.237-2.541). DATA CONCLUSION: Advanced MRI imaging markers of brain frailty, individually or combined as a total brain frailty score, were associated with worse functional outcomes after acute posterior circulation PAI. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Causal relationships between gut microbiota, plasma metabolites, and HIV infection: insights from Mendelian randomization and mediation analysis.

OBJECTIVE: Gut dysbiosis and metabolic abnormalities have been implicated in HIV infection. However, the exact causal relationships among the gut microbiota, metabolites, and HIV infection remain poorly understood. Our study involving Mendelian randomization (MR) and mediation analysis aims to unveil these causalities. METHODS: Genetic instrumental variables for the gut microbiota were retrieved from MiBioGen consortium (n = 18,340). Metabolism-related genetic variants were sourced from the CLSA cohort (n = 8299). GWAS summary statistics for symptomatic HIV infection were derived from the FinnGen study (n = 309,154), and the UK Biobank (n = 208,808). We performed the bidirectional two-sample MR to assess causalities with the inverse-variance weighted (IVW) method as the primary analysis. Moreover, we executed a mediation analysis using two-step MR methods. RESULTS: Compared to the causal effects of HIV infection on gut microbiota (or metabolites), those of gut microbiota (or plasma metabolites) on the risk of HIV infection were more substantial. Phylum Proteobacteria (OR: 2.114, 95% CI 1.042-4.288, P = 0.038), and genus Ruminococcaceae UCG013 (OR: 2.127, 95% CI 1.080-4.191, P = 0.029) exhibited an adverse causal effect on HIV infection, whereas genus Clostridium sensu stricto 1(OR: 0.491, 95% CI 0.252-0.956, P = 0.036) and family Erysipelotrichaceae (OR: 0.399, 95% CI 0.193-0.827, P = 0.013) acted as significant protective factors for HIV. The salicyluric glucuronide level (OR = 2.233, 95% CI 1.120-4.453, P = 0.023) exhibited a considerably adverse causal effect on HIV infection. Conversely, the salicylate-to-citrate ratio (OR: 0.417, 95% CI 0.253-0.688, P = 0.001) was identified as a protective factor for HIV. We identified only one bidirectional causality between 1-palmitoyl-GPI and HIV infection. Mechanistically, genus Haemophilus mediated the causal effects of three phospholipids on HIV infection risk: 1-palmitoyl-GPI (mediation proportion = 33.7%, P = 0.018), 1-palmitoyl-2-arachidonoyl-GPI (mediation proportion = 18.3%, P = 0.019), and 1-linoleoyl-2-linolenoyl-GPC (mediation proportion = 20.3%, P = 0.0216). Additionally, 5-Dodecenoylcarnitine (C12:1) mediated the causal effect of genus Sellimonas on the risk of HIV infection (mediation proportion = 13.7%, P = 0.0348). CONCLUSION: Our study revealed that gut microbiota and metabolites causally influence HIV infection risk more substantially than the reverse. We identified the bidirectional causality between 1-palmitoyl-GPI (16:0) and HIV infection, and elucidated four mediation relationships. These findings provide genetic insights into prediction, prevention, and personalized medicine of HIV infection.

Clinical value of dual-energy CT for predicting occult metastasis in central neck lymph nodes of papillary thyroid carcinoma.

