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Abstract Lipid nanoparticle-assisted mRNA inhalation therapy necessitates addressing challenges such as resistance to shear force damage, mucus penetration, cellular internalization, rapid lysosomal escape, and target protein expression. Here, we introduce the innovative “LOOP” platform with a four-step workflow to develop inhaled lipid nanoparticles specifically for pulmonary mRNA delivery. iLNP-HP08LOOP featuring a high helper lipid ratio, acidic dialysis buffer, and excipient-assisted nebulization buffer, demonstrates exceptional stability and enhanced mRNA expression in the lungs. By incorporating mRNA encoding IL-11 single chain fragment variable (scFv), scFv@iLNP-HP08LOOP effectively delivers and secretes IL-11 scFv to the lungs of male mice, significantly inhibiting fibrosis. This formulation surpasses both inhaled and intravenously injected IL-11 scFv in inhibiting fibroblast activation and extracellular matrix deposition. The HP08LOOP system is also compatible with commercially available ALC0315 LNPs. Thus, the “LOOP” method presents a powerful platform for developing inhaled mRNA nanotherapeutics with potential for treating various respiratory diseases, including idiopathic pulmonary fibrosis.

Abstract Background The global prevalence of autoimmune hepatitis (AIH) is increasing due in part to the lack of effective pharmacotherapies. Growing evidence suggests that fibroblast growth factor 4 (FGF4) is crucial for diverse aspects of liver pathophysiology. However, its role in AIH remains unknown. Therefore, we investigated whether FGF4 can regulate M1 macrophage and thereby help treat liver inflammation in AIH. Methods We obtained transcriptome-sequencing and clinical data for patients with AIH. Mice were injected with concanavalin A to induce experimental autoimmune hepatitis (EAH). The mechanism of action of FGF4 was examined using macrophage cell lines and bone marrow-derived macrophages. Results We observed higher expression of markers associated with M1 and M2 macrophages in patients with AIH than that in individuals without AIH. EAH mice showed greater M1-macrophage polarization than control mice. The expression of M1-macrophage markers correlated positively with FGF4 expression. The loss of hepatic Fgf4 aggravated hepatic inflammation by increasing the abundance of M1 macrophages. In contrast, the pharmacological administration of FGF4 mitigated hepatic inflammation by reducing M1-macrophage levels. The efficacy of FGF4 treatment was compromised following the in vivo clearance of macrophage populations. Mechanistically, FGF4 treatment activated the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT)-signal pathway in macrophages, which led to reduced M1 macrophages and hepatic inflammation. Conclusion We identified FGF4 as a novel M1/M2 macrophage-phenotype regulator that acts through the PI3K–AKT-signaling pathway, suggesting that FGF4 may represent a novel target for treating inflammation in patients with AIH.

Abstract Background Abnormal heart rate recovery (HRR), representing cardiac autonomic dysfunction, is an important predictor of cardiovascular disease. Prolonged sedentary time (ST) is associated with a slower HRR. However, it is not clear how much moderate-to-vigorous physical activity (MVPA) is required to mitigate the adverse effects of sedentary behavior on HRR in young and middle-aged adults. This study aimed to examine the joint association of ST and MVPA with abnormal HRR in this population. Methods A cross-sectional analysis was conducted on 1253 participants (aged 20–50 years, 67.8% male) from an observational study assessing cardiopulmonary fitness in Fujian Province, China. HRR measured via cardiopulmonary exercise tests on a treadmill was calculated as the difference between heart rate at peak exercise and 2 min after exercise. When the HRR was ≤ 42 beats·minute−1 within this time, it was considered abnormal. ST and MVPA were assessed by the IPAQ-LF. Individuals were classified as having a low sedentary time (LST [

Cerebral cavernous malformation (CCM) is a polygenic disease with intricate genetic interactions contributing to quantitative pathogenesis across multiple factors. The principal pathogenic genes of CCM, specifically KRIT1, CCM2, and PDCD10, have been reported, accompanied by a growing wealth of genetic data related to mutations. Furthermore, numerous other molecules associated with CCM have been unearthed. However, tackling such massive volumes of unstructured data remains challenging until the advent of advanced large language models. In this study, we developed an automated analytical pipeline specialized in single nucleotide variants (SNVs) related biomedical text analysis called BRLM. To facilitate this, BioBERT was employed to vectorize the rich information of SNVs, while a deep residue network was used to discriminate the classes of the SNVs. BRLM was initially constructed on mutations from 12 different types of TCGA cancers, achieving an accuracy exceeding 99%. It was further examined for CCM mutations in familial sequencing data analysis, highlighting an upstream master regulator gene fibroblast growth factor 1 (FGF1). With multi-omics characterization and validation in biological function, FGF1 demonstrated to play a significant role in the development of CCMs, which proved the effectiveness of our model. The BRLM web server is available at http://1.117.230.196.

Abstract Staircases are a frequently encountered obstacle in daily life, requiring individuals to navigate ascending and descending movements that place additional demands on the trunk and lower limbs compared to walking on level surfaces. Therefore, it is crucial to examine the biomechanical characteristics of the trunk and lower limbs in individuals with scoliosis during stair activity. The aim of this study was to investigate the biomechanical differences in trunk and lower limbs during daily stair activities between patients with scoliosis and a healthy population. Additionally, the study aimed to explore the relationship between trunk abnormalities and lower limb biomechanics, providing a clinical and objective assessment basis for scoliosis. The Qualisys system, based in Gothenburg, Sweden, was employed for data collection in this study, with a sampling frequency of 150 Hz. It captured the kinematics of the trunk and lower limbs, as well as the kinetics of the lower limbs during stair ascent and descent for both the 28 individuals with scoliosis and the 28 control participants. The results indicate that scoliosis patients demonstrated significantly higher asymmetry compared to the control group in various measures during ascent and decent. These include different parts of kinematics and kinetics. Scoliosis patients demonstrate noticeable variations in their movement patterns compared to the healthy population when engaging in stair activities. Specifically, during stair ascent, scoliosis patients exhibit a seemingly more rigid movement pattern, whereas descent is characterized by an unstable pattern.

Abstract Ceramic matrix composites (CMCs) play an important role in various load-bearing applications. However, fabricating CMCs with both high toughness and stiffness, which are normally mutually exclusive properties, is challenging. Here, we develop an SiOC composite film reinforced with nanoscale tungsten-based particles with a structure and property gradient by integrating hybrid nanoparticle inkjet printing and selective laser sintering. Mechanical results of the resulting SiOC-WOx films exhibit a stiffness-toughness co-enhancement, including a 2-fold improvement in hardness and modulus, and a 3.8-fold better fracture toughness than the matrix material. Moreover, the films exhibit interfacial bonding strengths of up to 86.6 MPa and operate stably at 1050 °C. This performance is attributed to a gradient in the metal-to-ceramic composition and uniformly dispersed self-assembled nanoscale reinforcing particles. This nanoparticle laser sintering method could be used to prepare other materials with structure and property gradients.

One-third of patients with autoimmune hepatitis (AIH) have cirrhosis at the time of diagnosis. The relevance of these variables, although unknown, is believed to be critical in AIH because of suspected interactions between the gut microbiome and genetic factors. Dysbiosis of the gut flora and elevated polymeric immunoglobulin receptor (pIgR) levels have been observed in both patients and mouse models. Moreover, there is a direct relationship between pIgR expression and transaminase levels in patients with AIH. In this study, we aimed to explore how pIgR influences the secretion of regenerating islet-derived 3 beta (Reg3b) and the flora composition in AIH using in vivo experiments involving patients with AIH and a concanavalin A-induced mouse model of AIH. Reg3b expression was reduced in pIgR gene (Pigr)-knockout mice compared to that in wild-type mice, leading to increased microbiota disruption. Conversely, exogenous pIgR supplementation increased Reg3b expression and maintained microbiota homeostasis. RNA sequencing revealed the participation of the interleukin (IL)-17 signaling pathway in the regulation of Reg3b through pIgR. Furthermore, the introduction of external pIgR could not restore the imbalance in gut microbiota in AIH, and the decrease in Reg3b expression was not apparent following the inhibition of signal transducer and activator of transcription 3 (STAT3). In this study, pIgR facilitated the upregulation of Reg3b via the STAT3 pathway, which plays a crucial role in preserving the balance of the intestinal microbiota in AIH. Through this research, we discovered new molecular targets that can be used for the diagnosis and treatment of AIH.

