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Background Few small‐sample studies have quantified the T‐wave alternans (TWA) value by 24‐hour ambulatory recordings or exercise stress tests in patients with long QT syndrome (LQTS). The cutoff point of TWA ≥47 μV was based on patients with myocardial infarction. In our study, we aimed to (1) evaluate the association of TWA with life‐threatening arrhythmic events (LAEs); (2) compare the predictive model of LAEs according to the TWA value measured by 24‐hour ambulatory recordings and exercise stress tests; and (3) propose a cutoff point for the high risk of LAEs in patients with LQTS. Methods and Results The study cohort included 110 patients with LQTS referred to our hospital, and the primary outcome was LAEs. Thirty‐one patients with LQTS (31/110 [28.2%]) developed LAEs during the following 24 (12–47) months. Peak TWA value quantified from 12 leads by 24‐hour ambulatory recordings in patients with LQTS with LAEs (LQTS–LAEs group) was significantly higher than LQTS without LAEs (LQTS–non‐LAEs group) (64.0 [42.0–86.0] μV versus 43.0 [36.0–53.0] μV; P

IntroductionIn team sports, athletes’ ability to make quick decisions plays a crucial role. Decision-making proficiency relies on the intricate balance of athletes’ perceptual and cognitive abilities, enabling them to assess the competitive environment swiftly and select the most appropriate actions from various options. Virtual reality (VR) technology is emerging as a valuable tool for evaluating and refining athletes’ decision-making skills. This study systematically examined the integration of VR technology into decision-making processes in team sports, aiming to identify more effective methods for presenting and interacting with virtual decision-making systems, thus enhancing the evaluation and refinement of athletes’ decision making abilities.MethodsFollowing the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, a thorough search of respected research databases, including Web of Science, PubMed, SPORTDiscus, ScienceDirect, PsycINFO, and IEEE, was conducted using carefully selected keywords.ResultsTwenty research papers meeting predefined inclusion criteria were included after careful evaluation. These papers were systematically analyzed to delineate the attributes of virtual decision-making task environments, the interactive dynamics inherent in motor decision-making tasks, and the significant findingsDiscussionThis review indicate that (1) the effectiveness of VR technology in assessing and improving athletes’ decision-making skills in team sports; (2) the construction of virtual environments using the Head-Mounted Display (HMD) system, characterized by enhanced ease and efficiency; (3) the potential for future investigations to explore computer simulations to create more expansive virtual motion scenarios, thus efficiently generating substantial task scenario material, diverging from the constraints posed by 360-degree panoramic videos; and (4) the integration of motion capture technology for identifying and monitoring athletes’ decision-making behaviors, which not only enhances ecological validity but also augments the transfer validity of virtual sports decision-making systems. Future research endeavors could explore integrating eye-tracking technology with virtual reality to gain insights into the intrinsic cognitive-action associations exhibited by athletes.

Ecological operation of hydraulic engineering is essential for the conservation of fishery resources. Water velocity is known to affect the spawning of fishes delivering drifting eggs. This study aims to explore the effects of water velocity stimulation on the ovarian maturation and antioxidant capacity of adult grass carp (Ctenopharyngodon idellus) through laboratory experiments in order to understand the physiological mechanism underlying the response of natural reproduction to ecological flows. We examined the histology, sex hormones and vitellogenin (VTG) concentrations of ovary, and the transcripts of key genes in the hypothalamus-pituitary-gonad (HPG) axis, as well as the antioxidant activities of ovary and liver in grass carp. The results showed that although there was no discernible difference on the ovarian development characteristics of grass carp under water velocity stimulation, estradiol, testosterone, progesterone, 17α,20β-dihydroxy-4-pregnen-3-one (17α,20β-DHP), and VTG concentrations were elevated, which was related to the transcriptional regulation of the HPG axis genes. The gene expression levels (gnrh2, fshβ, lhβ, cgα, hsd20b, hsd17b3, and vtg) in the HPG axis were significantly elevated under water velocity stimulation, while those of hsd3b1, cyp17a1, cyp19a1a, hsd17b1, star, and igf3 were suppressed. In addition, appropriate water velocity stimulation could enhance body health status by increasing the activities of antioxidant enzymes in the ovary and liver. The results of this study provide the fundamental knowledge and data support for ecological operation of hydropower projects and river ecological restoration.

Introduction: Chronic hepatitis B (CHB) is a worldwide infectious disease caused by hepatitis B virus (HBV). Optimizing antiviral treatment strategies could improve the functional cure (FC) rate of patients with CHB. This study aims to systematically review the FC rate of the de novo combination of nucleos(t)ide analogs (NAs) and pegylated interferon α (PEG-IFNα) versus that of PEG-IFNα monotherapy for CHB.Methods: Databases were searched until 31 December 2023. Selected studies included randomized controlled trials on the de novo combination of NAs and PEG-IFNα versus PEG-IFNα monotherapy for 48 weeks in patients with CHB to achieve FC, which was defined as hepatitis B surface antigen (HBsAg) loss and/or HBsAg seroconversion. Meta-analysis was conducted in accordance with the efficacy at the end of treatment and different time points during follow-up.Results: A total of 10 studies, encompassing 2,339 patients in total, were included. Subgroup analysis was conducted in accordance with whether first-line NAs were used. It found no statistically significant difference between HBsAg loss and HBsAg seroconversion at the end of treatment. Serum HBV DNA

BackgroundThe beneficial effects of fibroblast growth factor 21 (FGF21) and sodium butyrate (NaB) on protection against cholestasis-induced liver fibrosis are not well known. This study aimed to explore the effects of FGF21 and NaB on bile duct ligation (BDL)-induced liver fibrosis.MethodsWild-type (WT) and FGF21 knockout (KO) mice received BDL surgery for 14 days. Liver fibrosis was assessed by Masson’s staining for fibrosis marker expressions at the mRNA or protein levels. Adenovirus-mediated FGF21 overexpression in the WT mice was assessed against BDL damage. BDL surgeries were performed in WT and FGF21 KO mice that were administered either phosphate-buffered saline or NaB. The effects of NaB on the energy metabolism and gut microbiota were assessed using stable metabolism detection and 16S rRNA gene sequencing.ResultsBDL-induced liver fibrosis in the WT mice was accompanied by high induction of FGF21. Compared to the WT mice, the FGF21 KO mice showed more severe liver fibrosis induced by BDL. FGF21 overexpression protected against BDL-induced liver fibrosis, as proved by the decreasing α-SMA at both the mRNA and protein levels. NaB administration enhanced the glucose and energy metabolisms as well as remodeled the gut microbiota. NaB alleviated BDL-induced liver fibrosis in the WT mice but aggravated the same in FGF21 KO mice.ConclusionFGF21 plays a key role in alleviating cholestasis-induced liver damage and fibrosis. NaB has beneficial effects on cholestasis in an FGF21-dependent manner. NaB administration can thus be a novel nutritional therapy for treating cholestasis via boosting FGF21 signaling and regulating the gut microbiota.

DMP (Differences in Material Properties) often exists between temperature sensors and combustion chamber components of ICE (Internal Combustion Engine), resulting in IEs (Introduced Errors) in the temperature measuring process. In this paper, we present a comprehensive theoretical analysis of the correlation between introduced errors on chamber components and the DMP. The analysis process considers the characteristics of the chamber's heat transfer BC (Boundary Condition). Then, simulations are used to investigate the introduced error of hardness plug and thermocouple sensors on the top surface of an ICE aluminum alloy piston. The theoretical analysis results indicate that heat transfer BC can be segmented into the time-averaged and fluctuation parts, and IEs are linearly superimposed under these two parts of BCs. The heat conductivity impacts the time-averaged error and the product of heat conductivity, density, and heat capacity impacts the fluctuation error. The experimental and simulation results indicate that the max time-average error of the hardness plug on piston is 2.4 °C, with a fluctuation introduced error of 3.6 °C and a total introduced error of 6 °C; and the time-average introduced error of thermocouple sensor is 9.4 °C, with a fluctuation error of 5.8 °C and a total introduced error of 15.2 °C. Finally, a fluctuation error correction method is proposed to reduce error. After correction, the error is reduced by 71 % and 66 % for hardness plug and thermocouple, respectively.

