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Abstract Chemotherapy in combination with immunotherapy has gradually shown substantial promise to increase T cell infiltration and antitumor efficacy. However, paclitaxel in combination with immune checkpoint inhibitor targeting PD-1/PD-L1 was only used to treat a small proportion of metastatic triple-negative breast cancer (TNBC), and the clinical outcomes was very limited. In addition, this regimen cannot prevent paclitaxel-induced peripheral neuropathy. Therefore, there was an urgent need for a novel target to enhance the antitumor activity of paclitaxel and alleviate chemotherapy-induced peripheral neuropathy in breast cancer. Here, we found that Dickkopf-1 (DKK1) expression was upregulated in multiply subtypes of human breast cancer specimens after paclitaxel-based chemotherapy. Mechanistic studies revealed that paclitaxel promoted DKK1 expression by inducing EGFR signaling in breast cancer cells, and the upregulation of DKK1 could hinder the therapeutic efficacy of paclitaxel by suppressing the infiltration and activity of CD8+ T cells in tumor microenvironment. Moreover, paclitaxel treatment in tumor-bearing mice also increased DKK1 expression through the activation of EGFR signaling in the primary sensory dorsal root ganglion (DRG) neurons, leading to the development of peripheral neuropathy, which is charactered by myelin damage in the sciatic nerve, neuropathic pain, and loss of cutaneous innervation in hindpaw skin. The addition of an anti-DKK1 antibody not only improved therapeutic efficacy of paclitaxel in two murine subtype models of breast cancer but also alleviated paclitaxel-induced peripheral neuropathy. Taken together, our findings providing a potential chemoimmunotherapy strategy with low neurotoxicity that can benefit multiple subtypes of breast cancer patients.

ABSTRACT Background An effective method that is easy to implement and widely applicable for improving driving performance and reducing driving risks remains a challenge. Although fragrances are widely used in daily driving, there is a gap between empirical research on everyday blended fragrances and functional fragrances clinical reports. In this study, a deliberately chosen blend of scent without overtly stimulating or functional proven evidence was tested for its potential to enhance performance in a driving environment. Method Thirty qualified young drivers were recruited to participate in the experiment. They were asked to watch a 15‐min first‐person perspective driving video to simulate a driving environment and then complete questionnaires and three sets of behavioral experiments while their brain activity was monitored by EEG. Result Participants in the scented environment exhibited statistically significant advantages in two cognitive tasks during behavioral measures. These findings were effectively supported by the EEG data, showing that beta waves exhibited more activity in the occipital and prefrontal cortex, enhanced theta waves were observed in the prefrontal cortex, and the TAB index characterizing driving fatigue was suppressed in the prefrontal cortex. Conclusion This empirical evidence highlights the potential of pleasant, natural, and blended scents in enhancing driving performance, suggesting that promoting the aromatherapy while driving as an easily applicable approach in daily life seems justified and expands the application of aromatherapy in daily life.

Abstract Warfarin is a widely used anticoagulant, and its S‐enantiomer has higher potency compared to the R‐enantiomer. S‐warfarin is mainly metabolized by cytochrome P450 (CYP) 2C9, and its pharmacological target is vitamin K epoxide reductase complex subunit 1 (VKORC1). Both CYP2C9 and VKORC1 have genetic polymorphisms, leading to large variations in the pharmacokinetics (PKs) and pharmacodynamics (PDs) of warfarin in the population. This makes dosage management of warfarin difficult, especially in the case of drug–drug interactions (DDIs). This study provides a whole‐body physiologically‐based pharmacokinetic/PD (PBPK/PD) model of S‐warfarin for predicting the effects of drug–drug−gene interactions on S‐warfarin PKs and PDs. The PBPK/PD model of S‐warfarin was developed in PK‐Sim and MoBi. Drug‐dependent parameters were obtained from the literature or optimized. Of the 34 S‐warfarin plasma concentration‐time profiles used, 96% predicted plasma concentrations within twofold range compared to observed data. For S‐warfarin plasma concentration‐time profiles with CYP2C9 genotype, 364 of 386 predicted plasma concentration values (~94%) fell within the twofold of the observed values. This model was tested in DDI predictions with fluconazole as CYP2C9 perpetrators, with all predicted DDI area under the plasma concentration‐time curve to the last measurable timepoint (AUClast) ratio within twofold of the observed values. The anticoagulant effect of S‐warfarin was described using an indirect response model, with all predicted international normalized ratio (INR) within twofold of the observed values. This model also incorporates a dose‐adjustment method that can be used for dose adjustment and predict INR when warfarin is used in combination with CYP2C9 perpetrators.

Over the past decades, there has been ongoing effort to develop complex biomimetic tissue engineering strategies for in vitro cultivation and maintenance of organoids. The defined hydrogels can create organoid models for various organs by changing their properties and various active molecules. An increasing number of researches has been done on the application of hydrogels in organoids, and a large number of articles have been published on the topic. Although there have been existing reviews describing the application of hydrogels in the field of organoids, there is still a lack of comprehensive studies summarizing and analyzing the overall research trends in this field. The citation can be used as an indicator of the scientific influence of an article in its field. This study aims to evaluate the application of hydrogels in organoids through bibliometric analysis, and to predict the hotspots and developing trends in this field.