Abstract Background Non-small cell lung cancer (NSCLC) is one of the predominant malignancies globally. Percutaneous thermal ablation (PTA) has gained widespread use among NSCLC patients, with the potential to elicit immune responses but limited therapeutic efficacies for advanced-stage disease. T-helper type 9 (Th9) cells are a subset of CD4+ effector T cells with robust and persistent anti-tumor effects. This study proposes to develop PTA-Th9 cell integrated therapy as a potential strategy for NSCLC treatment. Methods The therapeutic efficacies were measured in mice models with subcutaneously transplanted, recurrence, or lung metastatic tumors. The tumor microenvironments (TMEs) were evaluated by flow cytometry. The cytokine levels were assessed by ELISA. The signaling molecules were determined by quantitative PCR and Western blotting. The translational potential was tested in the humanized NSCLC patient-derived xenograft (PDX) model. Results We find that PTA combined with adoptive Th9 cell transfer therapy substantially suppresses tumor growth, recurrence, and lung metastasis, ultimately extending the survival of mice with NSCLC grafts, outperforming both PTA and Th9 cell transfer monotherapy. Analysis of TMEs indicates that combinatorial therapy significantly augments tumor-infiltrating Th9 cells, boosts anti-tumor effects of CD8+ T cells, and remodels tumor immunosuppressive microenvironments. Moreover, combinatorial therapy significantly strengthens the regional and circulation immune response of CD8+ T cells in mice with tumor lung metastasis and induces peripheral CD8+ T effector memory cells in mice with tumor recurrence. Mechanically, PTA reinforces the anti-tumor ability of Th9 cells primarily through upregulating interleukin (IL)-1β and subsequently activating the downstream STAT1/IRF1 pathway, which could be effectively blocked by intercepting IL-1β signaling. Finally, the enhanced therapeutic effect of combinatorial therapy is validated in humanized NSCLC PDX models. Conclusions Collectively, this study demonstrates that combinatorial therapy displays robust and durable anti-tumor efficacy and excellent translational potential, offering excellent prospects for translation and emerging as a promising approach for NSCLC treatment.

This work reports on the creation of an electrochemical sensor for the real-time monitoring of paclitaxel (PCX) concentrations in biological fluids. The sensor is based on a poly-melamine-reduced graphene oxide nanocomposite-modified glassy carbon electrode (p-Melamine/rGO/GCE). The electrochemical sensor revealed a linear relationship between the peak current of the DPVs and PCX concentrations between 1 and 1180 μM, with a detection limit of 12 nM. The Ip value of PCX dropped to 98.15% of the starting value after 25 days, indicating excellent stability and repeatability of the p-Melamine/rGO/GCE sensors, which were assessed for long-term stability. The sensor's peak currents of PCX did not exhibit any significant variation when 50 μM organic compounds and inorganic ions were present, suggesting that it could find application in clinical samples. Relative standard deviation values for recovery tests on prepared urine samples ranged from 3.36% to 4.72%. In the area of chemotherapeutic agent monitoring, this work presents a novel method that shows remarkable sensitivity and selectivity in the real-time monitoring of PCX concentrations in biological fluids. The suggested sensor offers a practical and affordable means of tracking PCX concentrations in biological fluids in real time, with potential uses in therapeutic medication monitoring and clinical diagnostics.

Abstract Ductal carcinoma in situ (DCIS) represents pre-invasive breast carcinoma. In untreated cases, 25–60% DCIS progress to invasive ductal carcinoma (IDC). The challenge lies in distinguishing between non-progressive and progressive DCIS, often resulting in over- or under-treatment in many cases. With increasing screen-detected DCIS in these years, the nature of DCIS has aroused worldwide attention. A deeper understanding of the biological nature of DCIS and the molecular journey of the DCIS-IDC transition is crucial for more effective clinical management. Here, we reviewed the key signaling pathways in breast cancer that may contribute to DCIS initiation and progression. We also explored the molecular features of DCIS and IDC, shedding light on the progression of DCIS through both inherent changes within tumor cells and alterations in the tumor microenvironment. In addition, valuable research tools utilized in studying DCIS including preclinical models and newer advanced technologies such as single-cell sequencing, spatial transcriptomics and artificial intelligence, have been systematically summarized. Further, we thoroughly discussed the clinical advancements in DCIS and IDC, including prognostic biomarkers and clinical managements, with the aim of facilitating more personalized treatment strategies in the future. Research on DCIS has already yielded significant insights into breast carcinogenesis and will continue to pave the way for practical clinical applications.

Keloids represent a specific type of dermal tumor, where delayed treatment greatly heighten risks of recurrence. This study thus seeks to identify key genes for early keloid diagnosis and compare how immune cell infiltration between keloid lesion skin (KLS) and keloid adjacent non-lesional skin (KNL) differ. Utilizing two GEO datasets, which encompassed KLS (n=8) and KNL (n=6) samples, 564 differentially expressed genes (DEGs) were identified, with a primary emphasis on inflammation- and fibrosis-related pathways. The gene TFCP2L1 was pinpointed from the intersection of LASSO and SVM-RFE algorithms, exhibiting downregulation in KLS when juxtaposed with KNL. To aid prognosis and identification of potential immunotherapy targets, the CIBERSORT algorithm was employed to assess prelative proportions of immune cells. In the KNL samples, there was an observed increase in follicular helper T cells, activated NK cells, and activated dendritic cells. Conversely, M1 macrophages were elevated in KLS samples. TFCP2L1 exhibited a positive correlation with activated NK cells and activated dendritic cells, while it showed a negative correlation with M1macrophages. These findings highlight the intertwined roles of TFCP2L1 and immune cell infiltration, lending to TFCP2L1’s potential as a diagnostic biomarker for keloids and highlights how TFCP2L1 might influence keloid development through immune cell populations.

This study investigated the effects of dietary chlorogenic acid (CGA) on the productive and reproductive performance, egg quality, antioxidant function, and intestinal microenvironment of laying hens. Thus, 162 healthy Hy-Line Brown breeding hens (63 weeks old) were randomly allocated to 3 groups, each receiving a basal diet plus supplementation: 0, 250, and 500 mg/kg CGA, respectively. Per the in vitro test, CGA had obvious inhibitory effects on Salmonella enteritis and avian pathogenic Escherichia coli and strong free radical scavenging ability. Per the breeder laying hen experiment, the CGA diets had no significant influence on egg production or reproductive performance (P < 0.05). Nevertheless, compared with the control diet, 250 mg/kg CGA significantly increased eggshell thickness, egg weight, yolk color, and Haugh unit (P < 0.05). Compared with the control diet and 500 mg/kg CGA, 250 mg/kg CGA significantly (P < 0.05) elevated antioxidant capacity by reducing serum malondialdehyde content, upregulating heme oxygenase-1, and downregulating heat shock proteins mRNA levels in the ileum. Compared with the control diet and 500 mg/kg CGA, 250 mg/kg CGA (P < 0.05) enhanced intestinal barrier function, shown by the upregulation of ileal Occludin and Mucin-2 mRNA levels; furthermore, 250 mg/kg CGA (P < 0.05) increased anti-apoptotic capacity by increasing B-cell leukemia/lymphoma 2 gene expression and downregulated Bcl2 Associated X mRNA levels in the liver and ileum of late breeder laying hens (P < 0.05). Lastly, 250 mg/kg CGA (P < 0.05) increased cecal g_CHKCI001 and short-chain fatty acid-producing bacteria g_Prevotellaceae UCG-001, positively related to gut health, and in the cecum, 500 mg/kg CGA significantly (P < 0.05) increased g_Shuttleworthia abundance, negatively related to gut health. Our findings suggest that dietary inclusion of 250 mg/kg CGA promotes egg quality, intestinal microbial composition, gut barrier integrity, and the antioxidant capacity of aged breeder laying hens.