After 20 years of service, multiple web shear cracks were observed in 20 m-span prestressed concrete hollow slab beams. Shear enhancement is required to improve structural safety. To evaluate the strengthening effect of the new material on the hollow slab beam structure, fiber-reinforced cementitious composites (FRCC) were used to fill the cavities at the beam ends, and a comprehensive field load test was carried out on the shear-resistant performance of the actual bridge. The web principal stresses changed before and after strengthening under various working conditions, which were analyzed and compared with the performance of the traditional channel steel technique. The findings show that the web principal stresses are significantly reduced by more than 50 % after filling with FRCC, notably superior to the channel steel technique. In addition, both methods can reduce mid-span deflections by 10–20 %. The channel steel technique specifically enhances transverse connection capabilities. Furthermore, strain responses in the beam end sections were reduced by about 30–45 %. Finally, finite element simulations of single beam strengthening were also conducted to complement the experimental analysis. The simulation results show that the shear span ratio (λ), FRCC length and strand prestress loss remarkably impact the strengthening effect. The ultimate load capacity of the strengthened specimens decreases with the increase of λ and prestress loss and increases with the increase of FRCC length. In conclusion, the utilization of FRCC presents a superior alternative for shear enhancement in prestressed concrete hollow slab beams, offering substantial reductions in web principal stresses and enhanced structural performance compared to the traditional strengthening method.

Abstract Early postnatal alcohol exposure can have negative impacts on neonatal rat brain development and function. Our research explored the impacts of alcohol exposure from postnatal day 4 to PD9 on Sprague‒Dawley rat pups. Pups were intragastrically administered with either an alcohol milk solution or a pure milk solution twice daily. On PD10, brains were analyzed via histological and biochemical methods. Alcohol exposure led to growth impairment, behavioral abnormalities, and cognitive deficits. It also reduced microglial numbers in the hippocampus while activating the remaining microglia to secrete IL‐6. In addition, alcohol induced the upregulation of pro‐apoptotic factors and downregulation of the anti‐apoptotic protein BCL‐2 in the hippocampus by activating the JAK/STAT/SOCS3 signaling pathway. Similar effects were observed in vitro when BV‐2 cells were exposed to ethanol and HT‐22 cells were exposed to IL‐6. The drug AG490, a STAT3 inhibitor, mitigated IL‐6‐induced JAK/STAT activation and neuronal apoptosis in HT‐22 cells. Overall, these findings demonstrate that early‐life alcohol exposure triggers an inflammatory microglial response involving the release of IL‐6, which activates JAK/STAT signaling, leading to hippocampal neuronal apoptosis and developmental/cognitive impairments. AG490 may disrupt this inflammatory signaling cascade and cause neuronal damage.

Nuclear progesterone receptor (nPR) is a member of the nuclear receptor family known to play a critical role in gonad development, gametogenesis, and ovulation in vertebrates, and also important in pregnancy maintenance and parturition in mammals. However, its biological functions in ovoviviparity teleosts are less clear. This study aimed to determine the possible role of nPR in fish oogenesis, pregnancy and parturition using black rockfish as a model. The npr, which consists of 2076 bp and codes for a 691 amino acids protein, was cloned. Phylogenetic analysis revealed that the nPR of black rockfish is more conserved in teleosts. Quantitative real-time PCR analyses in various tissues showed that npr was mainly detected in the pituitary followed by the ovary, testis and brain, while it was very low or undetectable in the spleen, head kidney, intestine and gill. During the gonadal development process, the npr level showed no variation in the ovary. In testis, the mRNA level of npr showed varied expression in different developmental stages with the highest level in the maturation stage. Detection of npr expression during fertilization and the perinatal period further showed that nPR may play important roles in the regulation of pregnancy and the parturition. In situ hybridization further revealed that npr mRNA was observed in the follicular cell layer during the perinatal period. The results from in vitro experiments showed that npr level was significantly downregulated when the primary cultured follicular cells during vitellogenesis (stage Ⅳ) were exposed to hCG. Studies using primary culture of black rockfish ovarian cells during the perinatal period, treated in vitro revealed that genes related to PGs synthesis (pla2g4a, cox2) and matrix metalloproteinases (mmp2, mmp9) were upregulated in response to 17,20β-P. However, treatment with 17,20β-P downregulated npr expression. In conclusion, these data suggest that nPR plays an essential role in fertilization, pregnancy maintenance and parturition in black rockfish.

As a life-threatening chronic disease, cancer is characterized by tumor heterogeneity. This heterogeneity is associated with factors that lead to treatment failure and poor prognosis, including drug resistance, relapse, and metastasis. Therefore, precision medicine urgently needs personalized tumor models that accurately reflect the tumor heterogeneity. Currently, tumor organoid technologies are used to generate in vitro 3D tissues, which have been shown to precisely recapitulate structure, tumor microenvironment, expression profiles, functions, molecular signatures, and genomic alterations in primary tumors. Tumor organoid models are important for identifying potential therapeutic targets, characterizing the effects of anticancer drugs, and exploring novel diagnostic and therapeutic options. In this review, we describe how tumor organoids can be cultured and summarize how researchers can use them as an excellent tool for exploring cancer therapies. In addition, we discuss tumor organoids that have been applied in cancer therapy research and highlight the potential of tumor organoids to guide preclinical research.

Polymerase chain reaction (PCR) is a revolutionary biomolecule technology that drives the development of bioscience. The current work reports a high throughput oscillating-flow PCR structure. In this chip, eight microchannels can simultaneously serve as PCR reaction chambers for nucleic acid sample amplification. To maximize the potential of this design, the effect of the chip structure parameter, fluid velocity, and channel spacing is simulated by finite element analysis. The thermal simulation results show that (1) when the distance between two temperature drivers is 4 mm, the width ratio is 1:3, the length of a single channel is 24 mm, the wall thickness is 3 mm (x) × 20 mm (y) × 1 mm (z), the diameter is 0.3 mm, and the fluid velocity is within 1 mm/s, two uniform temperature zones of 95 and 65 °C for the PCR process can be constructed and (2) the influence of channel spacing on temperature distribution is not significant. When the spacing is 2 mm, the relative standard deviations of the temperature for denaturation and the annealing/extension zone were 0.0706% and 0.0061%, respectively. Here, the chip sizes are 30 mm (x) × 54 mm (y) × 3 mm (z).

Abstract Torenia fournieri Lind. is an ornamental plant that is popular for its numerous flowers and variety of colors. However, its genomic evolutionary history and the genetic and metabolic bases of flower color formation remain poorly understood. Here, we report the first T. fournieri reference genome, which was resolved to the chromosome scale and was 164.4 Mb in size. Phylogenetic analyses clarified relationships with other plant species, and a comparative genomic analysis indicated that the shared ancestor of T. fournieri and Antirrhinum majus underwent a whole genome duplication event. Joint transcriptomic and metabolomic analyses identified many metabolites related to pelargonidin, peonidin, and naringenin production in rose (TfR)‐colored flowers. Samples with blue (TfB) and deep blue (TfD) colors contained numerous derivatives of petunidin, cyanidin, quercetin, and malvidin; differences in the abundances of these metabolites and expression levels of the associated genes were hypothesized to be responsible for variety‐specific differences in flower color. Furthermore, the genes encoding flavonoid 3‐hydroxylase, anthocyanin synthase, and anthocyanin reductase were differentially expressed between flowers of different colors. Overall, we successfully identified key genes and metabolites involved in T. fournieri flower color formation. The data provided by the chromosome‐scale genome assembly establish a basis for understanding the differentiation of this species and will facilitate future genetic studies and genomic‐assisted breeding.

