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Summary: During malaria infection, Plasmodium sporozoites, the fast-moving stage of the parasite, are injected by a mosquito into the skin of the mammalian host. In the skin, sporozoites need to migrate through the dermal tissue to enter the blood vessel. Sporozoite motility is critical for infection but not well understood. Here, we used collagen hydrogels with tunable fiber structures, as an in vitro model for the skin. After injecting sporozoites into the hydrogel, we analyzed their motility in three-dimension (3D). We found that sporozoites demonstrated chiral motility, in that they mostly follow right-handed helical trajectories. In high-concentration collagen gel, sporozoites have lower instantaneous speed, but exhibit straighter tracks compared to low-concentration collagen gel, which leads to longer net displacement and faster dissemination. Taken together, our study indicates an inner mechanism for sporozoites to adapt to the environment, which could help with their successful exit from the skin tissue.

Diabetes mellitus induces a pathophysiological disorder known as diabetic cardiomyopathy and may eventually cause heart failure. Diabetic cardiomyopathy is manifested with systolic and diastolic contractile dysfunction along with alterations in unique cardiomyocyte proteins and diminished cardiomyocyte contraction. Multiple mechanisms contribute to the pathology of diabetic cardiomyopathy, mainly including abnormal insulin metabolism, hyperglycemia, glycotoxicity, cardiac lipotoxicity, endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, calcium treatment damage, programmed myocardial cell death, improper Renin-Angiotensin-Aldosterone System activation, maladaptive immune modulation, coronary artery endothelial dysfunction, exocrine dysfunction, etc. There is an urgent need to investigate the exact pathogenesis of diabetic cardiomyopathy and improve the diagnosis and treatment of this disease. The nuclear receptor superfamily comprises a group of transcription factors, such as liver X receptor, retinoid X receptor, retinoic acid-related orphan receptor-α, retinoid receptor, vitamin D receptor, mineralocorticoid receptor, estrogen-related receptor, peroxisome proliferatoractivated receptor, nuclear receptor subfamily 4 group A 1(NR4A1), etc. Various studies have reported that nuclear receptors play a crucial role in cardiovascular diseases. A recently conducted work highlighted the function of the nuclear receptor superfamily in the realm of metabolic diseases and their associated complications. This review summarized the available information on several important nuclear receptors in the pathophysiology of diabetic cardiomyopathy and discussed future perspectives on the application of nuclear receptors as targets for diabetic cardiomyopathy treatment.

Abstract Ir(III) carbene complexes have been explored as one of the best blue phosphors for their high performance. Herein, the authors designed and synthesized a series of blue‐emitting Ir(III) phosphors (f‐ct9a–c), featuring fac‐coordinated cyano‐imidazo[4,5‐b]pyridin‐2‐ylidene cyclometalates. These Ir(III) complexes exhibit true‐blue emission with a peak maximum spanning 448–467 nm, with high photoluminescence quantum yields of 81–88% recorded in degassed toluene. Moreover, OLED devices bearing phosphors f‐ct9a and f‐ct9b deliver maximum external quantum efficiencies (EQEmax) of 25.9% and 30.3%, together with Commission Internationale de L'Eclairage (CIEx,y) coordinates of (0.157, 0.225) and (0.142, 0.169), respectively. Remarkably, the f‐ct9b‐based device displays an incredible EQE of 29.0% at 5000 cd·m−2. The hyper‐OLED device based on f‐ct9b and ν‐DABNA exhibits an EQEmax of 34.7% and CIEx,y coordinates of (0.122, 0.131), affirming high potentials in achieving efficient blue electroluminescence.

Abstract Wearable sensors hold immense potential for real‐time and non‐destructive sensing of volatile organic compounds (VOCs), requiring both efficient sensing performance and robust mechanical properties. However, conventional colorimetric sensor arrays, acting as artificial olfactory systems for highly selective VOC profiling, often fail to meet these requirements simultaneously. Here, a high‐performance wearable sensor array for VOC visual detection is proposed by extrusion printing of hybrid inks containing surface‐functionalized sensing materials. Surface‐modified hydrophobic polydimethylsiloxane (PDMS) improves the humidity resistance and VOC sensitivity of PDMS‐coated dye/metal‐organic frameworks (MOFs) composites. It also enhances their dispersion within liquid PDMS matrix, thereby promoting the hybrid liquid as high‐quality extrusion‐printing inks. The inks enable direct and precise printing on diverse substrates, forming a uniform and high particle‐loading (70 wt%) film. The printed film on a flexible PDMS substrate demonstrates satisfactory flexibility and stretchability while retaining excellent sensing performance from dye/MOFs@PDMS particles. Further, the printed sensor array exhibits enhanced sensitivity to sub‐ppm VOC levels, remarkable resistance to high relative humidity (RH) of 90%, and the differentiation ability for eight distinct VOCs. Finally, the wearable sensor proves practical by in situ monitoring of wheat scab‐related VOC biomarkers. This study presents a versatile strategy for designing effective wearable gas sensors with widespread applications.

ObjectivesThis study aimed to investigate the management of vascular risk factors, with a specific focus on understanding the various factors affecting risk factor control through an in-depth analysis of clinical data and a longitudinal follow-up of patients who have experienced ischemic strokes.MethodsA total of 1,572 participants were included in the analysis. We assessed thresholds for blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and glycated hemoglobin (HbA1c) levels to uncover the contextual conditions and factors affecting vascular risk factor control. Moreover, the study also scrutinized medication compliance at intervals of 3, 6, and 12 months post-onset. Logistic regression was used to adjust for confounding factors.ResultsAt 3, 6, and 12 months, BP,LDL, hemoglobin control targets were achieved in 50.7, 51.8, and 50.6%; 51.5, 59.4, and 50.6%; 48.1, 44.0, and 48.4%,respectively. Notably, age was associated with the achievement of BP control (odds ratio [OR], 0.96; 95% confidence intervals [CI], 0.94–0.98; p

Carbon fiber–reinforced epoxy composites are widely used in the marine and aviation sectors due to their superior mechanical properties. As research into these materials progresses, the demand for materials with even more complex and superior properties has increased. Traditional trial-and-error methods are limited to optimizing single factors and are plagued by heavy workloads and prohibitive costs when applied to multifactor composite designs. Addressing these problems, this study introduces a nonparametric multiobjective optimization process for composite materials. This approach employs a Gaussian process (GP) to establish a multiobjective regression model and uses nondominated sorting genetic algorithm II (NSGA II) to determine the Pareto front. Pareto solutions were ranked in accordance with their similarity to ideal solutions and on the basis of predetermined preference weights. The results demonstrate variations in optimal outcomes contingent on the weight values assigned. The differences between the optimized results and experimental validations reached 12.9%, with the minimum deviation being 0.6%. The effectiveness of the proposed method was demonstrated. The strategy combines GP and NSGA II to extend design methods for small samples and materials with multiple attributes. This method enables the simultaneous optimization of multiple conflicting objectives, offering greater efficiency than addressing them individually.