OBJECTIVES: To predict the probability of occult lymph node metastasis (OLNM) in the central cervical by analyzing the dual-energy computed tomography (DECT) parameters derived from papillary thyroid carcinoma (PTC). METHODS: Data were retrospectively collected from patients with pathologically confirmed PTC who underwent arterial and venous phases of enhanced DECT with concurrent central neck lymph node dissection (CLND). Three clinical features, three shape-related features, and twenty-six DECT-derived parameters were measured. The univariate and multivariate analyses were applied to select the relevant parameters and develop the nomogram. RESULTS: A total 140 cases with negative diagnosis of cervical central lymph node metastases by preoperative evaluation were included, among which 88 patients with metastasis (OLNM +) and 52 patients without metastasis (OLNM -) were finally confirmed by pathology. (1) Anteroposterior/transverse diameter ratio (A/T) derived from the PTC focus had significant difference between the OLNM + and OLNM - groups (p < 0.05). (2) In the arterial phase, iodine concentration (ICarterial), normalized iodine concentration (NICarterial), effective atomic number (Zeff-arterial), electron density (EDarterial), and slope of energy curve (karterial) from PTC focus showed significant difference (all p < 0.05) between the two groups. In the venous phase, only the CT value under the 40 keV (HU40keVvenous) had differences (p < 0.05). (3) The nomogram was produced to predict the probability of OLNM, and the AUC, sensitivity, and specificity in the training and test cohort were 0.830, 75.0%, 76.9%, and 0.829, 65.9%, 84.6%, respectively. CONCLUSIONS: DECT parameters combined with shape-related feature derived from PTC might be used as predictors of OLNM in the central neck. CLINICAL RELEVANCE STATEMENT: Preoperative imaging evaluation combining shape-related features and dual-energy CT parameters could serve as a reference to discern occult lymph node metastasis in central neck during the surgically planning of papillary thyroid carcinoma. KEY POINTS: • Papillary thyroid carcinoma (PTC) patients may have occult lymph node metastasis (OLNM) in the central neck, which is extremely difficult to find by preoperative imaging examination. • Dual-energy CT quantitative evaluation has higher accuracy than conventional CT and can predicting OLNM in the central neck of PTC. • Dual-energy CT quantitative parameters and morphology of PTC can serve as a useful tool in predicting OLNM in the central neck, and as a guide for personalized treatment.

Deep medullary vein damage correlates with small vessel disease in small vessel occlusion acute ischemic stroke.

OBJECTIVES: We aim to investigate whether cerebral small vessel disease (cSVD) imaging markers correlate with deep medullary vein (DMV) damage in small vessel occlusion acute ischemic stroke (SVO-AIS) patients. METHODS: The DMV was divided into six segments according to the regional anatomy. The total DMV score (0-18) was calculated based on segmental continuity and visibility. The damage of DMV was grouped according to the quartiles of the total DMV score. Neuroimaging biomarkers of cSVD including white matter hyperintensity (WMH), cerebral microbleed (CMB), perivascular space (PVS), and lacune were identified. The cSVD score were further analyzed. RESULTS: We included 229 SVO-AIS patients, the mean age was 63.7 ± 23.1 years, the median NIHSS score was 3 (IQR, 2-6). In the severe DMV burden group (the 4th quartile), the NIHSS score grade (6 (3-9)) was significantly higher than other groups (p < 0.01). The grade scores for basal ganglia PVS (BG-PVS) were positively correlated with the degree of DMV (R = 0.67, p < 0.01), rather than centrum semivole PVS (CS-PVS) (R = 0.17, p = 0.1). In multivariate analysis, high CMB burden (adjusted odds ratio [aOR], 25.38; 95% confidence interval [CI], 1.87-345.23) was associated with severe DMV scores. In addition, BG-PVS was related to severe DMV burden in a dose-dependent manner: when BG-PVS score was 3 and 4, the aORs of severe DMV burden were 18.5 and 12.19, respectively. CONCLUSION: The DMV impairment was associated with the severity of cSVD, which suggests that DMV burden may be used for risk stratification in SVO-AIS patients. CLINICAL RELEVANCE STATEMENT: The DMV damage score, based on the association between small vessel disease and the deep medullary veins impairment, is a potential new imaging biomarker for the prognosis of small vessel occlusion acute ischemic stroke, with clinical management implications. KEY POINTS: • The damage to the deep medullary vein may be one mechanism of cerebral small vessel disease. • Severe burden of the basal ganglia perivascular space and cerebral microbleed is closely associated with significant impairment to the deep medullary vein. • The deep medullary vein damage score may reflect a risk of added vascular damage in small vessel occlusion acute ischemic stroke patients.

IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates.