Abstract Photoelectric synaptic device is a promising candidate component in brain‐inspired high‐efficiency neuromorphic computing systems. Implementing neuromorphic computing with broad bandwidth is, however, challenging owing to the difficulty in realizing broadband characteristics with available photoelectric synaptic devices. Herein, taking advantage of the type‐II heterostructure formed between environmentally friendly CuInSe2 quantum dots and organic semiconductor, broadband photoelectric synaptic transistors (BPSTs) that can convert light signals ranging from ultraviolet (UV) to near‐infrared (NIR) into post‐synaptic currents are demonstrated. Essential synaptic functions, such as pair‐pulse facilitation, the modulation of memory level, long‐term potentiation/depression transition, dynamic filtering, and learning‐experience behavior, are well emulated. More significantly, benefitting from broadband responses, information processing functions, including arithmetic computing and pattern recognition can also be simulated in a broadband spectral range from UV to NIR. Furthermore, the BPSTs exhibit obvious synaptic responses even at an ultralow operating voltage of −0.1 mV with an ultralow energy consumption of 75 aJ per event, and show their potential in flexible electronics. This study presents a pathway toward the future construction of brain‐inspired neural networks for high‐bandwidth neuromorphic computing utilizing energy‐efficient broadband photoelectric devices.

Abstract Gut microbiota can influence host gene expression and physiology through metabolites. Besides, the presence or absence of gut microbiome can reprogram host transcriptome and epitranscriptome as represented by N6‐methyladenosine (m6A), the most abundant mammalian mRNA modification. However, which and how gut microbiota‐derived metabolites reprogram host transcriptome and m6A epitranscriptome remain poorly understood. Here, investigation is conducted into how gut microbiota‐derived metabolites impact host transcriptome and m6A epitranscriptome using multiple mouse models and multi‐omics approaches. Various antibiotics‐induced dysbiotic mice are established, followed by fecal microbiota transplantation (FMT) into germ‐free mice, and the results show that bile acid metabolism is significantly altered along with the abundance change in bile acid‐producing microbiota. Unbalanced gut microbiota and bile acids drastically change the host transcriptome and the m6A epitranscriptome in multiple tissues. Mechanistically, the expression of m6A writer proteins is regulated in animals treated with antibiotics and in cultured cells treated with bile acids, indicating a direct link between bile acid metabolism and m6A biology. Collectively, these results demonstrate that antibiotic‐induced gut dysbiosis regulates the landscape of host transcriptome and m6A epitranscriptome via bile acid metabolism pathway. This work provides novel insights into the interplay between microbial metabolites and host gene expression.

BackgroundMetronidazole (MTZ) is among the first-line drugs against the human gastric pathogen Helicobacter pylori (H. pylori). MTZ is used as a prodrug that is activated by an oxygen-insensitive enzyme NADPH nitroreductase (RdxA). Loss-of-function mutations in rdxA make H. pylori MTZ resistant; however, experimental proof is lacking.MethodsWe collected 139 gastric biopsy samples from patients suspected of H. pylori infection in Shanghai, and amplified Hp-specific rdxA gene from 134 samples. All these rdxA genes were sequenced and phylogenetically compared. The effect of mutations on RdxA function was measured by expressing them in Escherichia coli DH5α by using the MTZ sensitivity test.ResultsIn total, 134 gastric biopsy samples were identified as H. pylori positive. Of the 134 samples, 74 and 6 had point mutations at the various sites or promoter region of rdxA, generating truncated and extended fused proteins, respectively. The remaining 54 were full-length with single nucleotide variation (SNV) compared with the wild-type RdxA from H. pylori, with 49 clustering with hpEastAsia, 3 with hpEurope, and 2 with hpNEAfrica. All 134 rdxA were expressed in E. coli DH5α; 22 and 112 resultant strains showed MTZ-sensitive and MTZ-resistant phenotypes, respectively. Comparative analysis of single nucleotide polymorphisms (SNPs) in the functional and inactivated RdxA revealed 14 novel mutations in RdxA, 5 of which conferred MTZ resistance: S18F, D59S, L62I, S79N, and A187V.ConclusionThe occurrence of MTZ resistance induced by site-mutation of RdxA in patients with H. pylori infection was 83.6% (112/134) in the Shanghai region. The major form of loss-of-function mutation was truncation of RdxA translation at a rate of 58/112 (51.8%). Molecular detection reliably determined the resistance of H. pylori to MTZ. Thus, the functional mutants involved in MTZ resistance facilitate clinical diagnosis and medication based on sequence analysis.

Abstract Background Breast cancer has the highest incidence rate of cancer worldwide, and brain metastases (BrM) are among the most malignant cases. While some patients have benefited from immune checkpoint inhibitors (ICIs), the complex anatomical structure of the brain and the heterogeneity of metastatic tumors have made it difficult to characterize the tumor immune microenvironment (TME) of metastatic tumors. Methods To address this, we used single‐cell RNA sequencing (scRNA‐seq) to analyze immune cells in the cerebrospinal fluid (CSF) of BrM patients with breast cancer, thereby providing a comprehensive view of the immune microenvironment landscape of BrM. Results Based on canonical marker genes, we identified nine cell types, and further identified their subtypes through differential expression gene (DEG) analysis. We compared the changes in cells and functions in the immune microenvironment of patients with different prognoses. Our analysis revealed a series of genes that promote tumor immune function (CCR5, LYZ, IGKC, MS4A1, etc.) and inhibit tumor immune function (SCGB2A2, CD24, etc.). Conclusions The scRNA‐seq in CSF provides a noninvasive method to describe the TME of breast cancer patients and guide immunotherapy.

Detectors capable of resolving the number of photons are essential in many applications, ranging from classic photonics to quantum optics and quantum communication. In particular, photon-number-resolving detectors based on arrays of superconducting nanostrips can offer a high detection efficiency, a low dark count rate, and a recovery time of a few nanoseconds. In this work, we use a detector of this kind for the unbiased generation of random numbers by following two different methods based on the detection of photons. In the former, we exploit the property that the light is equally distributed on each strip of the entire detector, whereas in the latter, we exploit the fact that, for a high average number of photons, the parity of the Poisson distribution of the number of photons emitted by the laser tends to be zero. In addition, since these two methods are independent, it is possible to use them at the same time.

Abstract Background Although the disturbance of circadian rhythms represents a significant clinical feature of major depressive disorder (MDD), the relationship between biological rhythm disturbances and the severity of suicidal ideation in individuals with MDD remains unclear. We aimed to explore the characteristics of different biological rhythm dimensions in MDD and their association with the severity of depressive symptoms and suicidal ideation. Methods A total of 50 MDD patients and 50 healthy controls were recruited and their general information was collected. The severity of depressive symptoms was assessed with the 17-item Hamilton Depression Rating Scale (HDRS17). The intensity of suicidal ideation was evaluated with the Beck Scale for Suicide Ideation (BSS). The Chinese version of the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) scale was utilized to assess the participants’ biological rhythm dysregulation. Multiple logistic regression analysis was conducted to explore the relationship between biological rhythm and the risk of MDD. Multiple linear regression analysis was performed in the MDD group to investigate the relationship between different biological rhythm dimensions and suicide ideation. Results Significant differences were observed between the MDD group and the control group in total BRIAN score (Z=-5.41, P

Abstract As the two most principal active substances in the corn silk, polysaccharides and flavonoids, the mechanism of interaction between them has been a topic of intense research. This study provides an in-depth investigation of the interaction mechanism between corn silk glycans and luteoloside (LUT) and the synergistic role that result from this interaction. The interaction mechanism was evaluated by isothermal titration calorimetry (ITC) and circular dichroism (CD), and the synergistic role was evaluated by the expression of glucose transporters (GLUT-1), insulin secretion and surface plasmon resonance (SPR). CD and ITC results indicated that the interaction between CSGs and LUT mainly driven by the Cotton effects, enthalpy and entropy-driven. This interaction precipitated the formation of complexes (CSGs/LUT complexes) between corn silk glycans (CSGs) with four different molecular weights and luteoloside (LUT). Furthermore, the CSGs and LUT play a synergistic role in glucose regulation through GLUT-1 expression and insulin secretion experiments, compared to single luteoloside group. Graphical Abstract

Abstract Highly stretchable porous materials are promising for flexible electronics but their fabrication is a great challenge. Herein, several kinds of highly stretchable conductive porous elastomers with low or negative Poisson’s ratios are achieved by uniaxial, biaxial, and triaxial hot-pressing strategies. The reduced graphene oxide/polymer nanocomposite elastomers with folded porous structures obtained by uniaxial hot pressing exhibit high stretchability up to 1200% strain. Furthermore, the meta-elastomers with reentrant porous structures combining high biaxial (or triaxial) stretchability and negative Poisson’s ratios are achieved by biaxial (or triaxial) hot pressing. The resulting elastomer-based wearable strain sensors exhibit an ultrawide response range (0-1200%). The materials can be applied for smart thermal management and electromagnetic interference shielding, which are achieved by regulating the porous microstructures via stretching. This work provides a versatile strategy to highly stretchable and negative-Poisson-ratio porous materials with promising features for various applications such as flexible electronics, thermal management, electromagnetic shielding, and energy storage.