Immune cells are key players in acute tissue injury and inflammation, including acute kidney injury (AKI). Their development, differentiation, activation status, and functions are mediated by a variety of transcription factors, such as interferon regulatory factor 8 (IRF8) and IRF4. We speculated that IRF8 has a pathophysiologic impact on renal immune cells in AKI and found that IRF8 is highly expressed in blood type 1 conventional dendritic cells (cDC1s), monocytes, monocyte-derived dendritic cells (moDCs) and kidney biopsies from patients with AKI. In a mouse model of ischemia‒reperfusion injury (IRI)-induced AKI, Irf8−/− mice displayed increased tubular cell necrosis and worsened kidney dysfunction associated with the recruitment of a substantial amount of monocytes and neutrophils but defective renal infiltration of cDC1s and moDCs. Mechanistically, global Irf8 deficiency impaired moDC and cDC1 maturation and activation, as well as cDC1 proliferation, antigen uptake, and trafficking to lymphoid organs for T-cell priming in ischemic AKI. Moreover, compared with Irf8+/+ mice, Irf8−/− mice exhibited increased neutrophil recruitment and neutrophil extracellular trap (NET) formation following AKI. IRF8 primarily regulates cDC1 and indirectly neutrophil functions, and thereby protects mice from kidney injury and inflammation following IRI. Our results demonstrate that IRF8 plays a predominant immunoregulatory role in cDC1 function and therefore represents a potential therapeutic target in AKI.

Drug resistance presents a formidable challenge in the realm of breast cancer therapy. Accumulating evidence suggests that enhancer of zeste homolog 2 (EZH2), a component of the polycomb repressive complex 2 (PRC2), may serve as a key regulator in controlling drug resistance. EZH2 overexpression has been observed in breast cancer and many other malignancies, showing a strong correlation with poor outcomes. This review aims to summarize the mechanisms by which EZH2 regulates drug resistance, with a specific focus on breast cancer, in order to provide a comprehensive understanding of the underlying molecular processes. Additionally, we will discuss the current strategies and outcomes of targeting EZH2 using both single agents and combination therapies, with the goal of offering improved guidance for the clinical treatment of breast cancer patients who have developed drug resistance.

Background and aims: Normal serum transaminases and immunoglobulin G (IgG) levels are surrogate markers for hepatic histologic disease activity in autoimmune hepatitis (AIH). This study aimed to evaluate liver inflammation in patients with AIH with normal serum alanine aminotransferase (ALT) and IgG levels. Methods: Two hundred and five AIH patients who underwent liver biopsy in four medical centers were included. Logistic regression analysis was used to identify risk factors associated with advanced inflammation. Results: One hundred and thirty-one (63.9 %) AIH patients had advanced liver inflammation, and 108 (52.7 %) patients had advanced liver fibrosis. 60.0 % of patients with normal ALT and 51.7 % of patients with normal ALT and IgG had advanced inflammation. However, 76.7 % and 35.0 % of patients with or without advanced fibrosis with normal ALT had advanced inflammation, while the corresponding proportions of advanced inflammation were 78.6 % and 26.7 % in patients with normal ALT and IgG, respectively. Moreover, 81.0 % and 44.8 % of patients with and without cirrhosis with normal ALT had advanced inflammation, while the corresponding proportions were 83.3 % and 29.4 % in patients with normal ALT and IgG, respectively. Red cell distribution width (OR = 1.325, 95%CI 1.045–1.681, P = 0.020) and PT (OR = 1.514, 95%CI 1.138–2.014, P = 0.004) were independent factors associated with advanced inflammation. Conclusions: High proportion of advanced inflammation was found in AIH patients with normal ALT and IgG levels despite without advanced fibrosis. Although using non-invasive methods may contribute to rule out liver fibrosis in AIH patients with normal ALT and IgG levels, liver biopsy is encouraged to assess liver inflammation.

Abstract CO2 fixation plays a key role to make biobased production cost competitive. Here, we use 3-hydroxypropionic acid (3-HP) to showcase how CO2 fixation enables approaching theoretical-yield production. Using genome-scale metabolic models to calculate the production envelope, we demonstrate that the provision of bicarbonate, formed from CO2, restricts previous attempts for high yield production of 3-HP. We thus develop multiple strategies for bicarbonate uptake, including the identification of Sul1 as a potential bicarbonate transporter, domain swapping of malonyl-CoA reductase, identification of Esbp6 as a potential 3-HP exporter, and deletion of Uga1 to prevent 3-HP degradation. The combined rational engineering increases 3-HP production from 0.14 g/L to 11.25 g/L in shake flask using 20 g/L glucose, approaching the maximum theoretical yield with concurrent biomass formation. The engineered yeast forms the basis for commercialization of bio-acrylic acid, while our CO2 fixation strategies pave the way for CO2 being used as the sole carbon source.

Abstract Background Rapid recognition of frailty in older patients in the ED is an important first step toward better geriatric care in the ED. We aimed to develop and validate a novel frailty assessment scale at ED triage, the Emergency Department Frailty Scale (ED-FraS). Methods We conducted a prospective cohort study enrolling adult patients aged 65 years or older who visited the ED at an academic medical center. The entire triage process was recorded, and triage data were collected, including the Taiwan Triage and Acuity Scale (TTAS). Five physician raters provided ED-FraS levels after reviewing videos. A modified TTAS (mTTAS) incorporating ED-FraS was also created. The primary outcome was hospital admission following the ED visit, and secondary outcomes included the ED length of stay (EDLOS) and total ED visit charges. Results A total of 256 patients were included. Twenty-seven percent of the patients were frail according to the ED-FraS. The majority of ED-FraS was level 2 (57%), while the majority of TTAS was level 3 (81%). There was a weak agreement between the ED-FraS and TTAS (kappa coefficient of 0.02). The hospital admission rate and charge were highest at ED-FraS level 5 (severely frail), whereas the EDLOS was longest at level 4 (moderately frail). The area under the Receiver Operating Characteristic curve (AUROC) in predicting hospital admission for the TTAS, ED-FraS, and mTTAS were 0.57, 0.62, and 0.63, respectively. The ED-FraS explained more variation in EDLOS (R2 = 0.096) compared with the other two methods. Conclusions The ED-Fras tool is a simple and valid screening tool for identifying frail older adults in the ED. It also can complement and enhance ED triage systems. Further research is needed to test its real-time use at ED triage internationally.

Depression is a common mental illness with widespread effects worldwide. At present, most relevant studies are performed by using free-view experiments to identify depression based on eye movements, which identify depression by analyzing the fixation patterns of subjects. However, technical and cost barriers make the rapid and objective detection of depression challenging. This study aimed to develop an objective and convenient method that utilizes eye tracking technology to detect depression. In this study, we designed an eye-tracking algorithm to localize pupil position and presented a variance entropy method to measure the fluctuating characteristics of eye movements. Video data were collected from 115 participants and 35 controls (mean age 24.99 years, standard deviation 6.14 years). The pupil position time series data were formed by the eye-tracking algorithm, and the variance entropy of the pupil position time series was calculated. Based on eye movement variance entropy, we used three machine learning models for classification detection: Logistic Regression, K-Nearest Neighbors, and Random Forest. The accuracy of machine learning in identifying whether a person had depression or not was 97.5%. The accuracy of the four class depression classification (severe, moderate, mild, and no depression) was 82.5%.The accuracy of identifying whether a person had anxiety or not was 95%. The accuracy of identifying whether a person had suicidal tendencies or not was 85%. The results showed that variance entropy based on the eye movement time series can be used as a valid bioindicator for detecting depression.

Pulsed light detection and rangings (LiDARs) are widely utilized in various applications such as navigation, robotic, and remote sensing for their high distance resolution, accuracy, and speed. When multiple echoes are received either from interferences or under harsh environmental conditions, conventional pulsed LiDARs fail to extract the distance information out of received signal. To overcome this problem, this paper introduces a multi-event detecting pulsed LiDAR that delivers multiple distance and intensity information when multiple echoes are received. The proposed system comprises an analog front-end (AFE), a timing discriminator with 8 comparators, a multi-event detector, and a time-to-amplitude converter (TAC) for the timing circuit, capable of capturing the distance and intensity information up to four echoes. For quantification, experiments based on multiple echoes with multiple local peaks are conducted using an electrical model generated from real situation. Each event delivers 3-bit intensity information, and the measured distance information with a 10-bit analog-to-digital converter (ADC) exhibits the time resolution of 146.5 ps and the integral nonlinearity (INL) of 1.17 LSB.