Abstract Background To report the microbiological isolates, aetiology, complications, antibiotic susceptibilities, and clinical remission of dacryocystitis and canaliculitis in a prominent tertiary ophthalmic teaching and referral hospital located in northern China and to offer appropriate recommendations for preventing and formulating drug treatment strategies. Methods This prospective study recruited a total of 477 participants who had been diagnosed with either dacryocystitis or canaliculitis. The cohort comprised 307 patients with chronic dacryocystitis, 111 patients with acute dacryocystitis, and 59 patients with canaliculitis. Purulent discharge from the lacrimal duct was collected using a sterile swab and immediately subjected to microbial culture. Antimicrobial susceptibility testing was conducted following established protocols. All participants were scheduled for follow-up visits within 14 days after receiving antibiotic therapy. Results The present findings indicated that women exhibited a higher susceptibility to the condition, as evidenced by the occurrence of 367 cases in comparison to 110 cases among men. Among the 477 patients, definitive causes were established in 59 individuals, accounting for 12.4% of the patients. Additionally, ocular complications were reported by 132 patients, representing 27.7% of the total. Monocular involvement was observed in the majority of cases, with 402 out of 477 patients (84.3%) affected, while binocular involvement was present in 75 patients (15.7%). In total, 506 microbiological strains were recovered from 552 eyes, with Staphylococcus epidermidis (16.4%) being the most prevalent microorganism. Other predominant isolates included Corynebacterium macginleyi (9.1%), Staphylococcus aureus (5.1%), Streptococcus pneumoniae (4.9%), Haemophilus (4.4%), Propionibacterium acnes (3.5%), and Eikenella corrodens (3.1%). Among the 12 isolated fungi, Candida parapsilosis accounted for 66.7%. The susceptibility to antimicrobial agents tested in gram-negative bacilli (79.5%) was observed to be higher than that of anaerobic bacteria (76.7%) and gram-positive cocci (55.4%). With pharmacological therapy, the remission rate of acute dacryocystitis (72.7%) was found to be higher than that of canaliculitis (53.3%) and chronic dacryocystitis (42.3%). Conclusions This study highlights the microbial spectrum of dacryocystitis and canaliculitis, particularly C.macginleyi, E.corrodens and C.parapsilosis, which are also more frequently isolated. Vancomycin and imipenem may be more effective treatment options. Most cases have an unknown aetiology, and essential preventive measures involve postoperative cleansing of the lacrimal passage following eye and nasal surgeries, as well as the proactive management of rhinitis.

Abstract Background Jianli pig, a renowned indigenous breed in China, has the characteristics of a two-end black (TEB) coat color, excellent meat quality, strong adaptability and increased prolificacy. However, there is limited information available regarding the genetic diversity, population structure and genomic regions under selection of Jianli pig. On the other hand, the genetic mechanism of TEB coat color has remained largely unknown. Results In this study, the whole genome resequencing of 30 Jianli pigs within a context of 153 individuals representing 13 diverse breeds was performed. The population structure analysis revealed that Jianli pigs have close genetic relationships with the Tongcheng pig breed, their geographical neighbors. Three methods (observed heterozygosity, expected heterozygosity, and runs of homozygosity) implied a relatively high level of genetic diversity and, a low inbreeding coefficient in Jianli compared with other pigs. We used Fst and XP-EHH to detect the selection signatures in Jianli pigs compared with Asian wild boar. A total of 451 candidate genes influencing meat quality (CREBBP, ADCY9, EEPD1 and HDAC9), reproduction (ESR1 and FANCA), and coat color (EDNRB, MITF and MC1R), were detected by gene annotation analysis. Finally, to fine-map the genomic region for the two-end black (TEB) coat color phenotype in Jianli pigs, we performed three signature selection methods between the TEB coat color and no-TEB coat color pig breeds. The current study, further confirmed that the EDNRB gene is a candidate gene for TEB color phenotype found in Chinese pigs, including Jinhua pigs, and the haplotype harboring 25 SNPs in the EDNRB gene may promote the formation of TEB coat color. Further ATAC-seq and luciferase reporter assays of these regions suggest that the 25-SNPs region was a strong candidate causative mutation that regulates the TEB coat color phenotype by altering enhancer function. Conclusion Our results advanced the understanding of the genetic mechanism behind artificial selection, and provided further resources for the protection and breeding improvement of Jianli pigs.

Macroautophagy (referred to as autophagy hereafter) is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles. Previous studies showed that autophagy protects against acetaminophen (APAP)-induced injury (AILI) via selective removal of damaged mitochondria and APAP protein adducts. The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes. In the present study, we showed that transcription factor EB (TFEB), a master transcription factor for lysosomal biogenesis, was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers. Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI, respectively. Mechanistically, overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2 (NRF2) activation to protect against AILI. We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists. Among these agonists, salinomycin, an anticoccidial and antibacterial agent, activated TFEB and protected against AILI in mice. In conclusion, genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.

Objective The objective of this study was to evaluate the effect of biogas slurry application on biomass production and the silage quality of corn. Methods A field experiment was conducted in which corn was grown using different biogas slurry application rates. The effect of 25% to 500% biogas slurry nitrogen replacement (T1 to T14) on the yield and quality indices of corn were studied by field plot experiments. Results The results revealed that biogas slurry application improved the stem diameter and relative feed value of corn silage in treatments T13 and T11. Moreover, the fermentation quality of corn silage was improved due to an increase in lactic acid content; in comparison with the chemical synthetic fertilizer (CF) group. The crude protein contents of corn silage had no obvious change with increasing biogas slurry application. However, the forage quality index of acid detergent fiber was decreased (p

Liquid-like surfaces have demonstrated immense potential in their ability to resist cell adhesion, a critical requirement for numerous applications across various domains. However, the conventional methodologies for preparing liquid-like surfaces often entail a complex multi-step polymer brush modification process, which is not only time-consuming but also presents significant challenges. In this work, we developed a single-cycle polymer brush modification strategy to build liquid-like surfaces by leveraging high-molecular-weight bis(3-aminopropyl)-terminated polydimethylsiloxane, which significantly simplifies the preparation process. The resultant liquid-like surface is endowed with exceptional slipperiness, effectively inhibiting bacterial colonization and diminishing the adherence of platelets. Moreover, it offers promising implications for reducing the dependency on anticoagulants in microfluidic systems constructed from PDMS, all while sustaining its antithrombotic attributes.