Abstract High‐resolution gravity field models of the Moon established from Gravity Recovery and Interior Laboratory satellite gravity data have been playing an important role in understanding the interior structure and tectonic evolution of the Moon. Due to the correlations in the high degree and order term coefficients of the gravity field models, the difference between satellite flight orbits, and the random noise of instruments, the high‐resolution gravity anomalies data derived from the models of high degree and order usually present serious multi‐directional striping and random noise, which clearly affect the subsequent interpretation of the data. We provide an omnidirectional filtering method based on the polynomial‐fitting principle to remove multi‐directional striping noise in the lunar satellite gravity anomalies data. A set of azimuth parameters are chosen to suppress all the directions of striping noise. The algorithms of data partitioning and iterative optimization are utilized to make our method suitable and stable for large‐scale data sets. Tests on the synthetic data and the real data from the Moon's Rümker region and globally verified the feasibility of our method with a better destriping effect than the traditional Gaussian filtering or degree‐order‐truncation methods.

BackgroundCurrently, there is no standard treatment for relapsed/refractory NK/T-cell lymphoma (NKTCL). Liposomal mitoxantrone (Lipo-MIT) showed good anti-tumor effect in patients with NKTCL, breaking the limitation of natural resistance of NKTCL to anthracyclines. To further improve the efficacy, we tried a combination therapy based on Lipo-MIT in patients with relapsed/refractory NKTCL.Methods12 patients with relapsed/refractory NKTCL were enrolled in this retrospective study, all of whom had previously received pegaspargase-based treatments. The salvage treatment was a combination regimen based on Lipo-MIT. The efficacy was evaluated after every two cycles.Results11 patients had stage IV NKTCL, and all but one patients had an NRI score of ≥3. The median previous lines of treatment was two (range, 1–4), and five patients were refractory to their last line of treatment. The best response rates were as follows: complete response (CR) in five (41.7%) patients, partial response in five (41.7%) patients, stable disease in one (8.3%) patient, and progressive disease in one (8.3%) patient. At a median follow-up of four months (range, 2–14), seven patients died, with a median PFS of five months and a median OS of seven months. The six-month PFS and OS rate was 44.4% and 52.1%, respectively. All patients had suffered from side effects, among which myelosuppression was most reported. Nine patients had grade three or more myelosuppression, and the median recovery time from myelosuppression was 14 days (2–35 days). Five patients had obvious skin hyperpigmentation, and the CR rate was significantly higher compared with those without skin hyperpigmentation (80% vs. 14.3%, p=0.023). Other side effects included liver insufficiency (N=4), coagulation dysfunction (N=4), acute pancreatitis (N=2), and immunotherapy-related adverse effects (irAEs, N=2).ConclusionCombination therapy based on Lipo-MIT has a high remission rate for relapsed/refractory NKTCL, but the duration of remission needs to be further extended. Lipo-MIT has obvious myelosuppression toxicity, and active supportive therapy should be given when combined with other cytotoxic drugs.

ObjectiveTo investigate the prevalence and associated factors of suicidal ideation and suicide attempts among adolescent and young adults in China from December 14, 2022 to February 28, 2023, when COVID-19 restrictions were lifted.MethodsStudents in middle and high schools and colleges and universities in the province of Sichuan, China were asked to complete on-line cross-sectional surveys. Information was collected about sociodemographics, experiences related to the COVID-19 pandemic, suicidal ideation and suicide attempts. Participants also filled out the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7 and the Social Support Rate Scale surveys. Factors associated with suicidal ideation or suicide attempts were explored using logistic regression.ResultsOf the 82,873 respondents (aged 12 to 24 years), 21,292 (25.7%) reported having thought of suicide at least once in their lifetime, 10,382 (12.5%) reported having thought about suicide within the previous 12 months, and 1,123 (1.4%) reported having attempted it within the previous 12 months. Risk of lifetime suicidal ideation was higher among middle school students than among older students. Risk of suicidal ideation and risk of suicide attempts correlated directly with severity of symptoms of depression and anxiety, and inversely with level of social support. Greater risk of suicidal ideation and suicidal attempts was associated with: being female, living in an urban environment, attending a boarding school, currently being in love, having parents who divorced or remarried, having parents who exhibit non-authoritative parenting behavior, having higher family income, having been COVID-19 infected, having been quarantined for a long time, and being dissatisfied with one’s education.ConclusionsSuicidal ideation and suicide attempts remain prevalent among young people in China. The potential associated factors identified in our study may be useful for targeting appropriate psychosocial interventions and developing mental health policies.

Toxoplasma gondii (T. gondii) is a worldwide zoonotic parasite that can infect almost warm-blood animals, including humans, which seriously affect the health of host. Cats are known to be the only definitive host of T. gondii and continuously excrete highly infectious oocysts. This parasite carried by the companion animals leads to a great public health risk. However, there is little information on epidemiology of T. gondii in urban cats in Kunming, Southwest China. In the present study, a total of 231 serum and fecal samples were collected in Kunming aera, and then seroprevalence of T. gondii IgG antibodies in serum and molecular investigation in feces were analyzed to elucidate T. gondii infection in urban cats. The results revealed that 168 of 231 cats (72.7%) were positive for T. gondii antibodies, and 1 of 74 cat feces (1.4%) also showed a positive PCR for T. gondii DNA. The positive fecal sample was sequenced and then phylogenetically analyzed, and the isolate of T. gondii in the present study was closely related to T. gondii strain CN. In addition, the food, water and age of cats were identified as the risk factor for seropositivity. Overall, our findings indicate the widespread occurrence of T. gondii infection in urban cats in Kunming, Southwest China and identify food, water and age are the risk factors associated with T. gondii infection, which can provide effective information for developing strategies to prevent and control this zoonosis.

Abstract Alloying is regarded as one of the most promising strategies for boosting performance of catalysts for hydrogen evolution reaction (HER) due to the adjustable electronic structure and intermediate adsorption. However, there is no theory (including d‐band center theory) can accurately guide the preparation and design of alloy catalysts, and thus resulting all the reported alloy catalysts are obtained by time‐consuming and laborious experimental exploration. Herein, we proposed a mean d‐band center (εas) as a new accurate descriptor for alloy activity prediction. Theoretical simulation and experiment results revealed that this descriptor exhibits a strong scaling relation with H adsorption energy. Besides, the obtained Cu–Ag alloy displays an optimal overpotential of 223 mV at 10 mA/cm2 in 0.5 mol/L H2SO4, which is more than 300 mV lower than those of pristine Cu (530 mV) and Ag (569 mV) powder. Our work provides a new idea toward designing highly efficient HER catalysts and broadens the applicability of d‐band theory to activity prediction of alloys.