Abstract Background As a dual-function metabolite, succinate has emerged in cell function and plays a key signaling role in linking mitochondrial function to other cellular functions. Succinate accumulation in the cytoplasm is commonly associated with hypoxia in the microenvironment and immune cell activation. Extracellular succinate released into the microenvironment is considered an inflammatory alarm that can be sensed by its membrane receptor SUCNR1, which boosts proinflammatory responses and acts akin to classical hormones and cytokines. Succinate plays an important role in the development of inflammatory diseases. Whether succinate facilitates the progression of endometriosis (EMs), characterized by chronic inflammation and peritoneal adhesion, is worth exploring. Objective We mimicked the ectopic milieu in vitro and in vivo to evaluate the main source and potential role of succinate in endometriosis. We assessed the molecular and functional effects of succinate on macrophages and peritoneal mesothelial cells in peritoneal cavity. The effect of succinate/SUCNR1 signaling on ectopic endometrial stromal cells (ESCs) was further explored in this study. Methods In this study, we used targeted organic acid metabolomics analysis and in vitro assays to assess the potential accumulation of succinate in the peritoneal fluid of EMs patients. We examined its correlation with disease severity, Visual Analogue Scale, and the Endometriosis Fertility Index. Flow cytometry, enzyme linked immunosorbent assay, western blot assay, quantitative real-time PCR, and other molecular biology techniques were used to explore the potential mechanisms. Results By mimicking the ectopic milieu, we constructed an in vitro co-culture system and found that M1 polarized macrophages and that the peritoneal mesothelial cell line (HMrSV5) mainly released succinate into their microenvironment and activated the succinate receptor (SUCNR1) signal, which further polarized the macrophages and significantly enhanced the invasive survival of ESCs, and the adhesion to the peritoneum. We further investigated the pathological effects of extracellular succinate in vivo using a xenograft mouse models of endometriosis. Conclusions Succinate-SUCNR1 signaling facilitates the creation of inflammatory cells and plays a vital role in EMs progression and peritoneal adhesion. Our work on the molecular mechanisms underlying succinate accumulation and function will help elucidate the phenotypic mysteries of pain and infertility in EMs. Video Abstract

The deep earth, deep sea, and deep space are the main parts of the national “three deep” strategy, which is in the forefront of the strategic deployment clearly defined in China’s 14th Five-Year Plan (2021–2025) and the Long-Range Objectives Through the Year 2035. It is important to reveal the evolutionary process and mechanism of deep tectonics to understand the earth’s past, present and future. The academic connotation of Geology in Time has been given for the first time, which refers to the multi-field evolution response process of geological bodies at different time and spatial scales caused by geological processes inside and outside the Earth. Based on the deep in situ detection space and the unique geological environment of China Jinping Underground Laboratory, the scientific issue of the correlation mechanism and law between deep internal time-varying and shallow geological response is given attention. Innovative research and frontier exploration on deep underground in situ geo-information detection experiments for Geology in Time are designed to be carried out, which will have the potential to explore the driving force of Geology in Time, reveal essential laws of deep earth science, and explore innovative technologies in deep underground engineering.

Abstract Lung squamous cell carcinoma (LUSC) is the second most common lung cancer worldwide, leading to millions of deaths annually. Although immunotherapy has expanded the therapeutic choices for LUSC and achieved considerable efficacy in a subset of patients, many patients could not benefit, and resistance was pervasive. Therefore, it is significant to investigate the mechanisms leading to patients’ poor response to immunotherapies and explore novel therapeutic targets. Using multiple public LUSC datasets, we found that Kallikrein-8 (KLK8) expression was higher in tumor samples and was correlated with inferior survival. Using a LUSC cohort (n = 190) from our center, we validated the bioinformatic findings about KLK8 and identified high KLK8 expression as an independent risk factor for LUSC. Function enrichment showed that several immune signaling pathways were upregulated in the KLK8 low-expression group and downregulated in the KLK8 high-expression group. For patients with low KLK8 expression, they were with a more active TME, which was both observed in the TCGA database and immune marker immunohistochemistry, and they had extensive positive relations with immune cells with tumor-eliminating functions. This study identified KLK8 as a risk factor in LUSC and illustrated the associations between KLK8 and cancer immunity, suggesting the potentiality of KLK8 as a novel immune target in LUSC.

Abstract The effects of Easydo Activator (EA), a new sonic irrigation system, on sealer penetration at the root apex were compared to needle irrigation (NI) and passive ultrasonic irrigation (PUI) in this study. Forty-two single-rooted teeth were prepared and randomly divided into three groups (n = 14): group 1: NI; group 2: PUI; and group 3: EA. A solution of 3% sodium hypochlorite (NaOCl) was used for irrigation. Nine teeth in each group were filled with AH Plus sealer mixed with CY5 fluorescent dye and a single gutta-percha cone. The sealer penetration area, maximum penetration depth and percentage of sealer penetration at 5 mm and 1 mm from the apex were analyzed by confocal laser scanning microscopy (CLSM). The remaining 5 teeth in each group were subjected to test smear layer scores by scanning electron microscopy (SEM). The CLSM evaluation showed that increases in the area, depth and percentage of sealer penetration were detected at 1 and 5 mm from the root apex in the PUI group compared with the NI group, and greater increases were observed in the EA group (P

Abstract Objective To evaluate the feasibility of an internet-facilitated community model for cervical cancer screening using self-collected HPV testing as primary screening. Method A population-based cervical cancer screening program was conducted in the suburb of Shenzhen, China, from September 2014 to July 2017. Women with 25–60 years of age and no pregnancy were eligible for participation. Participants could register for screening by logging in a website by themselves or with the aids of local community workers. A unique barcode was issued to each applicant upon successful registration. After registration, women could get sampling kits from community screening site/study clinic, collect vaginal samples privately or in group, and provide their sample for Hr-HPV tests on Cobas4800 and SeqHPV assays. Testing reports were checkable through personal account for all participant and phone calls were given to all women positive of Hr-HPV. Participants positive of both or either the 2 assays were identified as the positives. The positives could return the study clinic for triage or search medical care in other clinics. Colposcopy directed or ramdom biopsies were performed on all positives who returned to the study clinics. Results A total of 10,792 community women registered for screening, among whom, 10,010 provided their vaginal samples for tests. 99.5% of the participants were confirmed to have correct personal identifiable information and samples, and 98.9% of them got HPV testing results from both or either assays. No adverse event was reported. Conclusion When self-collected HPV testing is used as the primary testing, the internet-based data platform facilitates the screening in registration, data collection, and data tracking, and increases the screening coverage. Internet-facilitated community model is promising to cervical cancer control and applicable in regions with variety of resources.

This study aims to investigate the mechanical response and acoustic emission (AE) characteristic of pre-flawed sandstone under both monotonic and multilevel constant-amplitude cyclic loads. Specifically, we explored how coplanar flaw angle and load type impact the strength and deformation behavior and microscopic damage mechanism. Results indicated that being fluctuated before rising with increasing fissure angle under monotonic loading, the peak strength of the specimen first increased slowly and then steeply under cyclic loading. The effect of multilevel cyclic loading on the mechanical parameters was more significant. For a single fatigue stage, the specimen underwent greater deformation in early cycles, which subsequently stabilized. Similar variation pattern was also reflected by AE count/energy/b-value. Crack behaviors were dominated by the fissure angle and load type and medium-scale crack accounted for 74.83%–86.44% of total crack. Compared with monotonic loading, crack distribution of specimen under cyclic loading was more complicated. Meanwhile, a simple model was proposed to describe the damage evolution of sandstone under cyclic loading. Finally, SEM images revealed that the microstructures at the fracture were mainly composed of intergranular fracture, and percentage of transgranular fracture jumped under cyclic loading due to the rapid release of elastic energy caused by high loading rate.

