Mechanically Interlocked Polyrotaxane Networks with Collective Motions of Multiple Main-Chain Mechanical Bonds.

Type I main-chain polyrotaxanes (PRs) with multiple wheels threaded onto the axle are widely employed to design slide-ring materials. However, Type II main-chain PRs with axles threading into the macrocycles on the polymer backbones have rarely been studied, although they feature special topological structures and dynamic characteristics. Herein, we report the design and preparation of Type II main-chain PR-based mechanically interlocked networks (PRMINs), based on which the relationship between microscopic motion of mechanical bonds on the PRs and macroscopic mechanical performance of materials has been revealed. The representative PRMIN-2 exhibits a robust feature in tensile tests with high stretchability (1680%) and toughness (47.5 MJ/m3). Moreover, it also has good puncture performance with puncture energy of 22.0 mJ. Detailed rheological measurements and coarse-grained molecular dynamics (CGMD) simulation reveal that the embedded multiple [2]rotaxane mechanical bonds on the PR backbones of PRMINs could undergo a synergistic long-range sliding motion under external force, with the introduction of collective dangling chains into the network. As a result, the synchronized motions of coherent PR chains can be readily activated to accommodate network deformation and efficiently dissipate energy, thereby leading to enhanced mechanical performances of PRMINs.

Causal impact of statins on susceptibility to osteoarthritis: insights from a two-sample Mendelian randomization analysis.

BACKGROUND: Osteoarthritis is a widely prevalent cause of pain and disability among older adults. It is an incurable condition, and most treatments are aimed at alleviating symptoms. AIM: This study aimed to investigate the impact of statins on osteoarthritis by using a two-sample Mendelian randomization approach, using genetic variants associated with statin use as instrumental variables. METHOD: Information on single nucleotide polymorphisms associated with statin medication was obtained from the FinnGen study, and data on osteoarthritis were sourced from the UK Biobank. The inverse variance weighted method was used as the primary analytical approach for the Mendelian randomization analysis. Sensitivity analyses were conducted to evaluate horizontal pleiotropy and heterogeneity. To examine the genetic relationship between statins and osteoarthritis, linkage disequilibrium score regression-based estimates were used. RESULTS: Mendelian randomization analysis indicated a positive effect of statin use on the treatment of osteoarthritis (odds ratio 0.951, 95% confidence interval 0.914-0.99, p < 0.05). This conclusion was supported by various Mendelian randomization methods. Sensitivity analyses revealed no significant directional pleiotropy or influential single nucleotide polymorphisms that could compromise the overall causal inference. Linkage disequilibrium score regression-based estimates suggested a modest genetic correlation between statin use and osteoarthritis (Rg = 0.098, Se = 0.034, p < 0.05), thus reinforcing the robustness of the Mendelian randomization analysis. CONCLUSION: Statins reduce the risk of osteoarthritis, aligning with the results of observational studies. Further research is essential to validate these results and explore the underlying mechanisms in detail.

X-Paste improves wound healing in diabetes via NF-E2-related factor/HO-1 signaling pathway.

BACKGROUND: Diabetic foot ulcers (DFU), as severe complications of diabetes mellitus (DM), significantly compromise patient health and carry risks of amputation and mortality. AIM: To offer new insights into the occurrence and development of DFU, focusing on the therapeutic mechanisms of X-Paste (XP) of wound healing in diabetic mice. METHODS: Employing traditional Chinese medicine ointment preparation methods, XP combines various medicinal ingredients. High-performance liquid chromatography (HPLC) identified XP's main components. Using streptozotocin (STZ)-induced diabetic, we aimed to investigate whether XP participated in the process of diabetic wound healing. RNA-sequencing analyzed gene expression differences between XP-treated and control groups. Molecular docking clarified XP's treatment mechanisms for diabetic wound healing. Human umbilical vein endothelial cells (HUVECs) were used to investigate the effects of Andrographolide (Andro) on cell viability, reactive oxygen species generation, apoptosis, proliferation, and metastasis in vitro following exposure to high glucose (HG), while NF-E2-related factor-2 (Nrf2) knockdown elucidated Andro's molecular mechanisms. RESULTS: XP notably enhanced wound healing in mice, expediting the healing process. RNA-sequencing revealed Nrf2 upregulation in DM tissues following XP treatment. HPLC identified 21 primary XP components, with Andro exhibiting strong Nrf2 binding. Andro mitigated HG-induced HUVECs proliferation, metastasis, angiogenic injury, and inflammation inhibition. Andro alleviates HG-induced HUVECs damage through Nrf2/HO-1 pathway activation, with Nrf2 knockdown reducing Andro's proliferative and endothelial protective effects. CONCLUSION: XP significantly promotes wound healing in STZ-induced diabetic models. As XP's key component, Andro activates the Nrf2/HO-1 signaling pathway, enhancing cell proliferation, tubule formation, and inflammation reduction.