Over the past three decades, China has implemented extensive reforestation programs, primarily utilizing Chinese fir (Cunninghamia lanceolata (Lamb.) Hook) in southern China, to mitigate greenhouse gas emissions and counter extreme climate events. However, the effects of drought on the carbon sequestration capacity of these forests, particularly during the trunk wood stage, remain unclear. This study, conducted in Huitong, Hunan, China, from 2008 to 2013, employed the eddy covariance method to measure carbon dioxide (CO2) and water fluxes in Chinese fir forests, covering a severe drought year in 2011. The purpose was to elucidate the dynamics of carbon and water fluxes during a drought year and across multi-normal year averages. The results showed that changes in soil water content (−8.00%), precipitation (−18.45%), and relative humidity (−5.10%), decreases in air temperature (−0.09 °C) and soil temperature (−0.79 °C), and increases in vapor pressure deficit (19.18%) and net radiation (8.39%) were found in the drought year compared to the normal years. These changes in environmental factors led to considerable decreases in net ecosystem exchange (−40.00%), ecosystem respiration (−13.09%), and gross ecosystem productivity (−18.52%), evapotranspiration (−12.50%), and water use efficiency (−5.83%) in the studied forests in the drought year. In this study, the occurrence of seasonal drought due to uneven precipitation distribution led to a decrease in gross ecosystem productivity (GEP) and evapotranspiration (ET). However, the impact of drought on GEP was greater than its effect on ET, resulting in a reduced water use efficiency (WUE). This study emphasized the crucial role of water availability in determining forest productivity and suggested the need for adjusting vegetation management strategies under severe drought conditions. Our results contributed to improving management practices for Chinese fir plantations in response to changing climate conditions.

Affect plays a pivotal role in fostering creative performance, and there is increasing recognition that different levels and types of affect may exert distinct impacts on creative performance. Drawing upon self-determination theory, this study aims to explore a novel classification of affect—affect under need satisfaction and need thwarting—and examine its relationship with creative performance. Study 1 involved 75 participants to investigate the content of affect under need satisfaction and need thwarting. Study 2 explores the relationship between affect and creative performance using a sample of 115 employees from Beijing. The findings unveiled nine types of affect under need satisfaction (e.g., moderate levels of excited) and eleven types of affect under need thwarting (e.g., low levels of afraid). Positive associations were observed between affect under need satisfaction and creativity, while negative associations were found between affect under need thwarting and creativity. Empirical evidence corroborating the significant role of the new classification of affect in enhancing employee creativity within the context of Chinese academia and researchers is presented.

Abstract Introduction Glucokinase (GK) plays a pivotal role in maintaining glucose homeostasis; globalagliatin, a newly developed drug, is a GK activator (GKA). This study constitutes a randomized, open-label, two-cycle, two-crossover, single-dose, phase I clinical trial conducted at a single center with healthy Chinese volunteers, aiming to examine the influence of a high-fat meal on the pharmacokinetics (PK) of orally administered globalagliatin. Methods Twenty-four healthy volunteers were randomly divided into two groups, with a washout period of 16 days between the two cycles. The first cycle involved Group 1 volunteers who were orally administered globalagliatin 80 mg with 240 mL of water while fasting on Day 1. In contrast, Group 2 volunteers began oral administration of globalagliatin 80 mg with 240 mL of water, 30 min after consuming a high-fat meal (where high-fat content contributed to 54% of the total calories; the high-calorie meal amounted to 988.4 kcal). After the washout period, both groups of volunteers entered the second cycle of drug administration, with meals and medication being swapped on Day 17. Each volunteer collected blood samples at the following time points: 0 h (within 1 h before administration), and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, and 168 h after administration on both trial Day 1 and Day 17. The primary and secondary PK parameters were collected. The validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine the concentration of globalagliatin in collected plasma samples, and the results were analyzed using Phoenix WinNonlin software. Safety evaluation was conducted by detecting or observing various adverse events (AEs) and serious AEs (SAEs). Results All 24 healthy Chinese volunteers enrolled completed the study and underwent PK analysis. The maximum concentration (C max; ng/mL), area under the plasma concentration-time curve (AUC) from time zero to time of the last quantifiable concentration (AUC t ; h·ng/mL), and AUC from time zero extrapolated to infinity (AUC∞; h·ng/mL) of fasting administration were 22.35 ± 7.02, 725.74 ± 303.04, and 774.07 ± 343.89, respectively, while the C max, AUC t , and AUC∞ administered after a high-fat meal were 28.95 ± 12.60, 964.84 ± 333.99, and 1031.28 ± 392.80, respectively. The geometric mean ratios of C max, AUC t , and AUC∞ for high-fat meal/fasting administration of globalagliatin were 124.81%, 135.24%, and 135.42%, respectively, with 90% confidence intervals of 109.97–141.65, 124.24–147.20, and 124.42–147.39, respectively. Compared with the fasting state, healthy volunteers who consumed a high-fat meal showed a 24.8% increase in C max, a 35.2% increase in AUCt, and a 35.4% increase in AUC ∞ . The geometric mean of T max was 4.69 h under fasting conditions and 5.93 h in a high-fat state, with a median of 4.98 h. Among the 24 enrolled volunteers, 9 cases (37.5%) had 11 AEs, and 6 cases (25.0%) had 7 adverse drug reactions (ADRs) after medication, all of which were cured or improved without taking any treatment measures. There were no SAEs in this study, no volunteers withdrew from the study due to AEs or ADRs, and no hypoglycemic events occurred during the trial. Conclusion A high-fat meal increased the C max, AUCt, and AUC∞ of globalagliatin compared with fasting conditions in healthy Chinese adult volunteers. Meanwhile, globalagliatin showed favorable safety and tolerability under fasting or high-fat meal conditions.