Abstract Background While representing a model bacterium and one of the most used chassis in biomanufacturing, performance of Escherichia coli is often limited by severe stresses. A super-robust E. coli chassis that could efficiently tolerant multiple severe stresses is thus highly desirable. Sterols represent a featured composition that distinguishes eukaryotes from bacteria and all archaea, and play a critical role in maintaining the membrane integrity of eukaryotes. All sterols found in nature are directly synthesized from (S)-2,3-oxidosqualene. However, in E. coli, (S)-2,3-oxidosqualene is not present. Results In this study, we sought to introduce (S)-2,3-oxidosqualene into E. coli. By mining and recruiting heterologous enzymes and activation of endogenous pathway, the ability of E. coli to synthesize (S)-2,3-oxidosqualene was demonstrated. Further analysis revealed that this non-native chemical confers E. coli with a robust and stable cell membrane, consistent with a figurative analogy of wearing an “Iron Man’s armor”-like suit. The obtained Iron Man E. coli (IME) exhibited improved tolerance to multiple severe stresses, including high temperature, low pH, high salt, high sugar and reactive oxygen species (ROS). In particular, the IME strain shifted its optimal growth temperature from 37 °C to 42–45 °C, which represents the most heat-resistant E. coli to the best of our knowledge. Intriguingly, this non-native chemical also improved E. coli tolerance to a variety of toxic feedstocks, inhibitory products, as well as elevated synthetic capacities of inhibitory chemicals (e.g., 3-hydroxypropionate and fatty acids) due to improved products tolerance. More importantly, the IME strain was effectively inhibited by the most commonly used antibiotics and showed no undesirable drug resistance. Conclusions Introduction of the non-native (S)-2,3-oxidosqualene membrane lipid enabled E. coli to improve tolerance to various stresses. This study demonstrated the effectiveness of introducing eukaryotes-featured compound into bacteria for enhancing overall tolerance and chemical production.

The development of aggregation-induced emission luminogens (AIEgens) with high brightness and efficient photodynamic therapy (PDT) is of great value for the precise diagnosis and treatment of cancers. In this contribution, two novel AIEgens, TBBCyP and TBTCyP with D-A-π-A structure, were designed and prepared based on molecular rational design of electron-donating receptors. Experimental and theoretical results indicated that both TBBCyP and TBTCyP own bright AIE feature, satisfy photos ability, and generate efficient singlet oxygen (1O2). Notably, TBBCyP exhibited brighter emission and higher 1O2 yield in compared with TBTCyP, which could be ascribed to its weaker twisted intramolecular charge transfer (TICT) effect and narrower singlet-triplet energy gap (ΔEST). Moreover, it was proved that TBBCyP and TBTCyP showed a great mitochondrial specificity and desired intracellular ROS productivity for realizing the effective mitochondria-targeted PDT of cancer cells.

Risk assessment is utilized to evaluate the risk level of the system and guide further operation and planning of utilities. However, to lower the cost of communication and storing, only a coarse resolution profile of load and PV can be collected and used to evaluate the risk level of the system, which may lead to inaccurate assessment. To this end, this paper investigates the impact of load-PV profile resolution on distribution system risk assessment. A super-resolution Generative Adversarial Network with pre- and post-processing processes is proposed to restore the high-frequency component of the load-PV profile. Then, with the generated high-resolution profile, a risk assessment model based on the exterior point method is proposed to evaluate the risk level of the distribution system. Case studies in a modified 33-bus system showed that the proposed super-resolution method could achieve the best performance to restore the peak values and high-frequency component of the load-PV profile compared to the other four methods. In addition, compared to super-resolution Generative Adversarial Networks without the post-processing process, the accuracy of risk assessment can be significantly improved using the proposed super-resolution method, which proves that the post-processing process is necessary.

Background: Repeat cesareans pose significant maternal risks, whereas vaginal birth after cesarean (VBAC) offers better outcomes, with a complication rate of 2.4% compared with 3.6% for elective repeat cesareans and 14.1% for failed trial of labor after cesarean (TOLAC). TOLAC rates are low in China, and success rates vary between 60% and 80%. This study aims to develop a nomogram-based predictive model for VBAC in China and improve existing, less rigorous scoring models. Methods: This retrospective cohort study was conducted at Hangzhou Women's Hospital from February 2015 to March 2020, and included 159 parturient attempts at labor after one prior low transverse cesarean section. The participants were divided into two groups based on their mode of delivery for comparison: the VBAC and the TOLAC failure group. Univariate and multivariate logistic regression analyses were conducted to identify independent predictors for VBAC and develop a nomogram predictive model to estimate the success rate of TOLAC. The bootstrap method was used for internal validation of the models. Three different VBAC prediction models were evaluated by plotting receiver operating characteristic (ROC) curves, calibration curves, and decision curves. Results: A total of 127 women had VBAC and 32 women failed TOLAC, with a success rate of 79.9%. Three independent factors affecting the VBAC were identified: gestational age at delivery, Bishop score and newborn birth weight. A predictive nomogram model for the VBAC was constructed that incorporates these three factors. The model showed a good fit (χ2 = 11.94, p = 0.154) with an overall prediction accuracy of 81.1%. The area under the ROC curve was 0.83 (95% CI (confidence interval), 0.76–0.90) (p < 0.001) and the optimal cut-off value was 83.4%. The bootstrap internal validation showed that our predictive model maintained high overall accuracy and specificity, but exhibited low sensitivity and a low Kappa coefficient. Compared to the Grobman model and Jiaming Rao et al. model, our developed prediction model possesses the strongest discriminatory ability and the highest net benefit, followed by the model by Jiaming Rao et al. All three models demonstrate a high degree of fit. Conclusions: Shorter gestational age at delivery, lower newborn birth weight and higher cervical Bishop score are favorable factors for VBAC. The predictive nomogram model for the VBAC after a single cesarean section, constructed with these three factors, has good predictive efficacy. The model is simple to calculate and has practical value in the clinical selection of suitable candidates for TOLAC after a single cesarean section.

Anther and microspore cultures are efficient methods for inducing haploids in plants. The microspore culture by chromosome-doubling method can produce double haploid lines, developing pure lines within the first or second generations. This study aimed to induce haploid plants in Platycodon grandiflorum using the shed-microspore culture method. P. grandiflorum floral buds (n = 1503) were cultured in six types of medium to induce haploids. Anthers were placed on a solid–liquid double-layer medium and cold pre-treated at 9 °C for one week, followed by incubation in the dark at 25 °C. Embryogenesis was observed after approximately 70 days of culture, producing haploid plants through regeneration. Of the 1503 floral buds, embryos developed in 120 buds, resulting in the induction of 402 individuals. Among the media used, Schenk and Hildebrandt (SH) and 1/2SH exhibited high efficiency, with embryogenesis ratios of 12% and 13.4%, respectively. Additionally, the highest embryogenesis ratio (15.3%) was observed in flower buds sized 10 mm or less. Therefore, we established shed-microspore culture conditions to induce haploids in P. grandiflorum. Using this method, haploids can be efficiently induced in P. grandiflorum, shortening the breeding period by enabling the rapid development of inbred lines.