Safety and efficacy of baricitinib in steroid-resistant or relapsed immune thrombocytopenia: An open-label pilot study.

Patients with steroid-resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus-associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open-label, single-arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 109/L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6-month follow-up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6-20) days, and the median peak platelet count was 94 (IQR 72-128) × 109/L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP-modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP.

Tuning the magnetic properties of van der Waals Fe3GaTe2 crystals by Co doping.

Tuning the magnetic properties of two-dimensional van der Waals ferromagnets has special importance for their practical applications. Using first-principles calculations, we investigate the magnetic properties of Co-doped Fe3GaTe2 with different Co concentrations and different Co atomic sites. Calculation results show that Fe or Co atoms with relatively lower atomic concentrations preferentially occupy Fe1 sites with interlayer coupling, which is more energetically favorable. As the doping concentration of Co atoms increases, the total magnetic moment of the doped system decreases, while the average atomic magnetic moments of Fe1 and Fe2 increase and decrease, respectively, with Fe1 reaching ∼2.08µB. The spin polarization of the doped model 2Co-2 near the Fermi energy level is significantly reduced, while 4Co-3 exhibits an enhanced trend. At some doping level, a phase change from ferromagnetism to antiferromagnetism appears at high Co concentration. These results provide a theoretical basis for experimental studies and valuable information for the development of Fe3GaTe2-based spintronic devices.

Plant-derived natural compounds: A new frontier in inducing immunogenic cell death for cancer treatment.

Immunogenic cell death (ICD) can activate adaptive immune response in the host with normal immune system. Some synthetic chemotherapeutic drugs and natural compounds have shown promising results in cancer treatment by triggering the release of damage-associated molecules (DAMPs) to trigger ICD. However, most chemotherapeutic drugs exhibit non-selective cytotoxicity and may also induce and promote metastasis, thereby significantly reducing their clinical efficacy. Among the natural compounds that can induce ICD, plant-derived compounds account for the largest proportion, which are of increasing value in the treatment of cancer. Understanding which plant-derived natural compounds can induce ICD and how they induce ICD is crucial for developing strategies to improve chemotherapy outcomes. In this review, we focus on the recent findings regarding plant-derived natural compounds that induce ICD according to the classification of flavonoids, alkaloids, glycosides, terpenoids and discuss the potential mechanisms including endoplasmic reticulum (ER) stress, DNA damage, apoptosis, necroptosis autophagy, ferroptosis. In addition, plant-derived natural compounds that can enhance the ICD induction ability of conventional therapies for cancer treatment is also elaborated. The rational use of plant-derived natural compounds to induce ICD is helpful for the development of new cancer treatment methods.

Application of predictive model based on CT radiomics and machine learning in diagnosis for occult locally advanced esophageal squamous cell carcinoma before treatment: A two-center study.

PURPOSE: Development and validation of a radiomics model for predicting occult locally advanced esophageal squamous cell carcinoma (LA-ESCC) on computed tomography (CT) radiomic features before implementation of treatment. METHODS: The study retrospectively collected 574 patients with esophageal squamous cell carcinoma (ESCC) from two medical centers, which were divided into three cohorts for training, internal and external validation. After delineating volume of interest (VOI), radiomics features were extracted and subjected to feature selection using three robust methods. Subsequently, 10 machine learning models were constructed, among which the optimal model was utilized to establish a radiomics signature. Furthermore, a predictive nomogram incorporating both clinical and radiomics signatures was developed. The performance of these models was evaluated through receiver operating characteristic curves, calibration curves, decision curve analysis as well as measures including accuracy, sensitivity, and specificity. RESULTS: A total of 19 radiomics features were selected. The multilayer perceptron (MLP), which was found to be optimal, achieved an AUC of 0.919, 0.864 and 0.882 in the training, internal and external validation cohorts, respectively. Similarly, MLP showed good accuracy in distinguish occult LA-ESCC in subgroup of cT1-2N0M0 diagnosed by clinicians with 0.803 and 0.789 in two validation cohorts respectively. By incorporating the radiomics signature with clinical signature, a predictive nomogram demonstrated superior prediction performance with an AUC of 0.877 and accuracy of 0.85 in external validation cohort. CONCLUSION: The radiomics and machine learning model can offers improved accuracy in prediction of occult LA-ESCC, providing valuable assistance to clinicians when choosing treatment plans.