This paper is about the effectiveness of the Cobb-Douglas (C-D) production function in industrial optimization, estimating the number of factors used in the production process of the water industry, for instance, capital and human labor. Moreover, we have modeled a nonlinear optimization problem for a local water industry using two and three factors of production. For this purpose, we have taken into account the Cobb-Douglas production function with different production factors using the Lagrange multiplier method with the ordinary least squares method. In the course of the solution, a linear function is used to calculate the cost function, and the C-D production function is used to calculate the production function. The Lagrange multiplier method with the ordinary least squares method is then used to solve the constrained optimization problem for the product of production. Furthermore, we compared the outcomes from both examples of two- and three-factor C-D production functions in order to validate the Lagrange multiplier method for the C-D production function. Moreover, the three-factor C-D production function is solved by the Lagrange multiplier method with the ordinary least squares method, which provides optimal results as compared to previous studies in literature. The validity of the proposed methodology is explained by using the products of a local production industry in Pakistan.

DNA methylation plays a critical role in regulating gene expression during testicular development. However, few studies report on candidate genes related to the DNA methylation regulation of porcine testicular development. This study examined the differentially expressed genes (DEGs) and their methylation levels in testicular tissues from pigs at 60 days of age (60 d) and 180 days of age (180 d) using RNA-Seq and whole genome bisulfite sequencing (WGBS). It was determined that DNA methylation primarily occurs in the cytosine–guanine (CG) context, and the analysis identified 106,282 differentially methylated regions (DMRs) corresponding to 12,385 differentially methylated genes (DMGs). Further integrated analysis of RNA-Seq and WGBS data revealed 1083 DMGs negatively correlated with the expression of DEGs. GO analysis showed that these genes were significantly enriched in spermatogenesis, germ cell development, and spermatid differentiation. The screening of enriched genes revealed that hyper-methylation repressed ADAM30, ADAM3A, DPY19L2, H2BC1, MAK, RPL10L, SPATA16, and YBX2, while hypo-methylation elevated CACNA1I, CADM1, CTNNB1, JAM2, and PAFAH1B3 expression. Additionally, the methylation status of the key genes ADAM3A, ADAM30, YBX2, JAM2, PAFAH1B3, and CTNNB1 was detected by bisulfite sequencing PCR (BSP). This study offers insights into the epigenetic regulation mechanisms underlying porcine testicular development.

The main problems of forest parameter extraction and forest stand volume estimation using unmanned aerial vehicle light detection and ranging (UAV-LiDAR) technology are the lack of precision in individual tree segmentation and the inability to directly obtain the diameter at breast height (DBH) parameter. To address such limitations, the study proposed an improved individual tree segmentation method combined with a DBH prediction model to obtain the tree height (H) and DBH for calculating the volume of trees, thus realizing the accurate estimation of forest stand volume from individual tree segmentation aspect. The method involves the following key steps: (1) The local maximum method with variable window combined with the Gaussian mixture model were used to detect the treetop position using the canopy height model for removing pits. (2) The measured tree DBH and H parameters of the sample trees were used to construct an optimal DBH-H prediction model. (3) The duality standing tree volume model was used to calculate the forest stand volume at the individual tree scale. The results showed that: (1) Individual tree segmentation based on the improved Gaussian mixture model with optimal accuracy, detection rate r, accuracy rate p, and composite score F were 89.10%, 95.21%, and 0.921, respectively. The coefficient of determination R2 of the accuracy of the extracted tree height parameter was 0.88, and the root mean square error RMSE was 0.84 m. (2) The Weibull model had the optimal model fit for DBH-H with predicted DBH parameter accuracy, the R2 and RMSE were 0.84 and 2.28 cm, respectively. (3) Using the correctly detected trees from the individual tree segmentation results combined with the duality standing tree volume model estimated the forest stand volume with an accuracy AE of 90.86%. In conclusion, using UAV-LiDAR technology, based on the individual tree segmentation method and the DBH-H model, it is possible to realize the estimation of forest stand volume at the individual tree scale, which helps to improve the estimation accuracy.

Identifying template watermarks under severe geometric distortions is a significant scientific problem in the current watermarking research for remote sensing images. We propose a novel watermarking algorithm that integrates the ring-shaped template watermark with the multiscale local contrast measure (LCM) method. In the embedding stage, the ring-shaped template watermark is embedded into the discrete Fourier transform (DFT) magnitude coefficients, converting the watermark into small targets in the DFT domain. During the detection stage, the multiscale LCM, a classic infrared small target detection method, enhances these small targets and generates a contrast map. Peak detection is then performed on the contrast map to determine the radius of the template watermark. Finally, circular edge local binarization is applied to extract the watermark information. The proposed method enables synchronization recovery of watermarks under blind conditions. The experimental results demonstrate that the method possesses strong robustness against various geometric attacks such as rotation, scaling, translation, and cropping. It outperforms comparative algorithms in terms of robustness and also exhibits good imperceptibility.

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Let s, t be two positive integers and k be an algebraically closed field with char (k)∤st. We show that the Drinfeld double D(⋀st,t*cop) of generalized Taft–Hopf algebra ⋀st,t*cop has ribbon elements if and only if t is odd. Moreover, if s is even and t is odd, then D(⋀st,t*cop) has two ribbon elements, and if both s and t are odd, then D(⋀st,t*cop) has only one ribbon element. Finally, we compute explicitly all ribbon elements of D(⋀st,t*cop).

Let D(Rm,n(q)) be the Drinfeld double of Radford Hopf algebra Rm,n(q) and D(Hs,t) be the Drinfeld double of generalized Taft algebra Hs,t. Both D(Rm,n(q)) and D(Hs,t) have very symmetric structures. We calculate all Hopf automorphisms of D(Rm,n(q)) and D(Hs,t), respectively. Furthermore, we prove that the Hopf automorphism group AutHopf(D(Rm,n(q))) is isomorphic to the direct sum Zn⨁Zm of cyclic groups Zm and Zn, the Hopf automorphism group AutHopf(D(Hs,t)) is isomorphic to the semi-direct products k*⋊Zd of multiplicative group k* and cyclic group Zd, where s=td,k*=k\{0}, and k is an algebraically closed field with char (k)∤t.