Although deep learning techniques have potential in vehicle behavior prediction, it is difficult to integrate traffic rules and environmental information. Moreover, its black-box nature leads to an opaque and difficult-to-interpret prediction process, limiting its acceptance in practical applications. In contrast, ontology reasoning, which can utilize human domain knowledge and mimic human reasoning, can provide reliable explanations for the speculative results. To address the limitations of the above deep learning methods in the field of vehicle behavior prediction, this paper proposes a front vehicle behavior prediction method that combines deep learning techniques with ontology reasoning. Specifically, YOLOv5s is first selected as the base model for recognizing the brake light status of vehicles. In order to further enhance the performance of the model in complex scenes and small target recognition, the Convolutional Block Attention Module (CBAM) is introduced. In addition, so as to balance the feature information of different scales more efficiently, a weighted bi-directional feature pyramid network (BIFPN) is introduced to replace the original PANet structure in YOLOv5s. Next, using a four-lane intersection as an application scenario, multiple factors affecting vehicle behavior are analyzed. Based on these factors, an ontology model for predicting front vehicle behavior is constructed. Finally, for the purpose of validating the effectiveness of the proposed method, we make our own brake light detection dataset. The accuracy and mAP@0.5 of the improved model on the self-made dataset are 3.9% and 2.5% higher than that of the original model, respectively. Afterwards, representative validation scenarios were selected for inference experiments. The ontology model created in this paper accurately reasoned out the behavior that the target vehicle would slow down until stopping and turning left. The reasonableness and practicality of the front vehicle behavior prediction method constructed in this paper are verified.

Single nucleotide variant (SNV) detection is pivotal in various fields, including disease diagnosis, viral screening, genetically modified organism (GMO) identification, and genotyping. However, detecting SNVs presents significant challenges due to the fragmentation of nucleic acids caused by cellular apoptosis, molecular shearing, and physical degradation processes such as heating. Fragmented nucleic acids often exhibit variable lengths and inconsistent breakpoints, complicating the accurate detection of SNVs. This article delves into the underlying causes of nucleic acid fragmentation and synthesizes the strengths and limitations of next-generation sequencing technology, high-resolution melting curves, molecular probes, and CRISPR-based approaches for SNV detection in fragmented nucleic acids. By providing a detailed comparative analysis, it seeks to offer valuable insights for researchers working to overcome the challenges of SNV detection in fragmented samples, ultimately advancing the accurate and efficient detection of single nucleotide variants across diverse applications.

Non-alcoholic fatty liver disease (NAFLD), one of the most common chronic liver diseases with a prevalence of 23%–25% globally, is an independent risk factor for cardiovascular diseases (CVDs). Growing evidence indicates that the development of NAFLD, ranging from non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), advanced fibrosis to cirrhosis, and even hepatocellular carcinoma, is at substantial risk for CVDs, which clinically contribute to increased cardiovascular morbidity and mortality. Non-invasive serum markers assessing liver fibrosis, such as fibrosis-4 (FIB-4) score, aspartate transaminase-to-platelet ratio index (APRI), and NAFLD fibrosis score (NFS), are expected to be useful tools for clinical management of patients with CVDs. This review aims to provide an overview of the evidence for the relationship between the progression of NAFLD and CVDs and the clinical application of non-invasive markers of liver fibrosis in managing patients with CVDs.

The interaction between woody plants and mycorrhizal fungi is an important biological interaction; however, the driving factors behind the diversity of mycorrhizal trees formed through the symbiosis of mycorrhizal fungi and woody plants remain unclear. In this study, we collected and compiled the woody plant data of 34 forest dynamic plots containing 3350 species from habitats around the world and divided them into AM and EcM trees. We tested the contribution of AM and EcM trees to tree diversity and its components in forest communities worldwide. Our results showed that AM trees rather than EcM trees affect the tree diversity of forest communities, and that the diversity of AM trees has a significant latitudinal gradient pattern. Climate variables, especially temperature, are strongly correlated with the diversity patterns for AM trees rather than EcM trees. Topography is the most significant factor affecting the diversity of EcM trees. Our findings highlight the importance of AM trees for the tree diversity of forest communities worldwide. Our findings have important implications for understanding the response of complex woody plant communities with different types of mycorrhizal symbiosis to climate change.

Aim To describe the pattern of the prevalence of mental health problems during the first year of the COVID-19 pandemic and examine the impact of containment measures on these trends.Methods We identified articles published until 30 August 2021 that reported the prevalence of mental health problems in the general population at two or more time points. A crowd of 114 reviewers extracted data on prevalence, study and participant characteristics. We collected information on the number of days since the first SARS-CoV-2 infection in the study country, the stringency of containment measures and the number of cases and deaths. We synthesised changes in prevalence during the pandemic using a random-effects model. We used dose-response meta-analysis to evaluate the trajectory of the changes in mental health problems.Results We included 41 studies for 7 mental health conditions. The average odds of symptoms increased during the pandemic (mean OR ranging from 1.23 to 2.08). Heterogeneity was very large and could not be explained by differences in participants or study characteristics. Average odds of psychological distress, depression and anxiety increased during the first 2 months of the pandemic, with increased stringency of the measures, reported infections and deaths. The confidence in the evidence was low to very low.Conclusions We observed an initial increase in the average risk of psychological distress, depression-related and anxiety-related problems during the first 2 months of the pandemic. However, large heterogeneity suggests that different populations had different responses to the challenges imposed by the pandemic.

BackgroundAlthough there is solid epidemiological evidence supporting the connection between hypertension and gout, little has been said about the relationship between diastolic and systolic blood pressure and gout, the causal relationship and direction associated are uncertain, so we aim to research the causal relationship between diastolic and systolic blood pressure and gout.MethodsWe conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effect between 2 blood pressure phenotypes (including diastolic blood pressure and systolic blood pressure) and 5 gout phenotypes (including gout, drug-induced gout, idiopathic gout, unspecified gout, and strictly defined gout) using genome-wide association study statistics. The inverse variance weighting method was used to generate the main results, while sensitivity analyses using MR-Egger, weighted median, Cochran’s Q test, Egger intercept test, and leave-one-out analysis, were performed to assess the stability and reliability of the results.ResultsAfter the screening, we found a causal relationship between diastolic blood pressure and gout, idiopathic gout, unspecified gout, and strictly defined gout, and a causal relationship between systolic blood pressure and gout, idiopathic gout, unspecified gout, and strictly defined gout.ConclusionFrom a genetic predisposition, controlling blood pressure may reduce the risk of gout.

BackgroundHand, foot, and mouth disease (HFMD) is a common infectious disease in children. Enterovirus A71 (EV71) and coxsackievirus A16 (CA16) have been identified as the predominant pathogens for several decades. In recent years, coxsackievirus A6 (CA6) and coxsackievirus A10 (CA10) have played increasingly important roles in a series of HFMD outbreaks. We performed a retrospective analysis of the epidemiology of HFMD and the spectrum of different viral serotypes, to elucidate the genetic and phylogenetic characteristics of the main serotypes in the Jiashan area during 2016 to 2022.MethodsDescriptive epidemiological methods were used to analyze the time and population distribution of HFMD in Jiashan during 2016 to 2022 based on surveillance data. Molecular diagnostic methods were performed to identify the viral serotypes and etiological characteristics of HFMD. Phylogenetic analyses was based on VP1 region of CA16 and CA6.ResultsThe average annual incidence rate of HFMD fluctuated from 2016 to 2022. Children aged 1–5 years accounted for 81.65% of cases and boys were more frequently affected than girls. Except when HFMD was affected by the COVID-19 epidemic in 2020 and 2022, epidemics usually peak in June to July, followed by a small secondary peak from October to December and a decline in February. Urban areas had a high average incidence and rural areas had the lowest. Among 560 sample collected in Jiashan, 472 (84.29%) were positive for enterovirus. The most frequently identified serotypes were CA6 (296, 52.86%), CA16 (102, 18.21%), EV71 (16, 2.86%), CA10 (14, 2.50%) and other enteroviruses (44, 7.86%). There were 71 and 142 VP1 sequences from CA16 and CA6, respectively. Substitution of N218D, A220L and V251I was detected in CA16 and may have been related to viral infectivity. Phylogenetic analysis showed that CA16 could be assigned to two genogroups, B1a and B1b, while all the CA6 sequences belonged to the D3a genogroup.ConclusionCA6 and CA16 were the two major serotypes of enteroviruses circulating in the Jiashan area during 2016 to 2022. Continuous and comprehensive surveillance for HFMD is needed to better understand and evaluate the prevalence and evolution of the associated pathogens.