Purpose: Post-stroke cognitive impairment (PSCI) is a common complication of ischemic stroke episodes. Memory impairment is an important component of the poststroke cognitive syndrome. Microglial activation plays a critical role in stroke-induced neuroinflammation. Previous studies have reported that electroacupuncture (EA) provides neuroprotective effects by reducing the expression levels of the Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) and inhibiting neuroinflammation in rat model of ischemic stroke. Further understanding of the role and connections between P2X7R and microglial activation in EA-induced anti-inflammatory can reveal novel targets for post-stroke memory impairment treatment. Methods: A Middle cerebral artery occlusion and reperfusion (MCAO/R) model was established. We used 2’(3’)-O-(4-benzoyl) benzoyl ATP (BzATP) as a P2X7R agonist. Following MCAO/R injury, the rats underwent EA therapy at the Baihui (DU20) and Shenting (DU24) acupoints for seven consecutive days. The Barnes maze test was used to evaluate memory function. Following intervention, a T2 weighted images (T2WI) scan was performed to identify changes in cerebral infarction volume in MCAO/R rats. The levels of Interleukin-1β (IL-1β), Interleukin-6 (IL-6) and Interleukin-4 (IL-4), Interleukin-10 (IL-10) in the peri-infarct hippocampal were examined by ELISA. Immunofluorescence was employed to evaluate Iba-1+ / P2X7R+, Iba-1+/ iNOS+ and Iba-1+/ Arg-1+ cell populations in the peri-infarct hippocampal DG area. The protein expression of P2X7R, Nuclear factor E2-related factor 2 (Nrf2), Recombinant nlr family, pyrin domain containing protein 3 (NLRP3), Inducible nitric oxide synthase (iNOS) and Arginase-1 (Arg-1) in the peri-infarct hippocampal were investigated using western blot assays. Besides, we also measured the levels of reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA). Results: We found EA treatment reduced inflammation and oxidative stress, which is consistent with a decrease in P2X7R expression and improved learning and memory functions. In contrast, we found BzATP enhanced inflammation and oxidative stress. Moreover, our results showed EA treatment up-regulated Nrf2, down-regulated NLRP3, and promoted microglia M2 polarization. Finally, EA-mediated positive effects were reversed by intracerebroventricular injection of BzATP, which is consistent with an increase in P2X7R expression. Conclusion: EA ameliorates memory impairment in a rat model of ischemic stroke by reducing inflammation and ROS through the inhibition of P2X7R expression. In turn, this mechanism regulates Nrf2 and NLRP3 expression, suggesting EA is beneficial for ischemic stroke treatment using P2X7R as target.

Objectives The objective of this study was to evaluate the gender differences in the correlation between physical activity (PA) and cognitive subdomains in elderly individuals with type 2 diabetes (T2D) and mild cognitive impairment (MCI).Design Cross-sectional study.Setting The research was carried out in communities located in Fuzhou, Fujian Province and Beijing Municipality.Participants Community-dwelling elders with T2D and MCI aged 60 years or older were eligible for this study.Primary outcome measures and analyses The weekly PA score was assessed using the International Physical Activity Questionnaire (IPAQ). The cognitive subdomains were evaluated through a battery of cognitive assessments, including the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test Part B, Digit Symbol Substitution Test (DSST) and the Stroop Color-Word Test (SCWT). Multiple linear regression models were employed to examine the association between PA and cognitive subdomains in both male and female individuals.Results In older men, higher total IPAQ score was positively correlated with higher RAVLT (P=0.011) and SCWT (P=0.049). There was a significant interaction between the total PA score and gender in relation to RAVLT (P=0.008) and SCWT (P=0.027). Moreover, there was a positive correlation between moderate-vigorous PA level and RAVLT in older men (P=0.007). Additionally, a positive correlation was found between moderate-vigorous PA level and DSST in older women (P=0.038).Conclusion In older individuals with T2D and MCI, the association between PA and cognitive subdomains differs between men and women. This discrepancy may impact the customisation of exercise recommendations.

BackgroundOvarian stimulation (OS) for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in women with PCOS often results in multiple follicular development, yet some individuals experience poor or suboptimal responses. Limited data exist regarding the impact of poor/suboptimal ovarian response on pregnancy outcomes in women with PCOS.ObjectivesThe aim of this study was to evaluate whether the live birth rate (LBR) per fresh embryo transfer and cumulative live birth rate (CLBR) per aspiration cycle differ in women with PCOS defined by the Patient-Oriented Strategy Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria.MethodsA retrospective study involving 2,377 women with PCOS who underwent their first IVF/ICSI cycle at Sun Yat-sen Memorial Hospital from January 2011 to December 2020 was used. Patients were categorized into four groups based on age, antral follicle count, and the number of oocytes retrieved, according to the POSEIDON criteria. The LBR and CLBR were compared among these groups. Logistic regression analysis was performed to assess whether the POSEIDON criteria served as independent risk factors and identify factors associated with POSEIDON.ResultsFor patients

Abstract Background Mutated BRAF is identified in 1%–5% non‐small cell lung cancer (NSCLC) patients, with non‐V600 mutations accounting for 50%–70% of these. The most common non‐V600 mutation is BRAF G469V/A. Currently, there are no targeted therapies available for non‐V600 mutated patients. A recent report provided interesting preclinical evidence revealing sensitivity of BRAF G469V to epidermal growth factor receptor (EGFR) inhibitors, raising the possibility of repurposing anti‐EGFR agents. It is therefore worthy to characterize the clinical and molecular features of BRAF G469V/A‐mutant NSCLC to provide more insights for precision therapy. Methods We conducted a retrospective screening of 25,694 Chinese patients with advanced or metastatic NSCLC to identify individuals with mutated BRAF. Additionally, we performed similar screenings on patients with adenocarcinoma (LUAD) from The Cancer Genome Atlas (TCGA) cohort (n = 567) and the MSKCC cohort (n = 1152). Subsequently, we characterized the clinical and molecular features of the patients carrying BRAF mutations. Results BRAF G469V was identified in 28 (0.1%) patients from the Chinese NSCLC cohort and 5 (0.9%) from TCGA‐LUAD. Notably, none was identified in the MSKCC cohort. G469A was found in 79 (0.3%) Chinese patients, 2 (0.4%) from TCGA‐LUAD, and 9 (0.8%) from the MSKCC cohort. Relative allele frequency analysis suggested most BRAF mutations as driven clones. Tumor mutation burden (median 4 mutations/Mb) was not significantly different between patients carrying G469V, G469A, V600E, or other BRAF mutations. Surprisingly, KRAS mutations were found in approximately 50% of patients with G469V mutation and about 8% of patients with G469A mutation, representing a prominent potential resistance mechanism against EGFR inhibitors. Structural modeling suggested BRAF G469V and G469A as binding partners of gefitinib. Conclusion Our large‐scale analysis characterized the prevalence and mutational landscape of BRAF G469V/A‐mutant NSCLC and proposed gefitinib as a potential option, providing a basis for further investigations on treating BRAF‐mutated NSCLC.

Prenatal environmental exposure could be an essential health risk factor associated with neurodevelopmental disorders in offspring. However, the exact mechanisms underlying the impact of prenatal PM2.5 exposure on offspring cognition remain unclear. In our recent study using a PM2.5 exposed pregnant mouse model, we observed significant synaptic dysfunction in the hippocampi of the offspring. Concurrently, the epigenetic regulator of KDM5A and the Shh signaling pathway exhibited decreased activities. Significantly, changes in hippocampal KDM5A and Shh levels directly correlated with PM2.5 exposure intensity. Subsequent experiments revealed a marked reduction in the expression of Shh signaling and related synaptic proteins when KDM5A was silenced in cells. Notably, the effects of KDM5A deficiency were reversed significantly with the supplementation of a Shh activator. Furthermore, our findings indicate that Shh activation significantly attenuates PM2.5-induced synaptic impairments in hippocampal neurons. We further demonstrated that EGR1, a transcriptional inhibitor, plays a direct role in KDM5A’s regulation of the Shh pathway under conditions of PM2.5 exposure. Our results suggest that the KDM5A’s inhibitory regulation on the Shh pathway through the EGR1 gene is a crucial epigenetic mechanism underlying the synaptic dysfunction in hippocampal neurons caused by maternal PM2.5 exposure. This emphasizes the role of epigenetic regulations in neurodevelopmental disorders caused by environmental factors.