In this paper, we perform linear cryptanalysis of the stream cipher SNOW 5G, which is recommended by the international standardization group (SAGE) as one standard algorithm for 5G confidentiality and integrity protection over the wireless channel. SNOW 5G can be regarded as one member of the SNOW-V family, as it is modified from SNOW-Vi by SAGE with a slight improvement. As an overall contribution, we provide a comprehensive and elaborate theoretical analysis of linear approximations of SNOW 5G and provide the best public cryptanalysis result by far. Specifically, we first theoretically analyze the formats of linear masks of SNOW5G that can introduce high correlations, and then search for high-quality linear masks using a divide-and-conquer method based on the different cases of a critical intermediate linear mask. We find a linear approximation of SNOW 5G with correlation −2−67.67 and further launch a correlation attack against it with complexity 2279.8, improving the existing best correlation attack by a factor of 232.4. Our results are mainly from theoretical analysis, which involve little computation overhead and help to better understand the security of SNOW 5G.

BackgroundN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to induce PD models, but the effect of MPTP on the cells and genes of PD has not been fully elucidated.MethodsSingle-nucleus RNA sequencing was performed in the Substantia Nigra (SN) of MPTP mice. UMAP analysis was used for the dimensionality reduction visualization of the SN in the MPTP mice. Known marker genes highly expressed genes in each cluster were used to annotate most clusters. Specific Differentially Expressed Genes (DEGs) and PD risk genes analysis were used to find MPTP-associated cells. GO, KEGG, PPI network, GSEA and CellChat analysis were used to reveal cell type-specific functional alterations and disruption of cell-cell communication networks. Subset reconstruction and pseudotime analysis were used to reveal the activation status of the cells, and to find the transcription factors with trajectory characterized.ResultsInitially, we observed specific DEGs and PD risk genes enrichment in microglia. Next, We obtained the functional phenotype changes in microglia and found that IGF, AGRN and PTN pathways were reduced in MPTP mice. Finally, we analyzed the activation state of microglia and revealed a pro-inflammatory trajectory characterized by transcription factors Nfe2l2 and Runx1.ConclusionOur work revealed alterations in microglia function, signaling pathways and key genes in the SN of MPTP mice.

ObjectivesMast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide (SO2) is an important regulator of MC function. However, the mechanism underlying its role in MC degranulation remains unclear. This study aimed to investigate the mechanism by which endogenous SO2 controlled MC degranulation.MethodsHMC-1 and Rat basophilic leukemia cell MC line (RBL-2H3) were used in the cell experiments. SO2 content was detected by in situ fluorescent probe. MC degranulation represented by the release rate of MC β-hexosaminidase was determined using a colorimetric assay. Sulfenylation of galectin-9 (Gal-9) in MCs and purified protein was detected using a biotin switch assay. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the exact sulfenylation sites of Gal-9 by SO2. Animal models of passive cutaneous anaphylaxis (PCA) and hypoxia-driven pulmonary vascular remodeling were used to investigate the effect of SO2 on mast cell activation in vivo. Site-directed mutation of Gal-9 was conducted to confirm the exact site of SO2 and support the significance of SO2/Gal-9 signal axis in the regulation of MC degranulation.ResultsDegranulation was increased in AAT1-knockdowned MCs, and SO2 supplementation reversed the increase in MC degranulation. Furthermore, deficiency of endogenous SO2 contributed to IgE-mediated degranulation in vitro. Besides, SO2 inhibited IgE-mediated and hypoxia-driven MC degranulation in vivo. Mechanistically, LC-MS/MS analysis and site-directed mutation results showed that SO2 sulfenylated Gal-9 at cysteine 74. Sulfenylation of the 74th cysteine of Gal-9 protein was required in the SO2-inhibited MC degranulation under both physiological and pathophysiological conditions.ConclusionThese findings elucidated that SO2 inhibited MC degranulation via sulfenylating Gal-9 under both physiological and pathophysiological conditions, which might provide a novel treatment approach for MC activation-related diseases.

IntroductionSodium pheophorbide a (SPA) is a natural plant-derived photosensitizer, with high photoactivated antifungal activity against some phytopathogenic fungi. However, its fungicidal effect on Diaporthe mahothocarpus, a novel pathogen that causes Camellia oleifera leaf spot blight, is unclear.MethodsIn the present study, we explored its inhibitory effects on spore germination and mycelial growth of D. mahothocarpus. Then we determined its effects on the cell membrane, mycelial morphology, redox homeostasis, and cell death through bioassay. Finally, RNA-seq was used further to elucidate its mode of action at the transcriptional level.ResultsWe found that SPA effectively inhibited the growth of D. mahothocarpus, with half-maximal effective concentrations to inhibit mycelial growth and spore germination of 1.059 and 2.287 mg/mL, respectively. After 1.0 mg/mL SPA treatment, the conductivity and malondialdehyde content of D. mahothocarpus were significantly increased. Scanning electron microscopy and transmission electron microscopy indicated that SPA significantly affected the morphology and ultrastructure of D. mahothocarpus hyphae, revealing that SPA can destroy the mycelial morphology and cell structure, especially the cell membrane of D. mahothocarpus. Furthermore, transcriptome analysis revealed that SPA significantly suppressed the expression of genes involved in morphology, cell membrane permeability, and oxidative stress. Then, we also found that SPA significantly promoted the accumulation of reactive oxygen species (ROS) in of D. mahothocarpus, while it decreased the content of reduced glutathione, inhibited the enzyme activities of superoxide dismutase and catalase, and exacerbated DNA damage. Annexin V-FITC/PI staining also confirmed that 1.0 mg/mL SPA could significantly induce apoptosis and necrosis.DiscussionGenerally, SPA can induce ROS-mediated oxidative stress and cell death, thus destroying the cell membrane and hyphal morphology, and ultimately inhibiting mycelial growth, which indicates that SPA has multiple modes of action, providing a scientific basis for the use of SPA as an alternative plant-derived photoactivated fungicide against C. oleifera leaf spot blight.

PurposeTo evaluate the effectiveness of MRI-based radiomics models in distinguishing between Warthin tumors (WT) and misdiagnosed or ambiguous pleomorphic adenoma (PA).MethodsData of patients with PA and WT from two centers were collected. MR images were used to extract radiomic features. The optimal radiomics model was found by running nine machine learning algorithms after feature reduction and selection. To create a clinical model, univariate logistic regression (LR) analysis and multivariate LR were used. The independent clinical predictors and radiomics were combined to create a nomogram. Two integrated models were constructed by the ensemble and stacking algorithms respectively based on the clinical model and the optimal radiomics model. The models’ performance was evaluated using the area under the curve (AUC).ResultsThere were 149 patients included in all. Gender, age, and smoking of patients were independent clinical predictors. With the greatest average AUC (0.896) and accuracy (0.839) in validation groups, the LR model was the optimal radiomics model. In the average validation group, the radiomics model based on LR did not have a higher AUC (0.795) than the clinical model (AUC = 0.909). The nomogram (AUC = 0.953) outperformed the radiomics model in terms of discrimination performance. The nomogram in the average validation group had a highest AUC than the stacking model (0.914) or ensemble model (0.798).ConclusionMisdiagnosed or ambiguous PA and WT can be non-invasively distinguished using MRI-based radiomics models. The nomogram exhibited excellent and stable diagnostic performance. In daily work, it is necessary to combine with clinical parameters for distinguishing between PA and WT.