During endoplasmic reticulum (ER) stress, homeostatic signaling through the unfolded protein response (UPR) augments ER protein-folding capacity. If homeostasis is not restored, the UPR triggers apoptosis. We found that the ER transmembrane kinase/endoribonuclease (RNase) IRE1alpha is a key component of this apoptotic switch. ER stress induces IRE1alpha kinase autophosphorylation, activating the RNase to splice XBP1 mRNA and produce the homeostatic transcription factor XBP1s. Under ER stress--or forced autophosphorylation--IRE1alpha's RNase also causes endonucleolytic decay of many ER-localized mRNAs, including those encoding chaperones, as early events culminating in apoptosis. Using chemical genetics, we show that kinase inhibitors bypass autophosphorylation to activate the RNase by an alternate mode that enforces XBP1 splicing and averts mRNA decay and apoptosis. Alternate RNase activation by kinase-inhibited IRE1alpha can be reconstituted in vitro. We propose that divergent cell fates during ER stress hinge on a balance between IRE1alpha RNase outputs that can be tilted with kinase inhibitors to favor survival.

Identification of Isoliensinine as a Ferroptosis Suppressor with Iron-Chelating Activity.

Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of lipid peroxides. The high involvement of ferroptosis in diverse human diseases highlights the need for the identification of new chemotypes with anti-ferroptotic activity. Here, we performed a natural product library screening in HT1080 fibrosarcoma cells and identified licochalcone A (LA), isoeugenyl acetate (ISA), and isoliensinine (ISL) as suppressors of either RSL3- or IKE-induced ferroptosis. Mechanistically, ferroptosis resistance conferred by these compounds is mainly through GPX4/NRF2-independent mechanisms. Among them, only ISL could effectively rescue ferroptosis induced by FINO2, which is a stable oxidant of ferrous iron, suggesting that ISL may have the properties of an iron chelator. Consistent with the hypothesis, both computational tools and X-ray photoelectron spectroscopy supported the binding between ISL and iron ions. And ISL greatly inhibited excessive iron-dependent ferroptotic cell death through limiting intracellular iron accumulation. Furthermore, its iron chelator activity also protected mice from organ injury in an acute iron overload model. In conclusion, this study provided valuable insights for developing effective anti-ferroptosis agents from natural products, which represent a potential therapeutic strategy for treating ferroptosis-associated organ damage.

Oral administration of punicalagin attenuates imiquimod-induced psoriasis by reducing ROS generation and inflammation via MAPK/ERK and NF-κB signaling pathways.

Psoriasis, an immune-mediated chronic inflammatory skin disease, imposes a huge mental and physical burden on patients and severely affects their quality of life. Punicalagin (PU), the most abundant ellagitannin in pomegranates, has become a research hotspot owing to its diverse biological activities. However, its effects on psoriasis remain unclear. We explored the impact and molecular mechanism of PU on M5-stimulated keratinocyte cell lines and imiquimod (IMQ)-induced psoriasis-like skin inflammation in BABL/c mice using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), hematoxylin and eosin (H&E) stain, immunohistochemistry, and immunofluorescent. Administration of PU-enriched pomegranate extract at dosages of 150 and 250 mg/kg/day markedly attenuated psoriatic severity, abrogated splenomegaly, and reduced IMQ-induced abnormal epidermal proliferation, CD4+ T-cell infiltration, and inflammatory factor expression. Moreover, PU could decrease expression levels of pro-inflammatory cytokines, such as IL-1ß, IL-1α, IL-6, IL-8, TNF-α, IL-17A, IL-22, IL-23A, and reactive oxygen species (ROS), followed by keratinocyte proliferation inhibition in the M5-stimulated cell line model of inflammation through inhibition of mitogen-activated protein kinases/extracellular regulated protein kinases (MAPK/ERK) and nuclear factor kappaB (NF-κB) signaling pathways. Our results indicate that PU may serve as a promising nutritional intervention for psoriasis by ameliorating cellular oxidative stress and inflammation.

The efficacy and safety of cervical polypectomy with vaginoscopy in pregnant women.