ABSTRACT: To develop effective antibiotics alternatives is getting more and more important to poultry healthy production. The study investigated the effects of a microencapsulated essential oils and organic acids preparation (EOA) on growth performance, slaughter performance, nutrient digestibility and intestinal microenvironment of broilers. A total of 624 1-day-old male Arbor Acres broilers were randomly divided into 6 groups including the control group (T1) fed with basal diet, the antibiotic group (T2) supplemented with basal diet with 45 mg/kg bacitracin methylene disalicylate (BMD), and 4 inclusion levels of EOA-treated groups (T3, T4, T5, T6 groups) chickens given basal diet with 200, 400, 600, and 800 mg EOA/kg of diet, respectively. Results showed that compared with the control, the 200 mg/kg EOA group increased average daily gain (ADG) and average body weight (ABW) during the early stage (P < 0.05). EOA addition decreased crypt depth of the ileum (P < 0.05), but villus height to crypt depth ratio was increased by EOA addition at 200 and 400 mg/kg at d 21 (P < 0.05). Compared with the control, dietary addition EOA at 200, 400 and 600 mg/kg increased the lipase activity in the duodenum at d 21 (P < 0.05). Increased lactic acid bacteria population was found in cecal digesta of the 400 mg/kg EOA group at d 21 (P < 0.05), and higher concentration of butyric acid level was observed in cecal digesta at d 21 and d 42 in the 200 mg/kg EOA group compared with the control (P < 0.05). RT-PCR analysis found that dietary EOA addition decreased the gene expression of IL-1β, COX-2 and TGF-β4 in the ileum at d 21 (P < 0.05), while only the 200 mg/kg EOA increased the gene expression of IL-10, TGF-β4, Claudin-1, ZO-1, CATH-1, CATH-3, AvBD-1, AvBD-9 and AvBD-12 in the ileum at d 42 (P < 0.05) compared with the control. In summary, adding 200 mg/kg and 400 mg/kg of the EOA to the diet could improve the growth performance and intestinal microenvironment through improving intestinal morphology, increasing digestive enzymes activity and cecal lactic acid bacteria abundance and butyric acid content, improving intestinal barrier function as well as maintaining intestinal immune homeostasis. The improving effect induced by EOA addition in the early growth stage was better than that in the later growth stage. Overall, the EOA product might be an effective antibiotic alternative for broiler industry.

CRISPR-based gene drives offer promising prospects for controlling disease-transmitting vectors and agricultural pests. A significant challenge for successful suppression-type drive is the rapid evolution of resistance alleles. One approach to mitigate the development of resistance involves targeting functionally constrained regions using multiple gRNAs. In this study, we constructed a 3-gRNA homing gene drive system targeting the recessive female fertility gene Tyrosine decarboxylase 2 (Tdc2) in Drosophila suzukii, a notorious fruit pest. Our investigation revealed only a low level of homing in the germline, but feeding octopamine restored the egg-laying defects in Tdc2 mutant females, allowing easier line maintenance than for other suppression drive targets. We tested the effectiveness of a similar system in Drosophila melanogaster and constructed additional split drive systems by introducing promoter-Cas9 transgenes to improve homing efficiency. Our findings show that genetic polymorphisms in wild populations may limit the spread of gene drive alleles, and the position effect profoundly influences Cas9 activity. Furthermore, this study highlights the potential of conditionally rescuing the female infertility caused by the gene drive, offering a valuable tool for the industrial-scale production of gene drive transgenic insects.

BackgroundThere are few studies investigating the relationship between serum vitamin B6 and mortality risk in the elderly. This study hereby evaluated the associations between biomarkers of serum vitamin B6 status and cardiovascular, cancer, and all-cause mortality risks in the elderly.MethodsOur study included a total of 4,881 participants aged 60 years or older from the National Health and Nutrition Examination Survey (NHANES) 2005-2010. Serum vitamin B6 status was estimated based on levels of pyridoxal 5’-phosphate (PLP), 4-pyridoxic acid (4-PA), and vitamin B6 turnover rate (4-PA/PLP) detected by high-performance liquid chromatography. Survival status and corresponding causes of death were matched through the National Death Index records through December 31, 2019. Multivariate Cox regression model was adopted to assess the relationships between serum vitamin B6 status and the risk of mortality.ResultsDuring a median follow-up period of 10.33 years, 507 cardiovascular deaths, 426 cancer deaths, and 1995 all-cause deaths were recorded, respectively. In the multivariate-adjusted Cox model, the hazard ratios (HRs) and 95% confidence intervals (CIs) for the highest versus the lowest quartiles of PLP, 4-PA, and 4-PA/PLP were 0.70(0.54-0.90), 1.33(0.88-2.02), and 2.01(1.41-2.79) for cardiovascular mortality, 0.73(0.52-1.02), 1.05(0.71-1.57), and 1.95(1.25-3.05) for cancer mortality, and 0.62(0.53-0.74), 1.05(0.82-1.34), and 2.29(1.87-2.79) for all-cause mortality, respectively.ConclusionOur study found that lower serum PLP levels were associated with increased risks of cardiovascular and all-cause mortality among the elderly population. And higher vitamin B6 turnover rate was associated with increased risks of cardiovascular, cancer, and all-cause mortality.

Abstract Cuproptosis, an emerging form of programmed cell death, has received tremendous attention in cancer therapy. However, the efficacy of cuproptosis remains limited by the poor delivery efficiency of copper ion carriers. Herein, copper complex nanoparticles (denoted as Cu(I) NP) are developed that can efficiently deliver copper complex into cancer cells to induce cuproptosis. Cu(I) NP demonstrate stimulus‐responsive release of copper complexes, which results in mitochondrial dysfunction and promotes the aggregation of lipoylated dihydrolipoamide S‐acetyltransferase (DLAT), leading to cuproptosis. Notably, Cu(I) NP not only induce cuproptosis, but also elicit robust immune responses to suppress tumor growth. Overall, this study provides a promising strategy for cuproptosis‐based cancer therapy.

ObjectivesRegarding increased nuchal translucency (NT), the cutoff values used are heterogeneous in clinical practice, this study aims to assess the efficacy of prenatal detection for chromosomal abnormalities and pregnancy outcomes in fetuses with varying NT thicknesses, in order to provide data that supports informed prenatal diagnosis and genetic counseling for such cases.MethodsWe included 2,272 pregnant women under 35 with singleton pregnancies who underwent invasive prenatal diagnosis between 2014 and 2022. The cohort comprised 2,010 fetuses with increased NT (≥2.5 mm) and 262 fetuses with normal NT but exhibiting a single soft marker. Prenatal diagnoses were supported by chromosomal microarray (CMA) and copy number variation sequencing (CNV-seq) analyses.ResultsThe detection rates of numerical chromosomal abnormalities were 15.4% (309/2,010) and 17.3% (297/1,717) in the NT ≥2.5 and ≥ 3.0 groups, respectively. Pathogenic/likely pathogenic CNV incidence increased with NT thickness (χ2 = 8.60, p 0.05). Fetuses with NT thickness between 2.5 and 2.9 mm combined with the presence of soft markers or non-lethal structural abnormalities exhibited a significantly higher chromosomal abnormality risk (19.0%) compared to fetuses with isolated increased NT ranging from 3.5 to 4.4 mm (13.0%). Pregnancy termination rates increased with NT thickness (χ2 = 435.18, p