Common object detection and image segmentation methods are unable to accurately estimate the shape of the occluded fruit. Monitoring the growth status of shaded crops in a specific environment is challenging, and certain studies related to crop harvesting and pest detection are constrained by the natural shadow conditions. Amodal segmentation can focus on the occluded part of the fruit and complete the overall shape of the fruit. We proposed a Transformer-based amodal segmentation algorithm to infer the amodal shape of occluded tomatoes. Considering the high cost of amodal annotation, we only needed modal dataset to train the model. The dataset was taken from two greenhouses on the farm and contains rich occlusion information. We introduced boundary estimation in the hourglass structured network to provide a priori information about the completion of the amodal shapes, and reconstructed the occluded objects using a GAN network (with discriminator) and GAN loss. The model in this study showed accuracy, with average pairwise accuracy of 96.07%, mean intersection-over-union (mIoU) of 94.13% and invisible mIoU of 57.79%. We also examined the quality of pseudo-amodal annotations generated by our proposed model using Mask R-CNN. Its average precision (AP) and average precision with intersection over union (IoU) 0.5 (AP50) reached 63.91%,86.91% respectively. This method accurately and rationally achieves the shape of occluded tomatoes, saving the cost of manual annotation, and is able to deal with the boundary information of occlusion while decoupling the relationship of occluded objects from each other. Future work considers how to complete the amodal segmentation task without overly relying on the occlusion order and the quality of the modal mask, thus promising applications to provide technical support for the advancement of ecological monitoring techniques and ecological cultivation.

Abstract Mix‐dimensional heterojunctions (MDHJs) photodetectors (PDs) built from bulk and 2D materials are the research focus to develop hetero‐integrated and multifunctional optoelectronic sensor systems. However, it is still an open issue for achieving multiple effects synergistic characteristics to boost sensitivity and enrich the prospect in artificial bionic systems. Herein, electrically tunable Te/WSe2 MDHJs phototransistors are constructed, and an ultralow dark current below 0.1 pA and a large on/off rectification ratio of 106 is achieved. Photoconductive, photovoltaic, and photo‐thermoelectric conversions are simultaneously demonstrated by tuning the gate and bias. By these synergistic effects, responsivity and detectivity respectively reach 13.9 A W−1 and 1.37 × 1012 Jones with 400 times increment. The Te/WSe2 MDHJs PDs can function as artificial bionic visual systems due to the comparable response time to those of the human visual system and the presence of transient positive and negative response signals. This work offers an available strategy for intelligent optoelectronic devices with hetero‐integration and multifunctions.

Abstract Mixed‐phase stratiform clouds contain numerous liquid, mixed‐phase, and ice clusters, quantifying the cluster scales is potentially helpful to improve the parameterizations of microphysics and radiation models. However, the scales of hydrometeor clusters at different levels of stratiform clouds are not well understood. In this study, using airborne measurements and a large eddy simulation, we show that turbulence plays an important role in controlling the clusters with length of a few hundred meters, while the scales of larger clusters have stronger vertical variations from cloud base to top. The liquid clusters are the largest near the cloud top, while the lengths of ice clusters decrease from cloud base to top. The lengths of mixed‐phase clusters depend on the glaciation process, a faster glaciation results in smaller mixed‐phase clusters. The results improve our understanding on how the liquid and ice are mixed at different levels in stratiform clouds.

ObjectiveWe aimed to explore the relationship between remote resistance exercise programs delivered via a smartphone application and skeletal muscle mass among elderly patients with type 2 diabetes, utilizing real-world data.MethodsThe resistance exercises were provided through Joymotion®, a web-based telerehabilitation smartphone application (Shanghai Medmotion Medical Management Co., Ltd). The primary outcome was the changes in skeletal muscle index (SMI) before and after the remote resistance exercises programs. The secondary outcomes were changes in skeletal muscle cross-sectional area (SMA), skeletal muscle radiodensity (SMD) and intermuscular adipose tissue (IMAT).ResultsA total of 101 elderly patients with type 2 diabetes were analyzed. The participants had an average age of 72.9 ± 6.11 years for males and 74.4 ± 4.39 years for females. The pre- and post-intervention SMI mean (± SE) was 31.64 ± 4.14 vs. 33.25 ± 4.22 cm2/m2 in male, and 22.72 ± 3.24 vs. 24.28 ± 3.60 cm2/m2 in female respectively (all P < 0.001). Similarly, a statistically significant improvement in SMA, IMAT, and SMD for both male and female groups were also observed respectively (P < 0.001). Multiple linear regression models showed potential confounding factors of baseline hemoglobin A1c and duration of diabetes with changes in SMI in male, while hemoglobin A1c and high density lipoprotein cholesterol with changes in SMI in female.ConclusionRemote resistance exercises programs delivered by a smartphone application were feasible and effective in helping elderly patients with type 2 diabetes to improve their skeletal muscle mass.

Green and low-carbon development is an important part of global sustainable development. Green power trading provides strong support and assurance for promoting green and low-carbon development. Due to the long cycle of green power data chains and their susceptibility to malicious tampering, the integrity and traceability of data are difficult to guarantee. Therefore, this paper first proposes a security provenance model with enhanced relations based on the core structure of PROV and blockchain technology, which can securely capture provenance records, use the transfer time and number of transactions between various links in the traceability network as reasoning clues, realize the correlation tracing of the green electricity transfer process. Under the model, a traceability mechanism of green electricity is designed based on smart contracts. Trustworthy green electricity data collection is achieved through data filling and data verification techniques. Traceability query technique is adopted to achieve trustworthy traceability of green electricity. And the effectiveness of the proposed solution is demonstrated through simulation experiments.

In order to comprehend the dissimilarities in tobacco quality between Canada and Yunnan, a comparison of the aroma components was conducted using GC-MS and HPLC analysis, coupled with orthogonal partial least squares discriminant analysis (OPLS-DA). The study revealed the detection of a total of 81 aroma components and 22 non-volatile components in both varieties of tobacco leaves. Specifically, there were 102 components of Canada tobacco leaves and 103 components of Yunnan tobacco leaves. Subsequently, a screening was performed on these two types of tobacco leaves, identifying 51 differential components, which accounted for approximately 49.5 % of the overall components detected. Among these, Canada tobacco exhibited a higher concentration of 22 components, comprising roughly 36.4 % of the total, which were primarily composed of semi-volatile organic acids and sesquiterpenes. On the other hand, Yunnan tobacco was characterized by a comparatively higher content of 43 components, constituting approximately 63.6 %, including fatty acid esters, phenols, diterpenes, sugars, and amino acids. Comparatively, Canada tobacco demonstrated elevated levels of fatty acids and sesquiterpenes, while the content of fatty acid esters and diterpenes was relatively lower. These distinctions in aroma components potentially contribute to the varied sensory aroma profiles exhibited by the two types of tobacco.

BackgroundSocial transition is one of the multi-level mechanisms that influence health disparities. However, it has received less attention as one of the non-traditional social determinants of health. A few studies have examined China’s social transition and its impact on health inequality in self-rated health (SRH). Therefore, this study explores the impact of China’s market-oriented reforms—social transition and socioeconomic status (SES)—on residents’ SRH.MethodsUsing the cross-sectional data from the Chinese General Social Survey (CGSS) in 2017, we analyzed the effects of social transition and SES on the SRH of Chinese residents using the RIF (Recentered influence function) method. The RIF decomposition method investigated health differences among different populations and their determinants.ResultsSocial transition and SES have significant positive effects on the SRH of Chinese residents. The correlation between SES and the SRH of Chinese residents is moderated by social transition, implying that social transition can weaken the correlation between SES and the SRH of Chinese residents. The impacts of SES and social transition on SRH vary across populations.ConclusionPromoting social transition and favoring disadvantaged groups with more resources are urgently needed to promote equitable health outcomes.

Levels of the Wnt pathway components are abnormally altered in gastric cancer cells, leading to malignant cell proliferation, invasion and metastasis, poor prognosis and chemoresistance. Therefore, it is important to understand the mechanism of Wnt signaling pathway in gastric cancer. We systematically reviewed the molecular mechanisms of the Wnt pathway in gastric cancer development; and summarize the progression and the challenges of research on molecular agents of the Wnt pathway.