PURPOSES: This study aims to assess the effectiveness and safety of cervical polypectomy performed via vaginoscopy in pregnant women. METHODS: Pregnant patients diagnosed with cervical polyps were retrospectively included in Beijing Tiantan Hospital between April 2017 and April 2023. Group A underwent cervical polypectomy using a vaginoscopy technique without speculum, cervical forceps and anesthesia, while Group B received conservative management. The incidence of spontaneous abortion, preterm birth, preterm rupture of membranes (PROM), visual analog scale (VAS) scores, timing and method of delivery, and neonatal outcomes were analyzed. RESULTS: Of 90 pregnant patients included in the study, 48 patients receiving polypectomy under vaginoscopy were included into group A while 42 patients receiving conservative treatment were assigned into group B. At baseline, group A exhibited higher rates of vaginal bleeding pre-operation, as well as larger cervical polyp dimensions compared to group B. The median interval between vaginal bleeding and polypectomy was 3.5 weeks, with the median procedure typically performed at gestational week 19 in group A. There was no significant difference in the incidence of spontaneous abortion between the two groups (4.2% vs. 4.8%, p = 1.000). However, group A showed a significantly lower frequency of preterm birth (4.2% vs. 21.4%, p = 0.030) and premature rupture of membranes (PROM) (18.8% vs. 45.2%, p = 0.025) compared to group B. No disparities were observed in the timing, mode of delivery, and neonatal outcomes between the two groups. CONCLUSIONS: The utilization of vaginoscopy for cervical polypectomy has been shown to decrease the likelihood of preterm delivery and premature rupture of membranes in pregnant women with symptomatic cervical polyps. Therefore, performing cervical polypectomy via vaginoscopy without anesthesia provide a feasible and optimal ways in the management of this population.

Molybdenum inhibited the growth of Phytophthora nicotiana and improved the resistance of Nicotiana tabacum L. against tobacco black shank.

Tobacco black shank (TBS) is a soil-borne fungal disease caused by Phytophthora nicotiana (P. nicotianae), significantly impeding the production of high-quality tobacco. Molybdenum (Mo), a crucial trace element for both plants and animals, plays a vital role in promoting plant growth, enhancing photosynthesis, bolstering antioxidant capacity, and maintaining ultrastructural integrity. However, the positive effect of Mo on plant biotic stress is little understood. This study delves into the inhibitory effects of Mo on P. nicotianae and seeks to unravel the underlying mechanisms. The results showed that 16.32 mg/L of Mo significantly inhibited mycelial growth, altered mycelial morphological structure, damaged mycelial cell membrane, and ultimately led to the leakage of cell inclusions. In addition, 0.6 mg/kg Mo applied in soil significantly reduced the severity of TBS. Mo increased photosynthetic parameters and photosynthetic pigment contents of tobacco leaves, upregulated expression of NtPAL and NtPPO resistance genes, as well as improved activities of SOD, POD, CAT, PPO, and PAL in tobacco plants. Furthermore, Mo could regulate nitrogen metabolism and amino acids metabolism to protect tobacco plants against P. nicotianae infection. These findings not only present an ecologically sound approach to control TBS but also contribute valuable insights to the broader exploration of the role of microelements in plant disease management.

Multidimensional progressive single-cell sequencing reveals cell microenvironment composition and cancer heterogeneity in lung cancer.

Despite substantial advances in cancer biology and treatment, the clinical outcomes of patients with lung cancer remain unsatisfactory. The tumor microenvironment (TME) is a potential target. Using single-cell RNA sequencing, we could distinguish eight distinct cell types in the lung cancer microenvironment, demonstrating substantial intratumoral heterogeneity in 19 different lung cancer tumor samples. Through the re-dimensional grouping of cancer-associated fibroblasts (CAFs), myeloid cells, epithelial cells, natural killer (NK) cells, and T cells, the difference in the TME of lung cancer was revealed. We discovered SFTPB, SFN, and KRT8 as possible predictive biomarkers for lung cancer by assessing the gene expression patterns in epithelial cells. Examining cell-to-cell communications showed a robust association between the quantity of matrix CAFs, epithelial cells, and macrophages in the thrombospondin signaling pathway. Additionally, we found that the amyloid precursor protein signaling pathway primarily originated from the matrix, and inflammatory cancer-associated endothelial and fibroblast cells showed a co-expression relationship with myeloid cells and B cells. Through cell-to-cell correlation analysis, we found positive regulation between NK cells, regulatory T cells, GZMB-CD8 T cells, and GZMK-CD8 T cells, which could play a role in developing immune TMEs. These findings support studies on cancer heterogeneity and add to our understanding of lung cancer's cellular microenvironment.