Isorhamnetin Improves Oocyte Maturation by Activating the Pi3k/Akt Signaling Pathway.

SCOPE: Isorhamnetin is a natural flavonoid with various pharmacological activities, which can be widely and continuously ingested by humans and animals through their daily diet. The aim of this study is to explore the benefits and molecular mechanisms of isorhamnetin on oocyte maturation. METHODS AND RESULTS: Oocytes are incubated with isorhamnetin (5, 10, 20, and 30 µM) for 44 h. Isorhamnetin (10 µM) increases the polar body extrusion rate of oocytes. Furthermore, isorhamnetin alleviates oxidative stress by inhibiting reactive oxygen species levels and stimulating SOD2 protein expression. The changes in intracellular mitochondrial autophagy and apoptosis-related proteins (Bcl-2, Bax/Bcl-2, and C-Casp3) indicate that isorhamnetin inhibits oocyte apoptosis. Isorhamnetin inhibits endoplasmic reticulum stress by reducing the protein expression of CHOP and GRP78 and improving the normal distribution rate of endoplasmic reticulum. Mechanistic studies show that isorhamnetin activates the PI3K/Akt signaling pathway. CONCLUSION: Isorhamnetin promotes oocyte maturation by inhibiting oxidative stress, mitochondrial dysregulation, apoptosis, and endoplasmic reticulum stress, which have important potential for improving oocyte quality and treating female infertility.

Per2 mediated steroid hormone synthesis by regulating transcription of StAR in porcine granulosa cells.

Steroidogenesis is associated with circadian clock genes. However, the regulation of steroid hormone production in sow granulosal cells by Per2, a crucial circadian regulator, remains unexplored. In this study, we have identified the presence of Per2 in ovarian granulosa cells and have observed its circadian expression pattern. Employing siRNA to interfere with Per2 expression, our investigation revealed that Per2 knockdown notably elevated progesterone (P4) levels along with increasing the expression of StAR but interference of Per2 did not alter the rhythm of clock-related gene (Bmal1, Clock, Per1 and Cry1) in granulosa cells. Subsequent mechanistic analysis showed that Per2 formed complexes with PPARγ and interference with Per2 promoted the formation of the PPARγ:RXRα heterodimer. Importantly, we uncovered that PPARγ:RXRα heterodimer could control the expression of StAR via direct peroxisome proliferator response element (PPRE) binding to its promoter to regulate its activity, and knockdown of Per2 promoted the transcription of StAR via increasing the binding of PPARγ:RXRα ligands. Altogether, these findings indicated a noncanonical role of Per2 in controlling PPARγ:RXRα binding to regulate transcription of StAR and progesterone synthesis, thus revealing potential avenues of pharmacological and therapeutic intervention.

Immune response regulation by transduced mesenchymal stem cells with decorin gene on bleomycin-induced lung injury, fibrosis, and inflammation.

BACKGROUND: Pulmonary fibrosis is a pathological hallmark of lung injury. It is an aggressive disease that replaces normal lung parenchyma by fibrotic tissue. The transforming growth factor-beta-mothers against decapentaplegic homolog 3 (TGF-ß1-Smad3) signaling pathway plays a key role in regulating lung fibrosis. Decorin (DCN), a small leucine-rich proteoglycan, has a modulatory effect on the immune system by reversibly binding with TGF-ß and reducing its bioavailability. Mesenchymal stem cell (MSC) therapy is a new strategy that has an immune-modulatory capacity. OBJECTIVE: The aim of this study was to introduce a new therapeutic approach to harness remodeling in injured lung. MATERIAL AND METHODS: Bone marrow MSCs were isolated and transduced by decorin gene. Lung injury was induced by bleomycin and mice were treated with MSCs, MSCs-decorin, and decorin. Then, oxidative stress biomarkers, remodeling biomarkers, bronchoalveolar lavage cells, and histopathology study were conducted. RESULTS: Reduced catalase and superoxide dismutase increased due to treatments. Elevated malondialdehyde, hydroxyproline, TGF-ß levels, and polymorphonuclear cells count decreased in the treated groups. Additionally, the histopathology of lung tissues showed controlled inflammation and fibrosis. CONCLUSION: Transfected decorin gene to MSCs and used cell therapy could control remodeling and bleomycin-induced lung injury.