BackgroundVitamin E, which is also known as tocopherol, is a compound with a polyphenol structure. Its esterified derivative, Vitamin E succinate (VES), exhibits unique anticancer and healthcare functions as well as immunomodulatory effects. Natural polysaccharides are proved to be a promising material for nano-drug delivery systems, which show excellent biodegradability and biocompatibility. In this study, we employed a novel bletilla striata polysaccharide-vitamin E succinate polymer (BSP-VES) micelles to enhance the tumor targeting and anti-colon cancer effect of andrographolide (AG).MethodsBSP-VES polymer was synthesized through esterification and its structure was confirmed using 1H NMR. AG@BSP-VES was prepared via the dialysis method and the drug loading, entrapment efficiency, stability, and safety were assessed. Furthermore, the tumor targeting ability of AG@BSP-VES was evaluated through targeted cell uptake and in vivo imaging. The antitumor activity of AG@BSP-VES was measured in vitro using MTT assay, Live&Dead cell staining, and cell scratch test.ResultsIn this study, we successfully loaded AG into BSP-VES micelles (AG@BSP-VES), which exhibited good stability, biosafety and sustained release effect. In addition, AG@BSP-VES also showed excellent internalization capability into CT26 cells compared with NCM460 cells in vitro. Meanwhile, the specific delivery of AG@BSP-VES micelles into subcutaneous and in-situ colon tumors was observed compared with normal colon tissues in vivo during the whole experiment process (1–24 h). What’s more, AG@BSP-VES micelles exhibited significant antitumor activities than BSP-VES micelles and free AG.ConclusionThe study provides a meaningful new idea and method for application in drug delivery system and targeted treatment of colon cancer based on natural polysaccharides.

Summary: Background: Hearing impairment is a common condition in the elderly. However, a comprehensive understanding of its neural correlates is still lacking. Methods: We recruited 284 elderly adults who underwent structural MRI, magnetic resonance spectroscopy, audiometry, and cognitive assessments. Individual hearing abilities indexed by pure tone average (PTA) were correlated with multiple structural MRI-derived cortical morphological indices. For regions showing significant correlations, mediation analyses were performed to examine their role in the relationship between hearing ability and cognitive function. Finally, the correlation maps between hearing ability and cortical morphology were linked with publicly available connectomic gradient, transcriptomic, and neurotransmitter maps. Findings: Poorer hearing was related to cortical thickness (CT) reductions in widespread regions and gyrification index (GI) reductions in the right Area 52 and Insular Granular Complex. The GI in the right Area 52 mediated the relationship between hearing ability and executive function. This mediating effect was further modulated by glutamate and N-acetylaspartate levels in the right auditory region. The PTA-CT correlation map followed microstructural connectomic hierarchy, were related to genes involved in certain biological processes (e.g., glutamate metabolic process), cell types (e.g., excitatory neurons and astrocytes), and developmental stages (i.e., childhood to young adulthood), and covaried with dopamine receptor 1, dopamine transporter, and fluorodopa. The PTA-GI correlation map was related to 5-hydroxytryptamine receptor 2a. Interpretation: Poorer hearing is associated with cortical thinning and folding reductions, which may be engaged in the relationship between hearing impairment and cognitive decline in the elderly and have different neurobiological substrates. Funding: See the Acknowledgements section.

Background: Pyrethroids are widely used in agriculture and household pest management as one of the top three insecticides globally, yet the neurobehavioral impacts of human exposure to these chemicals have attracted increasing concern. Objective: The purpose of this study was to examine the associations between pyrethroid exposure and sleep disorders and whether exercise could attenuate these associations. Methods: We analyzed cross-sectional data from the 2007-2014 National Health and Nutrition Examination Survey to study the association between pyrethroid pesticide exposure and sleep disorders. The exposure level of pyrethroid metabolites in urine samples was measured. Physician diagnosis of sleep disorders was used to determine sleep disorders. Exercise level was judged by self-reported physical activity from the interviews. Results: Of the 5947 participants, sleep disorders had a weighted prevalence of 9.0 %, representing an approximation of 186,140,757 patients nationwide. We found a sex-specific association between high levels of 3-PBA and elevated risk of sleep disorders diagnosis in men (OR: 1.87; 95 % CI: 1.150–3.042; P = 0.01). In addition, less physical activity was associated with higher rates of sleep disorders as pyrethroid exposure levels increased (OR: 1.98; 95 % CI: 1.152–3.388; P = 0.02). Conclusion: This study further confirmed that pyrethroid exposure is associated with an elevated risk of sleep disorders in men. More importantly, we reported for the first time that vigorous physical activity attenuates the correlation between pyrethroid exposure and sleep disorders.

In this study, porous Ti/Magnéli Ti4O7 nanotube arrays (NTA) was fabricated to pretreat antibiotic wastewater. Characterization of the Ti4O7-NTA illustrated that highly ordered NTA was successfully generated on the porous Ti substrate, which enlarged the specific surface area by 1.67 times. The Ti4O7-NTA has a high oxygen evolution potential (2.60 V) as well as low interfacial charge transfer resistance (4.479 Ω cm−2). Ceftriaxone sodium (CRO) was completely removed from raw antibiotic wastewater after 3 h of treatment by the Ti4O7-NTA, under optimal operation conditions. The biodegradability and toxicity of the wastewater were also significantly enhanced and reduced, as the BOD/COD and EC50,48h values were increased to 0.48 and 57.62 % ± 2.16 %, respectively. The possible degradation pathway of CRO was proposed by LC‒MS. Cathodic polarization was proven to be an effective way to ensure the long-term durability of the Ti4O7-NTA.

Objective: The objective of this study was to explore the safety, efficacy, economy, and other aspects of frequently-used antitumor Chinese patent medicine injections through a comprehensive evaluation of evidence-based medical research to provide scientific information and decision-making basis for drug selection, rational drug use, public awareness of safe drug use, and medical insurance. Materials and Methods: The names of five frequently used antitumor Chinese patent medicine injections were used as search terms, including the compound Sophora flavescens injection, Kangai injection, Aidi injection, Kanglaite injection, and Brucea javanica oil emulsion injection. Relevant evidence-based medical research was extracted from the databases. A descriptive evaluation was conducted, and the Markov model was used for the cost-benefit analysis. Finally, the above injections are ranked by comprehensive scores using the multi-criteria decision analysis and Delphi method. Results: The five injections had their own advantages in enhancing the effectiveness of anti-tumor treatments, improving the quality of life for cancer patients, and reducing the incidence of adverse reactions. From the perspective of economy and other attributes, compound S. flavescens was superior to B. javanica oil, Aidi, Kangai, and Kanglaite. After a comprehensive evaluation of the above five injections, the compound S. flavescens injection received the highest score. Conclusions: Compound S. flavescens, Kangai, Aidi, B. javanica oil, and Kanglaite have their own advantages in effectiveness and no significant difference in safety. Compound S. flavescens injection has the highest comprehensive score. Clinical attention should be paid to monitoring the initial stage of medication and special groups.