BackgroundPrevious iodine nutrition monitoring has mainly focused on key populations such as pregnant women and children, and there are few reports on the status of iodine nutrition among adults in Xinjiang. ObjectiveTo understand the iodine nutrition and thyroid function status of healthy adults in northern and southern Xinjiang, and to explore the effect of iodine nutrition level on thyroid function. MethodsIn May 2021, a stratified cluster sampling method was used to select one county (city) with good and one county (city) with poor economic conditions in each of the northern and southern regions of Xinjiang as the survey sites, and about 100 households were sampled from each survey site to collect samples of edible salt as well as random urine samples and fastingvenous blood of healthy adults aged 18 years or older. Urinary iodine was determined by cerium arsenide catalytic spectrophotometric method, salt iodine by direct titration method, and thyroid hormones by chemiluminescence immunoassay. Non-parametric test was used for comparison of non-normal quantitative data, t-test and analysis of variance were used for comparison of normal quantitative data, χ2 test was used for comparison of rates, and Spearman correlation analysis was used for correlation between salt iodine intake and urinary iodine level. ResultsA total of 436 salt samples were collected, the median salt iodine level was 28.18 mg·kg−1, and the coverage rate of qualified iodized salt was >90% in both northern and southern Xinjiang regions (P>0.05). A total of 436 adult urine samples were collected, the median urinary iodine was 219.73 μg·L−1. The urinary iodine medians of adults in the northern and southern regions were 209.47 μg·L−1 and 244.80 μg·L−1, respectively, and it was higher in the southern region than that in the northern region (P0.05), in which subclinical hypothyroidism was predominant, with prevalence rates of 9.95% and 9.36% in the northern and southern regions, respectively. ConclusionSome adults in northern and southern Xinjiang have high iodine nutrition levels, and although no significant effect has been found on thyroid function in the population, the high iodine nutrition status still requires continuing concern. It is recommended to monitor the iodine nutritional status of adults continuously while strengthening health education for residents.

Abstract Background Upper limb dysfunction seriously affects the ability of stroke patients to perform activities of daily living. As a popular exercise therapy, Tai Chi may become an alternative intervention. However, the neurophysiological mechanism by which Tai Chi improves upper limb dysfunction in stroke patients is still unclear, which limits its further promotion and application. Therefore, conducting a strict randomized clinical trial is necessary to observe how Tai Chi affects upper limb dysfunction in stroke patients and to explore its neurophysiological mechanism. Methods/design This report describes a randomized, parallel-controlled trial with distributive concealment and evaluator blinding. A total of 84 eligible participants will be randomly assigned to the Tai Chi group or the control group in a 1:1 ratio. The participants in the Tai Chi group will receive 4 weeks of Tai Chi training: five 60-min sessions a week for a total of 20 sessions. The participants in the control group will not receive Tai Chi training. Both groups will receive medical treatment and routine rehabilitation training. The primary outcome measure is the mean change in the Fugl-Meyer Assessment Upper Extremity (FMA-UE) scale score between baseline and 4 weeks; the secondary outcomes are the mean changes in kinematic characteristics and the Wolf Motor Function Test (WMFT) and Stroke Impact Scale (SIS) scores. In addition, the corticomuscular coupling level and near-infrared brain functional imaging will be monitored to explore the mechanism by which Tai Chi improves upper limb function of stroke patients. Discussion This randomized controlled trial will examine the effectiveness of Tai Chi in stroke patients with upper limb dysfunction and explore the neurophysiological mechanism. Positive results will verify that Tai Chi can improve upper limb function of stroke patients. Trial registration Chinese Clinical Trial Registration Center, ChiCTR2200061376 (retrospectively registered). Registered June 22, 2022. http://www.chictr.org.cn/listbycreater.aspx . Manuscript Version: 3.0 Manuscript Date: October 10, 2023.

AbstractTo investigate the phylogenetic position of Isomyia Walker, 1860, a genus that suffered from frequent revisions of the taxonomic status following the subfamily Rhiniinae (Diptera, Calliphoridae), we sequenced, assembled, annotated, and analyzed the first complete mitochondrial genome (mitogenome) of Isomyia nebulosa (Townsend, 1917) in this study. This mitogenome is 16,438 bp in length, with a standard set of 13 protein-coding genes (PCGs), 22 tRNAs, two rRNAs, and an A + T riched non-coding region without genetic rearrangement as most dipteran mitogenomes, but long intergenic nucleotides (IGNs) between trnQ and trnM are found. The phylogeny yielded by both Bayesian inference and maximum-likelihood analysis for all mitochondrial PCGs and rRNAs of 23 mitogenomes supports the monophyly of the family Calliphoridae and the subfamilies Calliphorinae, Chrysomyinae, and Luciliinae. In addition, I. nebulosa diverged anterior to the above-mentioned three calliphorid subfamilies with high genetic distances.

Objectives: The prevalence of ceftriaxone-resistant Neisseria gonorrhoeae poses a significant threat to the effectiveness of gonorrhoea treatment. The aim of the present study was to analyse the characteristics of ceftriaxone-resistant N. gonorrhoeae, with a specific focus on high-level ceftriaxone-resistant strains. Methods: A total of 207 strains of N. gonorrhoeae were collected from hospitals in Zhejiang, China, between 2019 and 2020. From this collection, we selected 8 strains of ceftriaxone-resistant N. gonorrhoeae for whole-genome sequencing, genotyping, and molecular profile analysis. For clonal strains (FC428-like), we conducted a phylogenetic analysis to understand their origin and evolutionary path. Results: Among the selected strains, 5 demonstrated high-level ceftriaxone resistance (MIC 1–2 mg/L). The genotyping results showed that these isolates had a higher diversity of penA alleles than expected. Four isolates had mosaic penA-60.001 allele and the remaining four had different non-mosaic penA alleles. Phylogenetic analysis suggested that the emergence of FC428-like clones containing penA-60.001 may result from further dissemination of different FC428 subclones from different regions of China. The identification of high-level ceftriaxone resistance in non-mosaic penA gonococci, specifically in the ZJ20-3 isolate (penA-21.001) with an MIC of 2 mg/L, is a groundbreaking discovery. Conclusions: We present a comprehensive analysis of ceftriaxone-resistant N. gonorrhoeae isolates in Zhejiang, highlighting a significant diversity of penA alleles. The identification of strains exhibiting resistance to ceftriaxone at high levels in our study underscores the potential threat to existing protocols for gonorrhoea treatment. Consequently, we strongly emphasize the urgent need to enhance surveillance initiatives focused on ceftriaxone-resistant N. gonorrhoeae.

Abstract Background Reliable pre-surgical prediction of spreading through air spaces (STAS) in primary lung cancer is essential for precision treatment and surgical decision-making. We aimed to develop and validate a dual-delta deep-learning and radiomics model based on pretreatment computed tomography (CT) image series to predict the STAS in patients with lung cancer. Method Six hundred seventy-four patients with pre-surgery CT follow-up scans (with a minimum interval of two weeks) and primary lung cancer diagnosed by surgery were retrospectively recruited from three Chinese hospitals. The training cohort and internal validation cohort, comprising 509 and 76 patients respectively, were selected from Shanghai Chest Hospital; the external validation cohorts comprised 36 and 53 patients from two other centers, respectively. Four imaging signatures (classic radiomics features and deep learning [DL] features, delta-radiomics and delta-DL features) reflecting the STAS status were constructed from the pretreatment CT images by comprehensive methods including handcrafting, 3D views extraction, image registration and subtraction. A stepwise optimized three-step procedure, including feature extraction (by DL and time-base radiomics slope), feature selection (by reproducibility check and 45 selection algorithms), and classification (32 classifiers considered), was applied for signature building and methodology optimization. The interpretability of the proposed model was further assessed with Grad-CAM for DL-features and feature ranking for radiomics features. Results The dual-delta model showed satisfactory discrimination between STAS and non-STAS and yielded the areas under the receiver operating curve (AUCs) of 0.94 (95% CI, 0.92–0.96), 0.84 (95% CI, 0.82–0.86), and 0.84 (95% CI, 0.83–0.85) in the internal and two external validation cohorts, respectively, with interpretable core feature sets and feature maps. Conclusion The coupling of delta-DL model with delta-radiomics features enriches information such as anisotropy of tumor growth and heterogeneous changes within the tumor during the radiological follow-up, which could provide valuable information for STAS prediction in primary lung cancer.