Detectability of intracranial vessel wall atherosclerosis using black-blood spectral CT: a phantom and clinical study.

BACKGROUND: Computed tomography (CT) is the usual modality for diagnosing stroke, but conventional CT angiography reconstructions have limitations. METHODS: A phantom with tubes of known diameters and wall thickness was scanned for wall detectability, wall thickness, and contrast-to-noise ratio (CNR) on conventional and spectral black-blood (SBB) images. The clinical study included 34 stroke patients. Diagnostic certainty and conspicuity of normal/abnormal intracranial vessels using SBB were compared to conventional. Sensitivity/specificity/accuracy of SBB and conventional were compared for plaque detectability. CNR of the wall/lumen and quantitative comparison of remodeling index, plaque burden, and eccentricity were obtained for SBB imaging and high-resolution magnetic resonance imaging (hrMRI). RESULTS: The phantom study showed improved detectability of tube walls using SBB (108/108, 100% versus conventional 81/108, 75%, p < 0.001). CNRs were 75.9 ± 62.6 (mean ± standard deviation) for wall/lumen and 22.0 ± 17.1 for wall/water using SBB and 26.4 ± 15.3 and 101.6 ± 62.5 using conventional. Clinical study demonstrated (i) improved certainty and conspicuity of the vessels using SBB versus conventional (certainty, median score 3 versus 0; conspicuity, median score 3 versus 1 (p < 0.001)), (ii) improved sensitivity/specificity/accuracy of plaque (≥ 1.0 mm) detectability (0.944/0.981/0.962 versus 0.239/0.743/0.495) (p < 0.001), (iii) higher wall/lumen CNR of SBB of (78.3 ± 50.4/79.3 ± 96.7) versus hrMRI (18.9 ± 8.4/24.1 ± 14.1) (p < 0.001), and (iv) excellent reproducibility of remodeling index, plaque burden, and eccentricity using SBB versus hrMRI (intraclass correlation coefficient 0.85-0.94). CONCLUSIONS: SBB can enhance the detectability of intracranial plaques with an accuracy similar to that of hrMRI. RELEVANCE STATEMENT: This new spectral black-blood technique for the detection and characterization of intracranial vessel atherosclerotic disease could be a time-saving and cost-effective diagnostic step for clinical stroke patients. It may also facilitate prevention strategies for atherosclerosis. KEY POINTS: • Blooming artifacts can blur vessel wall morphology on conventional CT angiography. • Spectral black-blood (SBB) images are generated from material decomposition from spectral CT. • SBB images reduce blooming artifacts and noise and accurately detect small plaques.

Scutellarin alleviates microglia-mediated neuroinflammation and apoptosis after ischemic stroke through the PI3K/AKT/GSK3ß signaling pathway.

Microglia are resident immune cells in the central nervous system that are rapidly activated to mediate neuroinflammation and apoptosis, thereby aggravating brain tissue damage after ischemic stroke (IS). Although scutellarin has a specific therapeutic effect on IS, the potential target mechanism of its treatment has not been fully elucidated. In this study, we explored the potential mechanism of scutellarin in treating IS using network pharmacology. Lipopolysaccharide (LPS) was used to induce an in vitro BV-2 microglial cell model, while middle cerebral artery occlusion (MCAO) was used to induce an in vivo animal model. Our findings indicated that scutellarin promoted the recovery of cerebral blood flow in MCAO rats at 3 days, significantly different from that in the MCAO group. Western blotting and immunofluorescence revealed that scutellarin treatment of BV-2 microglial cells resulted in a significant reduction in the protein expression levels and incidence of cells immunopositive for p-NF-κB, TNF-α, IL-1ß, Bax, and C-caspase-3. In contrast, the expression levels of p-PI3K, p-AKT, p-GSK3ß, and Bcl-2 were further increased, significantly different from those in the LPS group. The PI3K inhibitor LY294002 had similar effects to scutellarin by inhibiting neuroinflammation and apoptosis in activated microglia. The results of the PI3K/AKT/GSK3ß signaling pathway and NF-κB pathway in vivo in MCAO models induced microglia at 3 days were consistent with those obtained from in vitro cells. These findings indicate that scutellarin plays a neuroprotective role by reducing microglial neuroinflammation and apoptosis mediated by the activated PI3K/AKT/GSK3ß/NF-κB signaling pathway.