Abstract Levetiracetam (LEV) is an anti‐epileptic drug approved for use in various populations. The pharmacokinetic (PK) behavior of LEV may be altered in the elderly and patients with renal and hepatic impairment. Thus, dosage adjustment is required. This study was conducted to investigate how the physiologically‐based PK (PBPK) model describes the PKs of LEV in adult and elderly populations, as well as to predict the PKs of LEV in patients with renal and hepatic impairment in both populations. The whole‐body PBPK models were developed using the reported physicochemical properties of LEV and clinical data. The models were validated using data from clinical studies with different dose ranges and different routes and intervals of administration. The fit performance of the models was assessed by comparing predicted and observed blood concentration data and PK parameters. It is recommended that the doses be reduced to ~70%, 60%, and 45% of the adult dose for the mild, moderate, and severe renal impairment populations and ~95%, 80%, and 57% of the adult dose for the Child Pugh‐A (CP‐A), Child Pugh‐B (CP‐B), and Child Pugh‐C (CP‐C) hepatic impairment populations, respectively. No dose adjustment is required for the healthy elderly population, but dose reduction is required for the elderly with organ dysfunction accordingly, on a scale similar to that of adults. A PBPK model of LEV was successfully developed to optimize dosing regimens for special populations.

Abstract Background Breast cancer brain metastases (BCBM) are highly heterogenous with widely differing survival. The prognosis of the oligometastatic breast cancer (BC) patients with brain metastases (BM) has not been well studied. We aimed to investigate the prognosis of BCBM patients with limited intracranial and extracranial metastatic lesions. Methods Four hundred and forty-five BCBM patients treated between 1st January 2008 and 31st December 2018 at our institute were included. Clinical characteristics and treatment information were obtained from patient’s medical records. The updated breast Graded Prognostic Assessment (Breast GPA) was calculated. Results The median OS after diagnosis of BM were 15.9 months. Median OS for patients with GPA 0–1.0, 1.5–2, 2.5–3 and 3.5–4 were 6.9, 14.2, 21.8, 42.6 months respectively. The total number of intracranial and extracranial metastatic lesions, in addition to the Breast GPA, salvage local therapy and systemic therapy (anti-HER2 therapy, chemotherapy and endocrine therapy) were demonstrated to be associated with prognosis. One hundred and thirteen patients (25.4%) had 1–5 total metastatic lesions at BM diagnosis. Patients with 1–5 total metastatic lesions had a significantly longer median OS of 24.3 months compared to those with greater than 5 total metastatic lesions with a median OS of 12.2 months (P

Five degraded products of limonoid, including two previously undescribed compounds (1, 3) and one pair of new natural products (4i, 4ii), were isolated from the root bark of Dictamnus dasycarpus Turcz. Their structures were elucidated by extensively spectroscopic methods (NMR, MS, ECD, etc), as well as quantum chemical calculations. The broadening NMR lines, along with the relaxation time and DOSY experiment revealed the self-aggregation of 1 in chloroform through H-bond between –COOH and –OH, which provided additional evidence to distinguish acid and ester/lactone in structure elucidation. Compounds 1–3 attenuated oleic acid-induced lipid accumulation in HepG2 cells significantly, with inhibition rates of 19.8%, 23.6%, and 13.5% at 10 μM, much stronger than fenofibrate, affording a novel scaffold for drug discovery against fatty liver disease.

ObjectivePaucity of information concerning the efficacy of gerontechnologies to support aging in place among community-dwelling older adults prevents potential users, healthcare professionals, and policymakers from making informed decisions on their use. The goal of this study was to identify gerontechnologies tested for home support in dyads of community-dwelling older adults with unimpaired cognition and their family caregivers, including their benefits and challenges. We also provide the level of evidence of the studies and recommendations to address the specific challenges preventing their use, dissemination, and implementation.MethodsWe conducted a systematic review of the literature published between 2016 and 2021 on gerontechnologies tested for home support in dyads. Two independent reviewers screened the abstracts according to the inclusion/exclusion criteria. A third reviewer resolved eligibility discrepancies. Data extraction was conducted by two independent reviewers.ResultsOf 1,441 articles screened, only 13 studies met the inclusion criteria with studies of moderate quality. Mostly, these gerontechnologies were used to monitor the older adult or the environment, to increase communication with family caregivers, to assist in daily living activities, and to provide health information. Benefits included facilitating communication, increasing safety, and reducing stress. Common challenges included difficulties using the technologies, technical problems, privacy issues, increased stress and dissatisfaction, and a mismatch between values and needs.ConclusionOnly a few gerontechnologies have proven efficacy in supporting community-dwelling older adults and their family caregivers. The inclusion of values and preferences, co-creation with end users, designing easy-to-use technologies, and assuring training are strongly recommended to increase acceptability and dissemination.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=310803, identifier CRD42022310803.

Intervertebral disc degeneration (IVDD) is a main cause of low back pain (LBP), which can lead to disability and thus generate a heavy burden on society. IVDD is characterized by a decrease in nucleus pulposus cells (NPCs) and endogenous mesenchymal stem cells (MSCs), degradation of the extracellular matrix, macrophage infiltration, and blood vessel and nerve ingrowth. To date, the therapeutic approaches regarding IVDD mainly include conservative treatment and surgical intervention. However, both can only relieve symptoms rather than stop or revert the progression of IVDD, since the pathogenesis of IVDD is not yet clear. Pyroptosis, which is characterized by Caspase family dependence and conducted by the Gasdermin family, is a newly discovered mode of programmed cell death. Pyroptosis has been observed in NPCs, annulus fibrosus cells (AFCs), chondrocytes, MSCs, macrophages, vascular endothelial cells and neurons and may contribute to IVDD. MSCs are a kind of pluripotent stem cell that can be found in almost all tissues. MSCs have a strong ability to secrete extracellular vesicles (EVs), which contain exosomes, microvesicles and apoptotic bodies. EVs derived from MSCs play an important role in pyroptosis regulation and could be beneficial for alleviating IVDD. This review focuses on clarifying the regulation of pyroptosis to improve IVDD by MSCs and EVs derived from MSCs.