Abstract Catastrophic forgetting in neural networks is a common problem, in which neural networks lose information from previous tasks after training on new tasks. Although adopting a regularization method that preferentially retains the parameters important to the previous task to avoid catastrophic forgetting has a positive effect; existing regularization methods cause the gradient to be near zero because the loss is at the local minimum. To solve this problem, we propose a new continuous learning method with Bayesian parameter updating and weight memory (CL-BPUWM). First, a parameter updating method based on the Bayes criterion is proposed to allow the neural network to gradually obtain new knowledge. The diagonal of the Fisher information matrix is then introduced to significantly minimize computation and increase parameter updating efficiency. Second, we suggest calculating the importance weight by observing how changes in each network parameter affect the model prediction output. In the process of model parameter updating, the Fisher information matrix and the sensitivity of the network are used as the quadratic penalty terms of the loss function. Finally, we apply dropout regularization to reduce model overfitting during training and to improve model generalizability. CL-BPUWM performs very well in continuous learning for classification tasks on CIFAR-100 dataset, CIFAR-10 dataset, and MNIST dataset. On CIFAR-100 dataset, it is 0.8%, 1.03% and 0.75% higher than the best performing regularization method (EWC) in three task partitions. On CIFAR-10 dataset, it is 2.25% higher than the regularization method (EWC) and 0.7% higher than the scaled method (GR). It is 0.66% higher than the regularization method (EWC) on the MNIST dataset. When the CL-BPUWM method was combined with the brain-inspired replay model under the CIFAR-100 and CIFAR-10 datasets, the classification accuracy was 2.35% and 5.38% higher than that of the baseline method, BI-R + SI.

Abstract Alfalfa, an essential forage crop known for its high yield, nutritional value, and strong adaptability, has been widely cultivated worldwide. The yield and quality of alfalfa are frequently jeopardized due to environmental degradation. Lignin, a constituent of the cell wall, enhances plant resistance to abiotic stress, which often causes osmotic stress in plant cells. However, how lignin responds to osmotic stress in leaves remains unclear. This study explored the effects of osmotic stress on lignin accumulation and the contents of intermediate metabolites involved in lignin synthesis in alfalfa leaves. Osmotic stress caused an increase in lignin accumulation and the alteration of core enzyme activities and gene expression in the phenylpropanoid pathway. We identified five hub genes (CSE, CCR, CADa, CADb, and POD) and thirty edge genes (including WRKYs, MYBs, and UBPs) by integrating transcriptome and metabolome analyses. In addition, ABA and ethylene signaling induced by osmotic stress regulated lignin biosynthesis in a contradictory way. These findings contribute to a new theoretical foundation for the breeding of high-quality and resistant alfalfa varieties.

Abstract Introduction As a result of the insufficient ocular anatomical parameters used to customize implantable collamer lens (ICL), many patients still cannot achieve a suitable vault after ICL implantation surgery. This study analyzed the characteristics of a new anatomical parameter crystalline lens rise (CLR) in a population with high myopia and explored the influence of CLR on the vault after ICL implantation. Methods Patients (298 eyes) with high myopia who underwent ICL implantation were enrolled to study CLR characteristics. Postoperatively, patients (159 eyes) were divided into five groups according to the value of CLR (A, CLR ≤ − 150; B, − 150 0 μm, of which 20 eyes (6.71%) had a CLR ≥ 300 μm. In 159 eyes, the CLR was negatively correlated with the vault at 1 day (R = − 0.497, P 0.05). Conclusion The CLR had a normal distribution in the high myopia population, and 13.42% of the CLR values were extreme (CLR ≤ − 150 μm or CLR ≥ 300 μm). A larger ICL diameter than that recommended by the manufacturer should be considered when the CLR is ≥ 300 μm and a smaller ICL diameter should be considered when the CLR is ≤ − 150 μm.

Abstract Covalent probes coupled with chemical proteomics represent a powerful method for investigating small molecule and protein interactions. However, the creation of a reactive warhead within various ligands to form covalent probes has been a major obstacle. Herein, we report a convenient and robust process to assemble a unique electrophile, an α-acyloxyenamide, through a one-step late-stage coupling reaction. This procedure demonstrates remarkable tolerance towards other functional groups and facilitates ligand-directed labeling in proteins of interest. The reactive group has been successfully incorporated into a clinical drug targeting the EGFR L858R mutant, erlotinib, and a pan-kinase inhibitor. The resulting probes have been shown to be able to covalently engage a lysine residue proximal to the ATP-binding pocket of the EGFR L858R mutant. A series of active sites, and Mg2+, ATP-binding sites of kinases, such as K33 of CDK1, CDK2, CDK5 were detected. This is the first report of engaging these conserved catalytic lysine residues in kinases with covalent inhibition. Further application of this methodology to natural products has demonstrated its success in profiling ligandable conserved lysine residues in whole proteome. These findings offer insights for the development of new targeted covalent inhibitors (TCIs).

Abstract Background Several studies have indicated that skin holds promise as a potential sample for detecting pathological α-Syn and serving as a diagnostic biomarker for α-synucleinopathies. Despite reports in Chinese PD patients, comprehensive research on skin α-Syn detection using RT-QuIC is lacking. Objective This study aimed to evaluate the diagnostic performance of skin samples using RT-QuIC from PD patients in the Chinese population. Methods Patients with sporadic PD and controls were included according to the British PD Association Brain Bank diagnostic criteria. The seeding activity of misfolded α-Syn in these skin samples was detected using the RT-QuIC assay after protein extraction. Biochemical and morphological analyses of RT-QuIC products were conducted by atomic force microscopy, transmission electron microscopy, Congo red staining, and dot blot analysis. Result 30 patients clinically diagnosed with PD and 28 controls with non-α-synucleinopathies were included in this study. 28 of 30 PD patients demonstrated positive α-Syn seeding activity by RT-QuIC assay. In contrast, no α-Syn seeding activity was detected in the 28 control samples, with an overall sensitivity and specificity of 93.3% and 100%, respectively (P

Abstract Background Nitrogen (N) metabolism-related key genes and conserved amino acid sites in key enzymes play a crucial role in improving N use efficiency (NUE) under N stress. However, it is not clearly known about the molecular mechanism of N deficiency-induced improvement of NUE in the N-sensitive rhizomatous medicinal plant Panax notoginseng (Burk.) F. H. Chen. To explore the potential regulatory mechanism, the transcriptome and proteome were analyzed and the three-dimensional (3D) information and molecular docking models of key genes were compared in the roots of P. notoginseng grown under N regimes. Results Total N uptake and the proportion of N distribution to roots were significantly reduced, but the NUE, N use efficiency in biomass production (NUEb), the recovery of N fertilizer (RNF) and the proportion of N distribution to shoot were increased in the N0-treated (without N addition) plants. The expression of N uptake- and transport-related genes NPF1.2, NRT2.4, NPF8.1, NPF4.6, AVP, proteins AMT and NRT2 were obviously up-regulated in the N0-grown plants. Meanwhile, the expression of CIPK23, PLC2, NLP6, TCP20, and BT1 related to the nitrate signal-sensing and transduction were up-regulated under the N0 condition. Glutamine synthetase (GS) activity was decreased in the N-deficient plants, while the activity of glutamate dehydrogenase (GDH) increased. The expression of genes GS1-1 and GDH1, and proteins GDH1 and GDH2 were up-regulated in the N0-grown plants, there was a significantly positive correlation between the expression of protein GDH1 and of gene GDH1. Glu192, Glu199 and Glu400 in PnGS1 and PnGDH1were the key amino acid residues that affect the NUE and lead to the differences in GDH enzyme activity. The 3D structure, docking model, and residues of Solanum tuberosum and P. notoginseng was similar. Conclusions N deficiency might promote the expression of key genes for N uptake (genes NPF8.1, NPF4.6, AMT, AVP and NRT2), transport (NPF1.2 and NRT2.4), assimilation (proteins GS1 and GDH1), signaling and transduction (genes CIPK23, PLC2, NLP6, TCP20, and BT1) to enhance NUE in the rhizomatous species. N deficiency might induce Glu192, Glu199 and Glu400 to improve the biological activity of GS1 and GDH, this has been hypothesized to be the main reason for the enhanced ability of N assimilation in N-deficient rhizomatous species. The key genes and residues involved in improving NUE provide excellent candidates for the breeding of medicinal plants.