Introduction This study comprehensively assessed the association between eight metabolites of urinary nicotine and cognitive impairment. Methods This cross-sectional study was based on the data of Shenzhen Aging Related Disorder Cohort (SADC), including 51 elderly community data variables such as demographic characteristics, neuropsychological assessment and environmental factors, from July 2017 to November 2018. Participant’s cognitive function was assessed by Mini-Mental State Examination (MMSE) scale and urinary nicotine metabolite [including cotinine N-β-D-glucuronide (CotGluc), rac 4-hydroxy-4-(3-pyridyl) butanoic acid dicyclohexylamine salt (HyPyBut), trans-3’-hydroxy cotinine O-β-D-glucuronide (OHCotGluc), and cotinine (Cot), etc.] concentrations were measured by high-performance liquid chromatographytandem mass spectrometry (LC-MS/MS). Generalized linear models and restricted cubic spline models were used to explore the relationships between the urinary levels of nicotine metabolite and cognitive function. Results A total of 296 individuals aged >60 years were included. Individuals in the third quartile of CotGluc had a 0.786 point (95% CI: -1.244 – -0.329) decrease or in the highest quartile of OHCotGluc had a 0.804 point (95% CI: -1.330 – -0.278) decreased in attention and calculation compared to those in the lowest quartile (all p for trend

To increase the hit efficiency and lethality of a flight vehicle, it is necessary to consider the vehicle’s guidance law concerning both impact time and angle constraints. In this study, a novel and straightforward impact time and angle control guidance law that is independent of time-to-go and small angle approximations is proposed with two stages using a data-driven method and proportional navigation guidance. First, a proportional navigation guidance-based impact angle control guidance law is designed for the second stage. Second, from various initial conditions on the impact angle control guidance simulation with various initial conditions, the input and output datasets are obtained to build a mapping network. Using the neural network technique, a mapping network model that can output the ideal flight path angle in flight is constructed for impact time control in the first stage. The proposed impact time and angle control guidance law reduces to the proportional navigation guidance law when the flight path angle error converges to zero. The simulation results show that the proposed guidance law delivers excellent performance under various conditions (including cooperative attack) and features better acceleration performance and less control energy than does the comparative impact time and angle control guidance law. The results of this research are expected to supplement those exploring various paradigms to solve the impact time and angle control guidance problem, as concluded in the current literature.

Abstract Study objectives Primary insomnia (PI) triggers a decline in cognitive function, and the thalamus plays an integral role in this process; however, the mechanisms are unclear. The purpose of this study was to investigate the altered functional connectivity (FC) of the thalamus in PI patients with mild cognitive impairment (MCI) and to explore the potential neural mechanisms of thalamic involvement in these patients. Methods This case–control study was conducted in older adults from various communities in Fuzhou, China with a PI diagnosis. These participants underwent neuropsychological assessment and were matched in a 1:2 ratio to the healthy control (HC) group and the PI group according to sex, age, and education level. Resting‐state functional magnetic resonance imaging was used to explore changes in thalamic FC in PI patients. To further compare changes in thalamic and whole‐brain FC, we further divided the PI group into cognitively normal patients and patients with MCI according to the diagnostic criteria for MCI. The relationship between abnormal FC and cognitive function was investigated. Results The 28 HCs and 58 participants with PI showed significant differences in Montreal Cognitive Assessment (MoCA) scores (p = .044). In comparison to the HC group, the PI group showed enhanced FC of the occipital thalamus with the left inferior occipital gyrus, right lingual gyrus, left middle temporal gyrus, left superior marginal gyrus, left dorsolateral superior frontal gyrus, and right anterior central gyrus. The MoCA total score and the executive function, attention, and abstraction scores of PI patients with MCI (PI–MCI) were worse than those of PI patients without MCI. In comparison to the simple PI group, FC was enhanced in the PI–MCI group between the left occipital thalamus and the middle occipital gyrus, and between the right occipital thalamus and the right superior frontal gyrus, left middle frontal gyrus, right superior occipital gyrus, and orbital inferior frontal gyrus. There was a significant negative correlation between the MoCA total score and the enhanced FC between the right occipital thalamus and right superior occipital gyrus (r = −.419, p = .042). Conclusion The early onset of cognitive impairment in patients with PI is associated with altered FC between the thalamus and the cortex. Enhanced FC between the thalamus and the visual cortex, that is, the superior occipital gyrus, which is involved in attentional processing, may play a role in the early onset of cognitive impairment in insomnia patients. Moreover, due to the fact that PI patients “overdraw” the compensatory capacity of these brain regions earlier, the PI–MCI may fall into the abyss of “decompensation” faster and face more severe cognitive impairments.

The study aimed to estimate the feasibility of α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD) to encapsulate Mosla chinensis essential oil (EO) by ultrasonic-assisted method. The physical properties variations, stabilization mechanisms, and formation processes of the inclusion complexes (ICs) were investigated using experimental methods, molecular docking, and molecular dynamics (MD) simulation. Scanning electron microscopy, fourier transform infrared spectroscopy, thermogravimetric analysis, and gas chromatography–mass spectrometry showed that the ICs were successfully prepared, which differentially improved the thermal stability and retained the chemical composition of EO. The dissolution profile showed that the Peppas model can be used to describe the diffuse release mechanism of EO. Finally, molecular docking and MD simulation theoretically confirmed the interaction and conformational changes of carvacrol (the main active component of Mosla chinensis EO) inside the cavity of CDs. The results indicate that hydrogen bonding was the primary driving force for the carvacrol spontaneous access to the cavity. Further, a binding dynamic balance occurs between carvacrol and β-CD, whereas a bind and away dynamic balance occurs in the IC between carvacrol and α-CD, γ-CD. The comprehensive results show that the medium cavity size of β-CD is a suitable host molecule for Mosla chinensis EO of encapsulation, release, and stabilization. A combination of experimental and theoretical calculations is useful for the pinpoint targeted design and optimization of CD molecular encapsulation of small entity molecules. β-CD was rationally screened as a better candidate for stabilizing EO, which provides an option for a meaningful path to realistic EO applications.

The advancement of molecular pathology techniques has led to the discovery of rare EGFR mutations for targeted therapy in lung cancer. Additionally, a substantial body of evidence indicates a connection between the development of lung cancer and genetic variations in the EGFR gene. Here, we present a case report of a patient with multifocal lung adenocarcinoma who possessed a rare germline mutation, EGFR R776H. An investigation into the family history of the patient exposed the notable incidence of lung adenocarcinoma, indicating a plausible genetic vulnerability to the ailment. To be specific, the patient's older brother and sister both suffered from lung cancer, which underlines the hereditary predisposition. Furthermore, it should be noted that the patient's daughter has inherited the germline mutation and also presented with multiple lung ground-glass nodules, emphasizing the clinical importance of this genetic variation. Following the lobectomy, the patient received treatment with almonertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), and at the latest follow-up, the patient has achieved partial remission. This case highlights the significance of taking into account germline possibilities when multiple lesions carry the same mutation. It stresses the importance of acquiring a comprehensive family history and performing genetic testing on leukocytes. Moreover, for the infrequent EGFR R776H mutation, third generation EGFR-TKIs may be a viable option.

A potential field solution is widely used to extrapolate the coronal magnetic field above the Sun’s surface to a certain height. This model applies the current-free approximation and assumes that the magnetic field is entirely radial beyond the source surface height, which is defined as the radial distance from the center of the Sun. Even though the source surface is commonly specified at 2.5 R _s (solar radii), previous studies have suggested that this value is not optimal in all cases. In this study, we propose a novel approach to specify the source surface height by comparing the areas of the open magnetic field regions from the potential field solution with predictions made by a magnetohydrodynamic model, in our case the Alfvén Wave Solar atmosphere Model. We find that the adjusted source surface height is significantly less than 2.5 R _s near solar minimum and slightly larger than 2.5 R _s near solar maximum. We also report that the adjusted source surface height can provide a better open flux agreement with the observations near the solar minimum, while the comparison near the solar maximum is slightly worse.