The ridge culture place planting system (RCPPS) is a promising technique for planting rapeseed that can promote the growth of rapeseed by late rice stubble, which has been widely adopted in the Yangtze River delta. To determine the optimum planting date for rape (Brassica napus L.) forage and grain yield in an intensive rice–rape rotation system, a field experiment was conducted with five transplantation dates (from 20 October to 30 November at 10 day intervals) in RCPPS. The forage/grain yield, nutrition, and growth parameters were analyzed. At podding, rape biomass yield was highest, and no significant differences were found among treatments. It was around 12.0% crude protein, 11.4% ether extract, 38.8% neutral detergent fiber, and 34.9% acid detergent fiber. In the treatments of 20 and 30 November, crude protein content increased and acid detergent fiber content decreased significantly. Compared with 20 October, the grain yield of rape transplanted in November decreased significantly by 17.2% to 22.5%. The grain yield was significantly correlated with the number of secondary branches, pods, and seeds. At the final flowering stage, rape transplanted in November had noticeably reduced leaf growth, rhizome width, and yield than 20 and 30 October. Overall, for multiple uses of rapeseed in the Yangtze River delta belt with RCPPS, it is optimal to plant in mid to late November for forage use with higher nutritional value, being coordinated with the previous rice crop, whereas late October is the appropriate planting time to obtain a higher grain yield.

The objective of this study was to evaluate the effects of dietary naringin supplementation on rumen fermentation, inflammatory response and bacterial communities in fattening goats fed high-concentrate diet. Twenty four Boer male goats were randomly divided into three groups and assigned to receive dietary treatments. The three dietary treatments were a normal diet, a high-concentrate diet and a high-concentrate diet supplemented with 500 mg of naringin/kg of dry matter intake. Rumen fluid and plasma samples were collected at the end of the animal trial. Rumen fluid were analysed for pH, short-chain fatty acids, endotoxin (lipopolysaccharide, LPS) and microbiota. Illumina Miseq sequencing of the 16S rRNA gene was applied to investigate ruminal bacterial communities. The concentrations of interleukin −6 and tumour necrosis factor alpha as well as LPS-binding protein, haptoglobin, serum amyloid A and the activities of antioxdant enzymes in plasma were analysed. The result showed that feeding the high concentrate diet shifted the ruminal fermentation pattern from acetate towards propionate and valerate, and improved growth performance compared with the control group. However, the high concentrate diet promoted ruminal pH reduction and LPS release, modified bacterial communities and increased systemic inflammatory response. Naringin supplementation increased molar proportions butyrate and decreased valerate. Naringin supplementation decreased inflammatory response and increased the activities of antioxdant enzymes in plasma. Moreover, naringin addition increased the relative abundance of Bacteroidetes at the phylum level and Rikenellaceae_RC9_gut_group at the genus level. Taken together, these results suggest that dietary supplementation with naringin attenuates high grain diet-induced inflammatory response and modifies ruminal fermentation. HIGHLIGHTS Dietary supplementation of naringin decreased inflammatory response and increased the activities of antioxdant enzymes in fattening goats. Naringin supplementation changed ruminal microbiota of fattening goats. Naringin has potential for use as feed additive to modify ruminal fermentation in a high-grain intensive ruminant production.

Abstract Background Spermine is frequently elevated in tumor tissues and body fluids of cancer patients and is critical for cancer cell proliferation, migration and invasion. However, the immune functions of spermine in hepatocellular carcinoma progression remains unknown. In the present study, we aimed to elucidate immunosuppressive role of spermine in hepatocellular carcinoma and to explore the underlying mechanism. Methods Whole-blood spermine concentration was measured using HPLC. Human primary HCC tissues were collected to examine the expression of CaSR, p-Akt, β-catenin, STT3A, PD-L1, and CD8. Mouse model of tumorigenesis and lung metastasis were established to evaluate the effects of spermine on hepatocellular carcinoma. Western blotting, immunofluorescence, real time PCR, digital Ca2+ imaging, and chromatin immunoprecipitation assay were used to investigate the underlying mechanisms by which spermine regulates PD-L1 expression and glycosylation in hepatocellular carcinoma cells. Results Blood spermine concentration in the HCC patient group was significantly higher than that in the normal population group. Spermine could facilitate tumor progression through inducing PD-L1 expression and decreasing the CD8+ T cell infiltration in HCC. Mechanistically, spermine activates calcium-sensing receptor (CaSR) to trigger Ca2+ entry and thereby promote Akt-dependent β-catenin stabilization and nuclear translocation. Nuclear β-catenin induced by spermine then activates transcriptional expression of PD-L1 and N-glycosyltransferase STT3A, while STT3A in turn increases the stability of PD-L1 through inducing PD-L1 protein N-glycosylation in HCC cells. Conclusions This study reveals the crucial function of spermine in establishing immune privilege by increasing the expression and N-glycosylation of PD-L1, providing a potential strategy for the treatment of hepatocellular carcinoma. Video Abstract

Abstract Economic forecasting is a scientific decision-making tool, and it is one of the important basis for the government to formulate economic plans, predict the implementation of the plan, and guide the implementation of the plan. Current knowledge about the use of online news in the prediction of economic patterns in China is limited, especially considering the spatio-temporal dynamics over time. This study explored the spatio-temporal patterns of economic output values in Yinzhou, Ningbo, China between 2018 and 2021, and proposed generalized linear model (GLM) and Geographically weighted regression (GWR) model to predict the dynamics using online news data. The results indicated that there were spatio-temporal variations in the economic dynamics in the study area. The online news showed a great potential to predict economic dynamics, with better performance in the GWR model. The findings suggested online news combining with spatio-temporal approach can better forecast economic dynamics, which can be seen as a pre-requisite for developing an online news-based surveillance system The advanced spatio-temporal analysis enables governments to garner insights about the patterns of economic dynamics over time, which may enhance the ability of government to formulate economic plans and to predict the implementation of the plan. The proposed model may be extended to greater geographic area to validate such approach.