Abstract Background Immune checkpoint inhibitors (ICIs) have transformed tumor treatment. However, the risk of pulmonary adverse events (PAEs) associated with ICI combination therapy is still unclear. We aimed to provide a PAE overview and risk ordering of ICIs used in tumor treatment. Methods We searched the databases of PubMed, PsycINFO, Embase, Cochrane Library, CINAHL, Web of Science, Scopus, and clinical trial websites during January 2011–April 2023 to identify phase II and III randomized clinical trials (RCTs) and single-arm clinical trials wherein at least one treatment arm received ICIs (e.g., ICI monotherapy, a combination of two ICIs, or ICIs in combination with conventional cancer therapy). We reported the results of PAEs. Additionally, we compared risks of PAEs between different drug classes using a Bayesian network meta-analysis. Results Among 143 RCTs and 24 single-arm trials, the incidence of all-grade and grade 3–4 PAEs were highest with programmed death L1 (PD-L1) plus cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and plus chemotherapy and anti-PD1 plus anti-CTLA4, the lowest with targeted therapy drug plus chemotherapy and anti-PD1 plus anti-PDL1. Anti-PD1 plus anti-CTLA4 and plus chemotherapy was the intervention with the highest risk for all-grade and 3–4 grade PAEs, and the intervention with the lowest risk was chemotherapy and anti-PD1 plus anti-PDL1. In terms of all-grade PAEs, chemotherapy was safer than ICI monotherapy. Except for the anti-PD1 plus anti-PDL1 regimen, no significant difference in the risk of grade 3–4 PAEs was detected between dual-ICIs and single-ICIs. Furthermore, the risk of PAEs associated with nivolumab, pembrolizumab, and atezolizumab may be dose dependent. Conclusions In the single-drug regimen, anti-PD1 caused the greatest incidence of PAEs. The risk of PAEs was higher with all single-ICIs than with chemotherapy. However, no significant difference in the risk of PAEs was detected between single-ICIs. In the combined regimen, anti-PD1 plus anti-CTLA4 and plus chemotherapy showed the greatest risk of PAEs, but there were no significant differences in risk between dual-ICIs and single-ICIs.

Abstract Flatbands play an important role in correlated quantum matter and have promising applications in photonic lattices. Synthetic magnetic fields and destructive interference in lattices are traditionally used to obtain flatbands. However, such methods can only obtain a few flatbands with most bands remaining dispersive. Here we realize all-band-flat photonic lattices of an arbitrary size by precisely controlling the coupling strengths between lattice sites to mimic those in Fock-state lattices. This allows us to go beyond the perturbative regime of strain engineering and group all eigenmodes in flatbands, which simultaneously achieves high band flatness and large usable bandwidth. We map out the distribution of each flatband in the lattices and selectively excite the eigenmodes with different chiralities. Our method paves a way in controlling band structure and topology of photonic lattices.

Abstract Background Host-microbial interactions are expected to affect species’ adaptability to climate change but have rarely been explored in ectothermic animals. Some studies have shown that short-term warming reduced gut microbial diversity that could hamper host functional performance. Results However, our longitudinal experiments in semi-natural conditions demonstrated that warming decreased gut microbiota diversity at 2 months, but increased diversity at 13 and 27 months in a desert lizard (Eremias multiocellata). Simultaneously, long-term warming significantly increased the antibacterial activity of serum, immune responses (higher expression of intestinal immune-related genes), and the concentration of short-chain fatty acids (thereby intestinal barrier and immunity) in the lizard. Fecal microbiota transplant experiments further revealed that increased diversity of gut microbiota significantly enhanced antibacterial activity and the immune response of lizards. More specifically, the enhanced immunity is likely due to the higher relative abundance of Bacteroides in warming lizards, given that the bacteria of Bacteroides fragilis regulated IFN-β expression to increase the immune response of lizards under a warming climate. Conclusions Our study suggests that gut microbiota can help ectotherms cope with climate warming by enhancing host immune response, and highlights the importance of long-term studies on host-microbial interactions and their biological impacts. Graphical Abstract Video Abstract

Abstract Airway epithelial transcriptome analysis of asthma patients with different severity was used to disentangle the immune infiltration mechanisms affecting asthma exacerbation, which may be advantageous to asthma treatment. Here we introduce various bioinformatics methods and develop two models: an OVA/CFA-induced neutrophil asthma mouse model and an LPS-induced human bronchial epithelial cell damage model. Our objective is to investigate the molecular mechanisms, potential targets, and therapeutic strategies associated with asthma severity. Multiple bioinformatics methods identify meaningful differences in the degree of neutrophil infiltration in asthma patients with different severity. Then, PTPRC, TLR2, MMP9, FCGR3B, TYROBP, CXCR1, S100A12, FPR1, CCR1 and CXCR2 are identified as the hub genes. Furthermore, the mRNA expression of 10 hub genes is determined in vivo and in vitro models. Reperixin is identified as a pivotal drug targeting CXCR1, CXCR2 and MMP9. We further test the potential efficiency of Reperixin in 16HBE cells, and conclude that Reperixin can attenuate LPS-induced cellular damage and inhibit the expression of them. In this study, we successfully identify and validate several neutrophilic signatures and targets associated with asthma severity. Notably, Reperixin displays the ability to target CXCR1, CXCR2, and MMP9, suggesting its potential therapeutic value for managing deteriorating asthma.

Abstract Targeting C5aR1 modulates the function of infiltrated immune cells including tumor-associated macrophages (TAMs). The gut microbiome plays a pivotal role in colorectal cancer (CRC) tumorigenesis and development through TAM education. However, whether and how the gut flora is involved in C5aR1 inhibition-mediated TAMs remains unclear. Therefore, in this study, genetic deletion of C5ar1 or pharmacological inhibition of C5aR1 with anti-C5aR1 Ab or PMX-53 in the presence or absence of deletion Abs were utilized to verify if and how C5aR1 inhibition regulated TAMs polarization via affecting gut microbiota composition. We found that the therapeutic effects of C5aR1 inhibition on CRC benefited from programming of TAMs toward M1 polarization via driving AKT2-mediated 6-phosphofructokinase muscle type (PFKM) stabilization in a TLR5-dependent manner. Of note, in the further study, we found that C5aR1 inhibition elevated the concentration of serum IL-22 and the mRNA levels of its downstream target genes encoded antimicrobial peptides (AMPs), leading to gut microbiota modulation and flagellin releasement, which contributed to M1 polarization. Our data revealed that high levels of C5aR1 in TAMs predicted poor prognosis. In summary, our study suggested that C5aR1 inhibition reduced CRC growth via resetting M1 by AKT2 activation-mediated PFKM stabilization in a TLR5-dependent manner, which relied on IL-22-regulated gut flora.

Abstract The development of iontronic skin (I-skin) capable of ultrafast sensing in a wide pressure range, comparable to human skin, is of paramount importance for intelligent robotics. However, this remains a major challenge due to the lack of iontronic array architectures that can achieve ultrafast readout and crosstalk-free under large capacitance response generated within a wide pressure range. Here, we report a frequency-coding architecture of artificial ion mechanoreceptor skin (AIM-skin) that can provide a universal mode of iontronic array sensing and bypass the dependence of complex integrated back-end interface electronics. Notably, the successful implementation of orthogonal frequency coding in the AIM-skin with high sensitivity and ultrawide pressure range achieve ultrafast parallel readout for the spatiotemporal mechanical stimuli. Furthermore, the parallel zero-potential mechanism (PZPM) of the architecture effectively mitigates electrical crosstalk between sensing units. We have demonstrated that combhination of proposed device and deep learning has a broad application prospect in intelligent human-machine interaction and real-time dynamic robotic manipulation.