Drop to Gate Nasal Drops Attenuates Sepsis-Induced Cognitive Dysfunction.

Nasal administration can bypass the blood-brain barrier and directly deliver drugs to the brain, providing a non-invasive route for central nervous system (CNS) diseases. Inspired by the appearance that a gate can block the outside world and the characteristics of the sol-gel transition can form a "gate" in the nasal cavity, a Drop to Gate nasal drop (DGND) is designed to set a gate in nose, which achieves protecting role from the influence of nasal environment. The DGND demonstrates the efficiency and application prospect of delivering drugs to the brain through the N-to-B. The effective concentration of single administration is increased through the hydrophobic interaction between C8-GelMA and SRT1720 (SA), and then cross-linked under UV to form nanogel, which can respond to MMP in the inflammatory microenvironment of sepsis-induced cognitive dysfunction. Finally, the SA/nanogel is compounded into the thermogel, which can respond to the nasal cavity temperature to form DGND in situ, increasing the residence time and delivery efficiency of drugs in the nasal cavity. In vitro, the DGND alleviates lipopolysaccharides (LPS)-induced BV2 inflammation. In vivo, DGND effectively targets the nasal mucosa and deliver drugs to the brain, which activate Sirt1 to alleviate inflammation mediated by microglia and improve cognitive dysfunction in sepsis mice.

Influence of health education based on the transtheoretical model on kinesiophobia levels and rehabilitation outcomes in elderly patients undergoing total knee arthroplasty.

Objective: In this study, we evaluated the effectiveness of health education based on the transtheoretical model in reducing symptoms of kinesiophobia and enhancing rehabilitation outcomes among elderly patients post-total knee arthroplasty. Methods: Elderly patients post-knee replacement surgery were randomly divided into a control group, which received standard health education, and an experimental group, which received transtheoretical model-based health education. The intervention commenced on the day after surgery and continued for a duration of six months. Assessments of kinesiophobia scores, rehabilitation self-efficacy, and knee function were conducted before the intervention, and then at one, three, and six months postoperatively. Results: Between January 2022 and December 2022, 130 elderly patients who met the eligibility criteria were enrolled and subsequently randomly assigned into two groups of equal size. Comparable baseline characteristics were observed between the two groups The experimental group demonstrated lower kinesiophobia scores and higher scores in rehabilitation self-efficacy and knee function at one, three, and six months following surgery, compared to the control group. Conclusion: Health education based on a transtheoretical model reduces the symptoms of kinesiophobia and enhances rehabilitation self-efficacy and knee functions in elderly patients after knee replacement surgery.

Efficacy of PD-1/PD-L1 inhibitors in advanced hepatocellular carcinoma: A systematic review and meta-analysis.

Objectives: This study aimed to investigate the efficacy and safety of programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors in patients with advanced hepatocellular carcinoma (HCC). Materials and Methods: PubMed, EMBASE, and the Cochrane Library were searched for articles published until November 2022. Studies reporting the efficacy of PD-1/PD-L1 inhibitors in patients with advanced HCC were eligible for inclusion. The outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and ≥ Grade 3 treatment-related adverse events (TrAEs). Results: Fourteen trials with 4515 patients with HCC were included. Our results showed that treatment with PD-1/PD-L1 inhibitors was associated with better ORR and DCR than that with control (placebo or sorafenib or lenvatinib) (odds ratio [OR], 3.89; 95% confidence interval (CI), 2.55-5.95 and OR, 1.47; 95% CI, 1.11-1.95, respectively). The overall hazard ratio (HR) of PFS and OS were 0.66 (95% CI 0.56-0.78) and 0.65 (95% CI 0.55-0.77), respectively. In subgroup analysis, PD-1/PD-L1 inhibitor combination therapy had an advantage in terms of PFS (HR: 0.57 vs. 0.81) compared to that of PD-1/PD-L1 monotherapy. The incidence of grade 3-5 TrAEs was not significantly higher with PD-1/PD-L1 inhibitors than that with the control (OR, 1.12; 95% CI, 0.70-1.81). However, the combination of PD-1inhibitor with higher incidence of Grade 3-5 TrAEs (OR: 2.04, 95% CI 0.66-6.32) than the combination PD-L1 inhibitor (OR: 0.95, 95% CI 0.50-1.81). Conclusion: The combination of PD-1/PD-L1 inhibitors and targeted agents significantly improved the clinical outcomes in patients with advanced HCC. However, the incidence of Grade 3-5 TrAEs with PD-1 inhibitor combination therapy was higher than the combination PD-L1 inhibitor.