BackgroundRecent studies show testosterone (T) deficiency worsens cognitive impairment in Alzheimer’s disease (AD) patients. Mitochondrial dysfunction, as an early event of AD, is becoming critical hallmark of AD pathogenesis. However, currently, whether T deficiency exacerbates mitochondrial dysfunction of men with AD remains unclear.ObjectiveThe purpose of this study is to explore the effects of T deficiency on mitochondrial dysfunction of male AD mouse models and its potential mechanisms.MethodsAlzheimer’s disease animal model with T deficiency was performed by castration to 3-month-old male APP/PS1 mice. Hippocampal mitochondrial function of mice was analyzed by spectrophotometry and flow cytometry. The gene expression levels related to mitochondrial biogenesis and mitochondrial dynamics were determined through quantitative real-time PCR (qPCR) and western blot analysis. SH-SY5Y cells treated with flutamide, T and/or H2O2 were processed for analyzing the potential mechanisms of T on mitochondrial dysfunction.ResultsTestosterone deficiency significantly aggravated the cognitive deficits and hippocampal pathologic damage of male APP/PS1 mice. These effects were consistent with exacerbated mitochondrial dysfunction by gonadectomy to male APP/PS1 mice, reflected by further increase in oxidative damage and decrease in mitochondrial membrane potential, complex IV activity and ATP levels. More importantly, T deficiency induced the exacerbation of compromised mitochondrial homeostasis in male APP/PS1 mice by exerting detrimental effects on mitochondrial biogenesis and mitochondrial dynamics at mRNA and protein level, leading to more defective mitochondria accumulated in the hippocampus. In vitro studies using SH-SY5Y cells validated T’s protective effects on the H2O2-induced mitochondrial dysfunction, mitochondrial biogenesis impairment, and mitochondrial dynamics imbalance. Administering androgen receptor (AR) antagonist flutamide weakened the beneficial effects of T pretreatment on H2O2-treated SH-SY5Y cells, demonstrating a critical role of classical AR pathway in maintaining mitochondrial function.ConclusionTestosterone deficiency exacerbates hippocampal mitochondrial dysfunction of male APP/PS1 mice by accumulating more defective mitochondria. Thus, appropriate T levels in the early stage of AD might be beneficial in delaying AD pathology by improving mitochondrial biogenesis and mitochondrial dynamics.

Summary: This study investigates the efficacy of proteomic analysis of human remains to identify active infections in the past through the detection of pathogens and the host response to infection. We advance leprosy as a case study due to the sequestering of sufferers in leprosaria and the suggestive skeletal lesions that can result from the disease. Here we present a sequential enzyme extraction protocol, using trypsin followed by ProAlanase, to reduce the abundance of collagen peptides and in so doing increase the detection of non-collagenous proteins. Through our study of five individuals from an 11th to 18th century leprosarium, as well as four from a contemporaneous non-leprosy associated cemetery in Barcelona, we show that samples from 2 out of 5 leprosarium individuals extracted with the sequential digestion methodology contain numerous host immune proteins associated with modern leprosy. In contrast, individuals from the non-leprosy associated cemetery and all samples extracted with a trypsin-only protocol did not. Through this study, we advance a palaeoproteomic methodology to gain insights into the health of archaeological individuals and take a step toward a proteomics-based method to study immune responses in past populations.

Background Data-dependent, bottom-up proteomics is widely used for identifying proteins and peptides. However, one key challenge is that 70% of fragment ion spectra consistently fail to be assigned by conventional database searching. This ‘dark matter’ of bottom-up proteomics seems to affect fields where non-model organisms, low-abundance proteins, non-tryptic peptides, and complex modifications may be present. While palaeoproteomics may appear as a niche field, understanding and reporting unidentified ancient spectra require collaborative innovation in bioinformatics strategies. This may advance the analysis of complex datasets. Methods 14.97 million high-impact ancient spectra published in Nature and Science portfolios were mined from public repositories. Identification rates, defined as the proportion of assigned fragment ion spectra, were collected as part of deposited database search outputs or parsed using open-source python packages. Results and Conclusions We report that typically 94% of the published ancient spectra remain unidentified. This phenomenon may be caused by multiple factors, notably the limitations of database searching and the selection of user-defined reference data with advanced modification patterns. These ‘spectra without stories’ highlight the need for widespread data sharing to facilitate methodological development and minimise the loss of often irreplaceable ancient materials. Testing and validating alternative search strategies, such as open searching and de novo sequencing, may also improve overall identification rates. Hence, lessons learnt in palaeoproteomics may benefit other fields grappling with challenging data.

Objective: Long-term alcohol consumption can cause organic damage to the brain, resulting in mental and nervous system abnormalities and intellectual impairment. Huanglian Jiedu decoction (HLJDD) is the classic representative of clearing heat and detoxifying. This study aimed to explore the effects and possible mechanisms of HLJDD on brain injury in chronic alcohol-exposed mice. Methods: The alcohol-exposed mice were treated with different doses of HLJDD to observe behavioral changes, hippocampal Aβ1-42 deposition, number and ultrastructural changes of neurons in the hippocampus and prefrontal cortex, and expressions of synaptic proteins. On this basis, transcriptome sequencing was used to analyze the differentially expressed genes in different treatment groups, and functional enrichment analysis was performed. Then, WB and RT-PCR were used to verify the expression of the pathway. Results: Chronic alcohol exposure reduced body weight in mice, led to motor cognitive impairment, increased Aβ1-42 in the hippocampus, decreased the number of neurons in the hippocampus and prefrontal cortex, and the expression of PSD95 and SYN in the hippocampus. HLJDD significantly improved the cognitive dysfunction of mice and alleviated the damage of the hippocampus and prefrontal cortex. Transcriptome sequencing results showed that the regulatory effects of HLJDD on chronic alcohol-exposed mice may be related to the RAS pathway. Further experiments confirmed that chronic alcohol exposure caused a significant increase in protein and gene expressions of the RAS-RAF-MEK-ERK pathway in mouse, and this activation was reversed by HLJDD. Conclusion: HLJDD may ameliorate brain damage caused by chronic alcohol exposure by regulating the RAS-RAF-MEK-ERK pathway.

BackgroundThe claustrum (CLA), a subcortical area between the insular cortex and striatum, innervates almost all cortical regions of the mammalian brain. There is growing evidence that CLA participates in many brain functions, including memory, cognition, and stress response. It is proposed that dysfunction or malfunction of the CLA might be the pathology of some brain diseases, including stress-induced depression and anxiety. However, the role of the CLA in fear memory and anxiety disorders remains largely understudied.MethodsWe evaluated the influences of neurotoxic lesions of the CLA using auditory-cued fear memory and anxiety-like behaviors in rats.ResultsWe found that lesions of anterior CLA (aCLA) but not posterior CLA (pCLA) before fear conditioning attenuated fear retrieval, facilitated extinction, and reduced freezing levels during the extinction retention test. Post-learning lesions of aCLA but not pCLA facilitated fear extinction and attenuated freezing behavior during the extinction retention test. Lesions of aCLA or pCLA did not affect anxiety-like behaviors evaluated by the open field test and elevated plus-maze test.ConclusionThese data suggested that aCLA but not pCLA was involved in fear memory and extinction. Future studies are needed to further investigate the anatomical and functional connections of aCLA subareas that are involved in fear conditioning, which will deepen our understanding of CLA functions.