Sybil Attacks Detection and Traceability Mechanism Based on Beacon Packets in Connected Automobile Vehicles.

Connected Automobile Vehicles (CAVs) enable cooperative driving and traffic management by sharing traffic information between them and other vehicles and infrastructures. However, malicious vehicles create Sybil vehicles by forging multiple identities and sharing false location information with CAVs, misleading their decisions and behaviors. The existing work on defending against Sybil attacks has almost exclusively focused on detecting Sybil vehicles, ignoring the traceability of malicious vehicles. As a result, they cannot fundamentally alleviate Sybil attacks. In this work, we focus on tracking the attack source of malicious vehicles by using a novel detection mechanism that relies on vehicle broadcast beacon packets. Firstly, the roadside units (RSUs) randomly instruct vehicles to perform customized key broadcasting and listening within communication range. This allows the vehicle to prove its physical presence by broadcasting. Then, RSU analyzes the beacon packets listened to by the vehicle and constructs a neighbor graph between the vehicles based on the customized particular fields in the beacon packets. Finally, the vehicle's credibility is determined by calculating the edge success probability of vehicles in the neighbor graph, ultimately achieving the detection of Sybil vehicles and tracing malicious vehicles. The experimental results demonstrate that our scheme achieves the real-time detection and tracking of Sybil vehicles, with precision and recall rates of 98.53% and 95.93%, respectively, solving the challenge of existing detection schemes failing to combat Sybil attacks from the root.

Radiomics from dual-energy CT-derived iodine maps predict lymph node metastasis in head and neck squamous cell carcinoma.

OBJECTIVE: To develop and validate an iodine maps-based radiomics nomogram for preoperatively predicting cervical lymph node metastasis (LNM) in head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: A total of 278 patients who pathologically confirmed as HNSCC were retrospectively recruited from two medical centers between June 2012 and July 2022. The training set (n = 152) and internal set (n = 67) were randomly selected from medical center A, and the patients from medical center B were enrolled as the external set (n = 69). The minority group in the training set was balanced by the adaptive synthetic sampling (ADASYN) approach. Radiomics features were extracted from dual-energy CT-derived iodine maps at arterial phase (AP) and venous phase (VP), respectively. Three radiomics signatures were constructed to predict the LNM by using a random forest algorithm. The independent clinical predictors for LNM were identified by multivariate analysis and combined with radiomics signatures to establish a radiomic-clinical nomogram. The performance of radiomic-clinical nomogram was evaluated with respect to its discrimination and clinical usefulness. RESULTS: The AP-VP-incorporated radiomics model exhibited a great predictive performance for LNM prediction with an area under curve (AUC) of 0.885 (95% CI, 0.836-0.933) in ADASYN-training set and confirmed in all validation sets. The nomogram that incorporated AP-VP radiomics signatures, CT-reported LN status, and histological grades yielded AUCs of 0.920 (95% CI, 0.881-0.959) in ADASYN-training set, 0.858 (95% CI, 0.771-0.944) in internal validation, and 0.849 (95% CI, 0.752-0.946) in external validation, with good calibration in all cohorts (p > 0.05). Decision curve analyses indicated the nomogram was clinically useful. In addition, the predictive performance of clinical-radiomics nomogram was also validation in combing cohorts. Stratified analysis confirmed the stability of nomogram, particularly in group negative for CT-reported LNM. CONCLUSION: Clinical-radiomics nomogram based on iodine maps exhibited promising performance in predicting LNM and providing valuable information for making individualized therapy decisions.

The mediating roles of depressive symptoms and social participation in the relationship between the effects of pain and cognitive function among Chinese older adults: A longitudinal study.