BackgroundThe mental health of healthcare workers during the coronavirus-2019 pandemic was seriously affected, and the risk of mental health problems was high. The present study sought to systematically evaluate the mental health problems of healthcare workers worldwide during the pandemic and to determine the latest global frequency of COVID-19 associated mental health problems.MethodsData in the Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, Elsevier, MEDLINE, PubMed, PsycINFO and the Web of Science before November 11, 2022, were systematically searched. Cohort, case-control and cross-sectional studies were included. The meta-analysis used a random effects model to synthesize the comprehensive prevalence rate of mental health problems. Subgroup analyses were performed based on time of data collection; whether the country was or was not developed; continent; doctors and nurses; doctors/nurses vs. other healthcare workers; and psychological evaluation scale.ResultsA total of 161 studies were included, including 341,014 healthcare workers worldwide, with women accounting for 82.8%. Occupationally, 16.2% of the healthcare workers were doctors, 63.6% were nurses and 13.3% were other medical staff. During the pandemic, 47% (95% confidence interval [CI], 35-60%) of healthcare workers reported job burnout, 38% (95% CI, 35-41%) experienced anxiety, 34% (95% CI 30-38%) reported depression, 30% (95% CI, 29-31%) had acute stress disorder, and 26% (95% CI, 21-31%) had post-traumatic stress disorder.ConclusionsThe study found that there were common mental health problems among health care workers during the COVID-19 pandemic. The most common was job burnout, followed by anxiety, depression, acute stress and post-traumatic stress disorder. Although the global pandemic has been brought under control, its long-term impact on the mental health of healthcare workers cannot be ignored. Additional research is required to develop measures to prevent, monitor and treat psychological disorders among healthcare workers.

ABSTRACT The increasing prevalence of hypervirulent (hv) and carbapenem-resistant (CR) Klebsiella pneumoniae (Kp) highlights the importance of timely and accurate differential diagnosis for epidemiological investigation and clinical management. A multiplex quantitative real-time PCR (qRT-PCR) assay for the simultaneous identification of hvKp and CR-Kp was developed and validated with excellent performance in sensitivity and specificity. Generally, the gltA gene for Kp, the iucA, rmpA and rmpA2 genes for hvKp, and the Klebsiella pneumoniae carbapenemases (KPC) gene for CR-Kp were included in the qRT-PCR assay. The detection limits for classic Kp (cKp), CR-cKp, hvKp, and CR-hvKp strains could all reach 50 genome equivalent copies and 20 CFUs per reaction with high accuracy (R 2 > 0.99) and reliability (CV values < 3%). Detection results from 84 Kp positive clinical samples showed 31 hvKp with 8 CR-hvKp and 53 cKp with 1 CR-cKp strains. The presence of virulence-associated factors for the identified hvKp and KPC genes for CR-Kp was confirmed by previously developed conventional PCR and antimicrobial susceptibility tests, respectively. Furthermore, the qRT-PCR identified hvKp strains showed mortality rates of ≥40% in the outbred murine infection model, while no death for the identified cKp strains. These results indicated that our multiplex qRT-PCR assay could accurately identify hvKp and CR-Kp strains, which will be of great use for the rapid and accurate diagnosis in a clinical setting and the surveillance of the circulating Kp. IMPORTANCE Globally, the increasing number of hypervirulent Klebsiella pneumoniae (hvKp) and carbapenem-resistant Kp (CR-Kp) infections poses a huge public health challenge with high morbidity and mortality. Worrisomely, due to the mobility of elements carrying virulence and drug-resistance genes, the increasing prevalence of CR-hvKp has also been found with an overwhelming mortality rate in recent years. However, the current detection methods for hvKp and CR-Kp have many disadvantages, such as long turnaround time, complex operation, low sensitivity, and specificity. Herein, a more sensitive, rapid, single-reaction, and multiplex quantitative real-time PCR was developed and validated to differentiate the circulating lineages of Kp with excellent performance in sensitivity and specificity, providing a useful tool for the differential diagnosis and the surveillance of the circulating Kp.

Abstract Auscultation is crucial for the diagnosis of respiratory system diseases. However, traditional stethoscopes have inherent limitations, such as inter-listener variability and subjectivity, and they cannot record respiratory sounds for offline/retrospective diagnosis or remote prescriptions in telemedicine. The emergence of digital stethoscopes has overcome these limitations by allowing physicians to store and share respiratory sounds for consultation and education. On this basis, machine learning, particularly deep learning, enables the fully-automatic analysis of lung sounds that may pave the way for intelligent stethoscopes. This review thus aims to provide a comprehensive overview of deep learning algorithms used for lung sound analysis to emphasize the significance of artificial intelligence (AI) in this field. We focus on each component of deep learning-based lung sound analysis systems, including the task categories, public datasets, denoising methods, and, most importantly, existing deep learning methods, i.e., the state-of-the-art approaches to convert lung sounds into two-dimensional (2D) spectrograms and use convolutional neural networks for the end-to-end recognition of respiratory diseases or abnormal lung sounds. Additionally, this review highlights current challenges in this field, including the variety of devices, noise sensitivity, and poor interpretability of deep models. To address the poor reproducibility and variety of deep learning in this field, this review also provides a scalable and flexible open-source framework that aims to standardize the algorithmic workflow and provide a solid basis for replication and future extension: https://github.com/contactless-healthcare/Deep-Learning-for-Lung-Sound-Analysis .

Abstract Background People with mild cognitive impairment (MCI) experience a loss of cognitive functions, whose mechanism is characterized by aberrant structure‒function (SC-FC) coupling and topological attributes of multiple networks. This study aimed to reveal the network-level SC-FC coupling and internal topological changes triggered by computerized cognitive training (CCT) to explain the therapeutic effects of this training in individuals with MCI. Methods In this randomized block experiment, we recruited 60 MCI individuals and randomly divided them into an 8-week multidomain CCT group and a health education control group. The neuropsychological outcome measures were the Montreal Cognitive Assessment (MoCA), Chinese Auditory Verbal Learning Test (CAVLT), Chinese Stroop Color–Word Test (SCWT), and Rey–Osterrieth Complex Figure Test (Rey CFT). The brain imaging outcome measures were SC-FC coupling and topological attributes using functional MRI and diffusion tensor imaging methods. We applied linear model analysis to assess the differences in the outcome measures and identify the correspondence between the changes in the brain networks and cognitive functions before and after the CCT. Results Fifty participants were included in the analyses after the exclusion of three dropouts and seven participants with low-quality MRI scans. Significant group × time effects were found on the changes in the MoCA, CAVLT, and Rey CFT recall scores. The changes in the SC-FC coupling values of the default mode network (DMN) and somatomotor network (SOM) were higher in the CCT group than in the control group (P(unc.) = 0.033, P(unc.) = 0.019), but opposite effects were found on the coupling values of the visual network (VIS) (P(unc.) = 0.039). Increasing clustering coefficients in the functional DMN and SOM and subtle changes in the nodal degree centrality and nodal efficiency of the right dorsal medial prefrontal cortex, posterior cingulate cortex, left parietal lobe, somatomotor area, and visual cortex were observed in the CCT group (P

Abstract Lung cancer and liver cancer are the leading and third causes of cancer death, respectively. Both lung and liver cancer are with clear major risk factors. A thorough understanding of their burdens in the context of globalization, especially the convergences and variations among WHO regions, is useful in precision cancer prevention worldwide and understanding the changing epidemiological trends with the expanding globalization. The Global Burden of Disease (GBD) and WHO Global Health Observatory (GHO) database were analyzed to evaluate the burden metrics and risk factors of trachea, bronchus, and lung (TBL) cancer and liver cancer. Western Pacific Region (WPR) had the highest age-standardized incidence rate (ASIR) for both liver cancer (11.02 [9.62–12.61] per 100,000 population) and TBL cancer (38.82 [33.63–44.04] per 100,000 population) in 2019. Disability-adjusted life years (DALYs) for liver and TBL cancer elevated with the increasing sociodemographic index (SDI) level, except for liver cancer in WPR and TBL cancer in European Region (EUR). Region of the Americas (AMR) showed the biggest upward trends of liver cancer age-standardized rates (ASRs), as well as the biggest downward trends of TBL cancer ASRs, followed by Eastern Mediterranean Region (EMR). Alcohol use and smoking were the leading cause of liver and TBL cancer death in most WHO regions. Variances of ASRs for liver and TBL cancer among WHO memberships have been decreasing during the past decade. The homogenization and convergence of cancer burdens were also demonstrated in different agegroups and sexes and in the evolution of associated risk factors and etiology. In conclusion, our study reflects the variations and convergences in the liver and lung cancer burdens among the WHO regions with the developing globalization, which suggests that we need to be acutely aware of the global homogeneity of the disease burden that accompanies increasing globalization, including the global convergences in various populations, risk factors, and burden metrics. Graphical Abstract