Summary: Osteoporosis has gradually become a major public health problem. Further elucidation of the pathophysiological mechanisms that induce osteoporosis and identification of more effective therapeutic targets will have important clinical significance. Experiments in vitro on bone marrow stem cells (BMSCs) subjected to osteogenic and adipogenic differentiation and in vivo on surgical bilateral ovariectomy (OVX) mouse models revealed that exosomes of vascular endothelial cells (EC-EXOs) can promote osteogenic differentiation of BMSCs and inhibit BMSC adipogenic differentiation through miR-3p-975_4191. Both miR-3p-975_4191 and curcumin can target tumor necrosis factor (TNF) and act synergistically to regulate BMSCs fate differentiation and delay the progression of osteoporosis. Our findings suggest that EC-EXOs may exert a synergistic effect with curcumin in reversing the progression of osteoporosis by targeting TNF via miR-3p-975_4191. Our study may provide therapeutic options and potential therapeutic targets for osteoporosis and thus has important clinical implications.

Although high-silica granites can provide unique insights into the maturity of the continental crust and rare metal enrichment, the origin of high-silica granitic magmatism remains uncertain. In this paper, we present an integrated study of zircon U-Pb geochronology and trace elements, whole-rock geochemistry, and Sr-Nd isotopes for two typical high-silica granites (namely, the Longbao granitic porphyry and the Yushu granite) found in the North Qiangtang terrane, central Tibetan Plateau. Zircon geochronological data indicate that these high-silica granites crystallized at 217–214 Ma. All the samples from the Longbao granitic porphyry and the Yushu granite exhibited high SiO2, low MgO, depletion of Ba, Nb, Sr, P, and Ti, and enrichment of Th and U. They exhibited relatively high (87Sr/86Sr)i ratios of 0.7120–0.7136 and low εNd(t) values of −8.58 ∼ −7.58; together with their old ages according to the two-stage Nd model (1.6–1.7 Ga), these features indicate the involvement of crustal materials. Geochemical and isotopic variation indicated that the high-silica granites studied were mainly produced by the dehydration melting of a muscovite (Ms)-bearing source, and that the Triassic turbidites might be a good candidate for the magma source. Combining this evidence with new regional studies, it can be concluded that partial melting of Triassic turbidites induced by slab roll-back might be the key factor controlling the origin of Late Triassic magmatism in the North Qiangtang terrane.

Background: Diabetic cardiomyopathy is one common cardiovascular complication without effective treatments. Dihydromyricetin (DHY), a natural dihydroflavonol compound extracted from Ampelopsis grossedentata, possesses versatile pharmacologically important effects. In our current research, we planned to evaluate the impact and probable DHY mechanisms in high glucose (HG)-induced cardiomyocytes. Methods: Primary cardiomyocytes were pretreated with different concentrations of DHY (0, 20, 40, 80, 160, and 320 μM) for various time (0, 1, 2, 4, 12, and 24 h). They were then stimulated for 48 h with 5.5 mmol/L normal glucose (NG) and 33.3 mmol/L high glucose (HG). Cell viability, adenosine-triphosphate (ATP) levels, and lactate dehydrogenase (LDH) release of cardiomyocytes were detected. JC-1 staining was employed to measure the mitochondrial membrane potential. MitoSOX staining and dihydroethidium (DHE) staining were applied to evaluate the oxidative stress levels. TDT mediated dUTP nick end labeling (TUNEL) was used to measure apoptotic levels. Expressions of calcium/calmodulin-dependent protein kinase II (CaMKII), phospholamban (PLB), optic atrophy 1 (OPA1), dynamin-related protein 1 (DRP1), caspase 3, mixed kinase lineage domain like protein (MLKL), receptor interacting protein kinase 3 (RIPK3), and receptor interacting protein kinase 1 (RIPK1) were detected by immunofluorescence and/or Western blot. Results: DHY improved cell viability, enhanced ATP level, and decreased LDH content in HG-stimulated cardiomyocytes, suggesting DHY attenuating cell injury. DHY reduced number of TUNEL positive cells, inhibited RIPK3 and cleaved-caspase 3 expression, implying DHY alleviated necroptosis in HG-stimulated cardiomyocytes. DHY diminished JC-1 monomers, DHE and MitoSOX fluorescence intensity as well as DRP1 expression but increased JC-1 aggregates intensity and OPA1 expression, indicating that DHY attenuated oxidative stress in HG-stimulated cardiomyocytes. DHY also attenuated CaMKII activity by suppressed PLB phosphorylation and inhibited CaMKII oxidation in HG-stimulated cardiomyocytes. Conclusions: HG-induced cardiomyocytes injury was alleviated wherein DHY attenuated necroptosis, repressed ROS production, and inhibited CaMKII oxidation, suggesting that DHY may serve as potential agent to prevent and treat diabetic cardiomyopathy.

BackgroundDifferences in border zone contribute to different outcomes post-infarction, such as left ventricular aneurysm (LVA) and myocardial infarction (MI). LVA usually forms within 24 h of the onset of MI and may cause heart rupture; however, LVA surgery is best performed 3 months after MI. Few studies have investigated the LVA model, the differences in border zones between LVA and MI, and the mechanism in the border zone.MethodsThe LVA, MI, and SHAM mouse models were used. Echocardiography, Masson’s trichrome staining, and immunofluorescence staining were performed, and RNA sequencing of the border zone was conducted. The adipocyte-conditioned medium-treated hypoxic macrophage cell line and LVA and MI mouse models were employed to determine the effects of the hub gene, adiponectin (ADPN), on macrophages. Quantitative polymerase chain reaction (qPCR), Western blot analysis, transmission electron microscopy, and chromatin immunoprecipitation (ChIP) assays were conducted to elucidate the mechanism in the border zone. Human subepicardial adipose tissue and blood samples were collected to validate the effects of ADPN.ResultsA novel, simple, consistent, and low-cost LVA mouse model was constructed. LVA caused a greater reduction in contractile functions than MI owing to reduced wall thickness and edema in the border zone. ADPN impeded cardiac edema and promoted lymphangiogenesis by increasing macrophage infiltration post-infarction. Adipocyte-derived ADPN promoted M2 polarization and sustained mitochondrial quality via the ADPN/AdipoR2/HMGB1 axis. Mechanistically, ADPN impeded macrophage HMGB1 inflammation and decreased interleukin-6 (IL6) and HMGB1 secretion. The secretion of IL6 and HMGB1 increased ADPN expression via STAT3 and the co-transcription factor, YAP, in adipocytes. Based on ChIP and Dual-Glo luciferase experiments, STAT3 promoted ADPN transcription by binding to its promoter in adipocytes. In vivo, ADPN promoted lymphangiogenesis and decreased myocardial injury after MI. These phenotypes were rescued by macrophage depletion or HMGB1 knockdown in macrophages. Supplying adipocytes overexpressing STAT3 decreased collagen disposition, increased lymphangiogenesis, and impaired myocardial injury. However, these effects were rescued after HMGB1 knockdown in macrophages. Overall, the IL6/ADPN/HMGB1 axis was validated using human subepicardial tissue and blood samples. This axis could serve as an independent factor in overweight MI patients who need coronary artery bypass grafting (CABG) treatment.ConclusionThe IL6/ADPN/HMGB1 loop between adipocytes and macrophages in the border zone contributes to different clinical outcomes post-infarction. Thus, targeting the IL6/ADPN/HMGB1 loop may be a novel therapeutic approach for cardiac lymphatic regulation and reduction of cell senescence post-infarction.