Decline in cognitive function poses a substantial burden on individuals, families, and society. However, the longitudinal potential mechanism underlying the link of pain and cognitive function remains unclear. Using data of 4247 participants aged 60 years and over from the China Health and Retirement Longitudinal Study in 2011, 2013, 2018, and 2020, we discussed the longitudinal predictive effect of pain on cognitive function and the mediating effects of depressive symptoms and social participation. The longitudinal mediation model analysis revealed that pain could not directly influence cognitive function, but it could indirectly predict cognitive function through the independent mediation effects of depressive symptoms and social participation. Moreover, the association between pain and cognitive function was serially mediated by depressive symptoms and social participation. Diversified interventions aimed at relieving pain and depressive symptoms, and increasing social participation in older adults would be beneficial for their cognitive function.

Exenatide and Metformin Improve Serum Indices and Intestinal Flora in patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease.

The aim of the study was to investigate th e in flue nce of Exenatide comb ined with Met formin on fasti ng blood glucose, postpr andial glucose, triglycerides, total cholesterol, alanine aminotransferase, aspartate aminotransferase, and inte s tinal flora in typ e 2 diab etes mellitus cases with non-alcoholic fatty liver disease. A total of 128 type 2 diabetes mellitus patients with non-alcoholic fatty liver disease, diagnosed from Januar y 2019 to January 2022, were included and randomly assigned to either G roup A (n=64) or Gro up B (n =64). Group A received Metformin, while Group B received Exenatide injection and Metfor min. After 24 weeks of treat ment, blood glucose indices (fasting blood glucose and postprandial glucose), blood lipid indices (triglycerides and total cholesterol), liver func tion indices (alanine aminotransferase and aspar tate aminotransferase) were all lower in Group B than in Group A (p<0.001 for all). Counts o f Escherichia coli and Enterococcus faecalis were lower in Group B than in Group A (both p<0.05), counts of Bifidobacteria and Lactobacillus were highe r i n Group B than in Grou p A (both p<0.05). Combin ation of Exenati de and Metformi n may have synergistic effects in improving metabo lic an d hepatic pa rameters, a s well as re gulat ing intestinal flora, which cou ld provide a pro misin g therapeutic option for the management of these patients.

Role of TGF-ß3 in modulating inflammatory responses and wound healing processes in ischemic ulcers in atherosclerotic patients.

Ischemic ulcers pose a multifaceted clinical dilemma for patients with atherosclerosis, frequently compounded by suboptimal wound healing mechanisms. The dual function of Transforming Growth Factor Beta 3 (TGF-ß3) in ischemic ulcer healing is not fully comprehended, despite its involvement in modulating inflammatory responses and tissue regeneration. The main aim of this investigation was to clarify the functions and mechanisms by which TGF-ß3 regulates inflammatory responses and promotes wound healing in patients with ischemic ulcers who have atherosclerosis. Between August 2022 and November 2023, this cross-sectional investigation was conducted on 428 patients diagnosed with atherosclerotic ischemic ulcers in Haikou, China. The expression and function of TGF-ß3 were examined throughout the different stages of wound healing, including inflammation, proliferation and remodelling. In addition to documenting patient demographics and ulcer characteristics, an analysis was conducted on biopsy samples to determine the expression of TGF-ß3, pro-inflammatory and anti-inflammatory markers. A subset of patients were administered topical TGF-ß3 in order to evaluate its therapeutic effects. The expression pattern of TGF-ß3 was found to be stage-dependent and significant, exhibiting increased levels during the phase of inflammation and reduced activity in subsequent phases. TGF-ß3 levels were found to be greater in ulcers that were larger and deeper, especially in inflammatory phase. TGF-ß3 applied topically induced discernible enhancement in ulcer healing parameters, such as reduction in ulcer depth and size. The therapeutic significance of TGF-ß3 was emphasised due to its twofold function of regulating the inflammatory environment and facilitating the regeneration of damaged tissues. Ischemic ulcer lesion healing is significantly influenced by TGF-ß3, which functions as an anti-inflammatory and pro-inflammatory mediator. Its correlation with ulcer characteristics and stages of healing suggests that it may have utility as a targeted therapeutic agent.