Substrate diversity of NSUN enzymes and links of 5-methylcytosine to mRNA translation and turnover.

Maps of the RNA modification 5-methylcytosine (m5C) often diverge markedly not only because of differences in detection methods, data depand analysis pipelines but also biological factors. We re-analysed bisulfite RNA sequencing datasets from five human cell lines and seven tissues using a coherent m5C site calling pipeline. With the resulting union list of 6,393 m5C sites, we studied site distribution, enzymology, interaction with RNA-binding proteins and molecular function. We confirmed tRNA:m5C methyltransferases NSUN2 and NSUN6 as the main mRNA m5C "writers," but further showed that the rRNA:m5C methyltransferase NSUN5 can also modify mRNA. Each enzyme recognises mRNA features that strongly resemble their canonical substrates. By analysing proximity between mRNA m5C sites and footprints of RNA-binding proteins, we identified new candidates for functional interactions, including the RNA helicases DDX3X, involved in mRNA translation, and UPF1, an mRNA decay factor. We found that lack of NSUN2 in HeLa cells affected both steady-state levels of, and UPF1-binding to, target mRNAs. Our studies emphasise the emerging diversity of m5C writers and readers and their effect on mRNA function.

Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population: An integrated genomic and transcriptional analysis.

Objective: The clinical significance of homologous recombination deficiency (HRD) in breast cancer, ovarian cancer, and prostate cancer has been established, but the value of HRD in non-small cell lung cancer (NSCLC) has not been fully investigated. This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care. Methods: A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled. HRD status was assessed using the AmoyDx Genomic Scar Score (GSS), with a score of ≥50 considered HRD-positive. Genomic, transcriptomic, tumor microenvironmental characteristics and prognosis between HRD-positive and HRD-negative patients were analyzed. Results: Of the patients, 25.1% (89/355) were HRD-positive. Compared to HRD-negative patients, HRD-positive patients had more somatic pathogenic homologous recombination repair (HRR) mutations, higher tumor mutation burden (TMB) (P<0.001), and fewer driver gene mutations (P<0.001). Furthermore, HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes, MET and MYC in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutant NSCLC, and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC. HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity. HRD-negative NSCLC showed activated signatures of major histocompatibility complex (MHC)-II, interferon (IFN)-γ and effector memory CD8+ T cells. HRD-positive patients had a worse prognosis and shorter progression-free survival (PFS) to targeted therapy (first- and third-generation EGFR-TKIs) (P=0.042). Additionally, HRD-positive, EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens. Conclusions: Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC. Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC. This study highlights potential actionable alterations in HRD-positive NSCLC, suggesting possible combinational therapeutic strategies for these patients.

Unconscious and Conscious Gaze-Triggered Attentional Orienting: Distinguishing Innate and Acquired Components of Social Attention in Children and Adults with Autistic Traits and Autism Spectrum Disorders.

Typically developing (TD) individuals can readily orient attention according to others' eye-gaze direction, an ability known as social attention, which involves both innate and acquired components. To distinguish between these two components, we used a critical flicker fusion technique to render gaze cues invisible to participants, thereby largely reducing influences from consciously acquired strategies. Results revealed that both visible and invisible gaze cues could trigger attentional orienting in TD adults (aged 20 to 30 years) and children (aged 6 to 12 years). Intriguingly, only the ability to involuntarily respond to invisible gaze cues was negatively correlated with autistic traits among all TD participants. This ability was substantially impaired in adults with autism spectrum disorder (ASD) and in children with high autistic traits. No such association or reduction was observed with visible gaze cues. These findings provide compelling evidence for the functional demarcation of conscious and unconscious gaze-triggered attentional orienting that emerges early in life and develops into adulthood, shedding new light on the differentiation of the innate and acquired aspects of social attention. Moreover, they contribute to a comprehensive understanding of social endophenotypes of ASD.