Abstract This study aimed to evaluate the efficacy and safety of induction immunochemotherapy followed by definitive chemoradiotherapy (CRT) for unresectable locally advanced non‐small cell lung cancer (LA‐NSCLC). We identified unresectable stage III NSCLC patients who received induction immunochemotherapy. Overall survival (OS) and progression‐free survival (PFS) were the primary endpoints. From February 2019 to August 2022, 158 patients were enrolled. Following the completion of induction immunochemotherapy, the objective response rate (ORR) and disease control rate (DCR) were 52.5% and 83.5%, respectively. The ORR of CRT was 73.5%, representing 68.4% of the total cohort. The median PFS was 17.8 months, and the median OS was 41.9 months, significantly higher than in patients who received CRT alone (p

Deficiency in regulatory T cells (Tregs) is an important mechanism underlying the pathogenesis of pediatric aplastic anemia, but its specific mechanism is unclear. In our study, we aimed to investigate whether IL-2/STAT5 can regulate the proliferation of Tregs in aplastic anemia (AA) by regulating their expression of B lymphocyte-induced mature protein-1 (BLIMP-1) or interferon regulatory factor 4 (IRF4). Through clinical research and animal experiments, we found that poor activation of the IL-2/STAT5 signaling pathway may leads to low expression of BLIMP-1 in Tregs of children with AA, which leads to defects in the differentiation and proliferation of Tregs in AA. In AA model mice, treatment with IL-2c reversed the decrease in Treg proportions and reduction in Blimp-1 expression in Tregs by increasing the phosphorylation of Stat5 in Tregs. In AA, deficiency of IRF4 expression in Tregs is closely related to the deficiency of Tregs, but is not regulated by the IL-2/STAT5 pathway.

Nitrogen fertilizer supports agricultural intensification, but its manufacturing results in substantial contaminated sites. Ammonia nitrogen is the main specific pollutant in retired nitrogen fertilizer sites with potential human health and odor risks. However, few studies focus on ammonia nitrogen risk assessment at contaminated sites, particularly considering its solid-liquid partitioning process (Kd) and ammonium/ammonia equilibrium process (R) in the soil. This study took a closed nitrogen fertilizer factory site as an example and innovatively introduced Kd and R to scientifically assess the human health and odor risk of ammonia nitrogen. The risk control values (RCVs) of ammonia nitrogen based on human health and odor risk were also derived. The maximum concentration of ammonia nitrogen was 3380 mg/kg in the unsaturated soil, which was acceptable for human health because the health RCVs were 5589 ∼ 137,471 mg/kg in various scenarios. However, odor risk was unacceptable for RCVs were 296 ∼ 1111 mg/kg under excavation scenarios and 1118 ∼ 35,979 mg/kg under non-excavation scenarios. Of particular concern, introducing Kd and R in calculation increased the human health and odor RCVs by up to 27.92 times. Despite the advancements in ammonia risk assessment due to the introduction of Kd and R, odor risk during excavation remains a vital issue. These findings inform a more scientific assessment of soil ammonia risk at contaminated sites and provide valuable insights for the management and redevelopment of abandoned nitrogen fertilizer plant sites.

Summary: Background: Concurrent chemoradiotherapy is the standard nonoperative treatment for locally advanced esophageal squamous cell carcinoma. However, local recurrence is still the main failure pattern, accounting for more than half of all treatment failures, indicating that the sensitivity of radiotherapy still needs to be improved. This trial aimed at demonstrating whether PD-1 inhibitors followed by chemoradiotherapy could promote esophageal tumor vascular normalization, alleviate hypoxia, and thus enhance radiosensitivity and improve local control. Methods: We did a multicenter, single-arm, phase 2 trial in China. Patients with locally advanced esophageal cancer were enrolled in this study. In induction phase, patients received two cycles of sintilimab, paclitaxel and carboplatin once per 21 days. In concurrent phase, patients were treated with five cycles of carboplatin and paclitaxel once per week concurrent with radiotherapy of 50.4Gy delivered in 28 fractions. The primary endpoint was 2-year local control rate. Hypoxia and vessel normalization was assessed before and after induction phase using immunofluorescence and perfusion CT. This trial is registered with ClinicalTrials.gov (NCT03985046). Findings: Seventy-five patients with esophageal cancer were enrolled in this study between October 2019 and April 2021. The median follow-up of surviving patients was 33.6 months (IQR 29.3–35.7). The 2-year local control rate was 81.7% (95% confidence interval, 72.7%–90.7%), which was much higher than that in concurrent chemoradiation only (71.3%) in previous studies. Vascular normalization and hypoxia alleviation were observed in both biopsy specimens and perfusion CT. Interpretation: The addition of induction immunotherapy to standard concurrent chemoradiotherapy could improve radiosensitivity for locally advanced esophageal cancer as non-surgical treatment. New treatment combination led to higher local control rate through promoting vascular normalization and alleviating hypoxia. Our findings suggest that induction immunotherapy followed by concurrent chemoradiotherapy could be a potential option in future treatment. Funding: National Natural Science Foundation of China and Shanghai Rising-Star Program.

Background: Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome (Barakat syndrome) is a rare autosomal dominant disorder caused by mutations in the gene encoding GATA3 on chromosome 10p14. Method: Informed consent was obtained from a 38-year-old female patient. 5 mL of venous blood was collected and sent for whole-exome sequencing. GATA3 constructs of both wild-type and mutant were transfected into HEK-293 T cells. Three-dimensional modeling, luciferase-reporter gene test, western blotting and cellular immunofluorescence were used to evaluate the effect of the mutation. Results: A novel frameshift mutation c. 677dup(p.Pro227AlafsTer77), named P227Afs, was found in GATA3. Three-dimensional modeling revealed that the mutation caused the loss of the dual zinc finger structures 1 and 2 (ZNF1 and ZNF2) of the synthesized protein. Expression of wild-type GATA3 produced a six-fold increase in luciferase activity when compared with pcDNA3.1 vector only (P

Abstract Background To compare the triage performance of HPV viral loads reflected by cycle threshold values (CtV) from two different HPV testing assays: the PCR based Cobas4800 and the isothermal amplification based AmpFire assay. Methods We used the data from a sub-study of The Chinese Multi-Center Screening Trial and analyzed the data of the cases positive in both Cobas4800 and AmpFire assays with recorded CtV. Spearman’s correlation was applied to analyze the association between CtV from AmpFire and Cobas4800 assays, as well as the correlation between CtV and the histological lesion grades. The 50th percentile of CtV was used as the cutoff to construct triage algorithms for HPV-positive cases. McNemar’s test was used to analyze the differences in sensitivity and specificity for detecting CIN2 + and CIN3 + in different triage algorithms. Results Four hundred forty-six HPV positive women who had consistent HPV results from Cobas4800 and AmpFire in terms of the HPV genotype and reported Ct values were included in the analysis. The mean CtV of hrHPV tested by Cobas4800 and AmpFire were linear correlated. Direct association were showed between the severity of cervical lesions and the HPV viral loads reflected by CtV of hrHPV, HPV16, non-16/18 hrHPV and A9 group from both assays. HPV16/18 genotyping combined with low-CtV for non-16/18 hrHPV, especially A9 group, were demonstrated to be satisfactory in the sensitivity and specificity for detecting CIN2 + or CIN3 + . Conclusion Ct value represented a good triage marker in both PCR-based and isothermal amplification HPV detection.