Abstract Background Fast and accurate forest aboveground biomass (AGB) estimation and mapping is the basic work of forest management and ecosystem dynamic investigation, which is of great significance to evaluate forest quality, resource assessment, and carbon cycle and management. The Ice, Cloud, and Land Elevation Satellite-2 (ICESat-2), as one of the latest launched spaceborne light detection and ranging (LiDAR) sensors, can penetrate the forest canopy and has the potential to obtain accurate forest vertical structure parameters on a large scale. However, the along-track segments of canopy height provided by ICESat-2 cannot be used to obtain comprehensive AGB spatial distribution. To make up for the deficiency of spaceborne LiDAR, the Sentinel-2 images provided by google earth engine (GEE) were used as the medium to integrate with ICESat-2 for continuous AGB mapping in our study. Ensemble learning can summarize the advantages of estimation models and achieve better estimation results. A stacking algorithm consisting of four non-parametric base models which are the backpropagation (BP) neural network, k-nearest neighbor (kNN), support vector machine (SVM), and random forest (RF) was proposed for AGB modeling and estimating in Saihanba forest farm, northern China. Results The results show that stacking achieved the best AGB estimation accuracy among the models, with an R2 of 0.71 and a root mean square error (RMSE) of 45.67 Mg/ha. The stacking resulted in the lowest estimation error with the decreases of RMSE by 22.6%, 27.7%, 23.4%, and 19.0% compared with those from the BP, kNN, SVM, and RF, respectively. Conclusion Compared with using Sentinel-2 alone, the estimation errors of all models have been significantly reduced after adding the LiDAR variables of ICESat-2 in AGB estimation. The research demonstrated that ICESat-2 has the potential to improve the accuracy of AGB estimation and provides a reference for dynamic forest resources management and monitoring.

IntroductionDengue fever (DF) is a mosquito-borne viral disease caused by the dengue virus (DENV). In recent years, Hangzhou has undergone a DF epidemic, particularly in 2017, with an outbreak of 1,128 patients. The study aimed to investigate the genetic diversity and molecular evolution among the DF clinical isolates during and after the outbreak to aid in mapping its spread.MethodsTo understand the genetic diversity, 74 DENV-2 strains were isolated from DF epidemic cases between 2017 and 2019. Combining whole genome sequencing (WGS) technology, additional phylogenetic, haplotype, amino acid (AA) substitution, and recombination analyses were performed.ResultsThe results revealed that strains from 2017 were closely related to those from Singapore, Malaysia, and Thailand, indicating an imported international transmission. Local strains from 2018 were clustered with those recovered from 2019 and were closely associated with Guangzhou isolates, suggesting a within-country transmission after the significant outbreak in 2017. Compared to DENV-2 virus P14337 (Thailand/0168/1979), a total of 20 AA substitutions were detected. Notably, V431I, T2881I, and K3291T mutations only occurred in indigenous cases from 2017, and A1402T, V1457I, Q2777E, R3189K, and Q3310R mutations were exclusively found in imported cases from 2018 to 2019. The recombination analysis indicated that a total of 14 recombination events were observed.ConclusionThis study may improve our understanding of DENV transmission in Hangzhou and provide further insight into DENV-2 transmission and the local vaccine choice.

Objective: Little is known about the effects of SARS-CoV-2 coronavirus disease (COVID-19) on quality of life and social participation in individuals with traumatic brain injury. We aimed to compare social participation and health-related quality of life (HRQoL) in a sample of individuals with TBI before and during the second wave of COVID-19 and explored the relationships between the perceived impacts of COVID-19, social participation, and HRQoL. Patients and methods: Eighteen individuals with traumatic brain injury with a mean (standard deviation) age of 47.7 (17.0) years at 48.2 (10.5) months post-injury were administered a questionnaire on overall disability and participation (Mayo-Portland Adaptability Inventory-4th edition; MPAI-4), HRQoL (Quality of Life after Brain Injury Questionnaire; QOLIBRI), and the Coronavirus Impacts Questionnaire before and during the second wave of the COVID-19 pandemic at an interval of 6.4 (SD = 8.2) months. Results: Compared with pre-pandemic levels, individuals with traumatic brain injury reported a statistically significant decrease in the QOLI-BRI total score and its emotional subscale (with medium to large effect sizes), but without statistically significant differences in MPAI-4 scores. Increased difficulties with access to resources during COVID-19 were associated with increased adjustment problems on the MPAI-4, and with daily life and autonomy difficulties, emotional issues, and lower physical functioning on the QOLIBRI. Conclusion: The relationships identified in this exploratory correlational study suggest that COVID-19 had a negative impact on quality of life in individuals with traumatic brain injury, but not specifically on their social participation. LAY ABSTRACT Little is known about the effects of SARS-CoV-2 coronavirus disease (COVID-19) on the lives of individuals with traumatic brain injury. This study compared social participation and health-related quality of life in individuals with TBI before and during the second wave of COVID-19 and explored relationships between the perceived impacts of COVID-19, social participation, and health-related quality of life, but not specifically on social participation in individuals with traumatic brain injury. Also, increased difficulties with access to resources during COVID-19 were associated with increased adjustment problems, daily life and autonomy difficulties, emotional issues, and lower physical functioning.

In order to safeguard image copyrights, zero-watermarking technology extracts robust features and generates watermarks without altering the original image. Traditional zero-watermarking methods rely on handcrafted feature descriptors to enhance their performance. With the advancement of deep learning, this paper introduces “ZWNet”, an end-to-end zero-watermarking scheme that obviates the necessity for specialized knowledge in image features and is exclusively composed of artificial neural networks. The architecture of ZWNet synergistically incorporates ConvNeXt and LK-PAN to augment the extraction of local features while accounting for the global context. A key aspect of ZWNet is its watermark block, as the network head part, which fulfills functions such as feature optimization, identifier output, encryption, and copyright fusion. The training strategy addresses the challenge of simultaneously enhancing robustness and discriminability by producing the same identifier for attacked images and distinct identifiers for different images. Experimental validation of ZWNet’s performance has been conducted, demonstrating its robustness with the normalized coefficient of the zero-watermark consistently exceeding 0.97 against rotation, noise, crop, and blur attacks. Regarding discriminability, the Hamming distance of the generated watermarks exceeds 88 for images with the same copyright but different content. Furthermore, the efficiency of watermark generation is affirmed, with an average processing time of 96 ms. These experimental results substantiate the superiority of the proposed scheme over existing zero-watermarking methods.

Abstract Insulin and incretin-based drugs are important antidiabetic agents with complex effects on cell growth and metabolism. Emerging evidence shows that insulin and incretin-based drugs are associated with altered risk of biliary tract cancer (BTC). Observational study reveals that insulin is associated with an increased risk of extrahepatic cholangiocarcinoma (ECC), but not intrahepatic cholangiocarcinoma (ICC) or gallbladder cancer (GBC). This type-specific effect can be partly explained by the cell of origin and heterogeneous genome landscape of the three subtypes of BTC. Similar to insulin, incretin-based drugs also exhibit very interesting contradictions and inconsistencies in response to different cancer phenotypes, including BTC. Both epidemiological and experimental evidence suggests that incretin-based drugs can be a promoter of some cancers and an inhibitor of others. It is now more apparent that this type of drugs has a broader range of physiological effects on the body, including regulation of endoplasmic reticulum stress, autophagy, metabolic reprogramming, and gene expression. In particular, dipeptidyl peptidase-4 inhibitors (DPP-4i) have a more complex effect on cancer due to the multi-functional nature of DPP-4. DPP-4 exerts both catalytic and non-enzymatic functions to regulate metabolic homeostasis, immune reaction, cell migration, and proliferation. In this review, we collate the epidemiological and experimental evidence regarding the effect of these two classes of drugs on BTC to provide valuable information.

Improving connectivity is the most commonly used approach employed in biodiversity conservation to mitigate habitat fragmentation. Graph-based networks relying on species-oriented definitions of nodes and edges are powerful tools for evaluating landscape connectivity. However, few studies have examined the effects of seasonal variation and uncertainty in parameterization of habitat suitability on the identification of priority sites. Here, a combination of the habitat suitability index, morphological spatial pattern analysis (MSPA), and graph-network analysis were combined to assess the influence of habitat variability on the identification of priority sites for reintroduction of South China tiger (Panthera tigris amoyensis). The combined approach was applied to the Hupingshan and Houhe National Nature Reserve and neighbourhood that are considered the most suitable places to harbour small populations of South China tigers. Six spatial or temporally static assessment scenarios for habitat suitability were used to account for uncertainties in the habitat requirement parameterizations of wild boars as the main prey for South China tigers. For each assessment scenario, three classification schemes (i.e., the P50, P70, and P90 schemes) were adopted to explain uncertainties in priority sites evaluation. In the static scenario, the minimum area of priority sites in the P50, P70, and P90 schemes was 321, 354, and 2,371 km2, respectively, while the areas encompassed by priority sites in the P50, P70, and P90 schemes considering the seasonal variability and habitat uncertainty were 0.2, 1.6, and 229.5 km2, respectively. These results suggest that priority areas with high conservation value differed among the six assessment scenarios. Conservation planning of landscapes consequently should consider the impacts of changes in landscape structures caused by seasonal variation and uncertainty in the parameterization of habitat suitability for the assessment of landscape priority sites rather than relying on purely spatial or temporally static connectivity analyses.

Abstract Introduction NLRP3 inflammasome responses and gut microbiota have been shown an important role in lung cancer, however, the relationship between gut microbiota and NLRP3 inflammasome responses in lung cancer with Qi-yin deficiency remains elusive. Methods To investigate the effect of the traditional Chinese medicine BuFeiXiaoJiYin (BFXJY) on NLRP3 inflammasome responses and dysbiosis in lung cancer with Qi-yin deficiency, the female BALB/cA-nu mice were treated with LPS and ATP to induce inflammation, and were intragastrically treated with warm Chinese medicine and smoked with shavings to induce Qi-yin deficiency, as well as were injected with 1 × 107/ml A549 cells to simulate lung cancer. Then the three different doses of BuFeiXiaoJiYin (BFXJY) and positive control (CRID3) were used for intervention in mice for 27 consecutive days. Then, we estimated the protection effect of BFXJY on lung cancer mice with Qi-yin deficiency, through deterring tumor growth, NLRP3 inflammasome, PKC signaling, and homeostasis of gut microbiota. Results In this study, we found that BFXJY could inhibit the tumor growth in lung cancer with Qi-yin deficiency by reducing the production of IL-1β and IL-18 and inhibiting NLRP3 inflammasome activation, which might be associated with the inhibition of PKC signaling. Furthermore, BFXJY could promote microbial diversity and balance the microbial composition changes induced by inflammation and Qi-yin deficiency in lung cancer. Conclusion BuFeiXiaoJiYin ameliorates the NLRP3 inflammation response and gut microbiota in mice with lung cancer companied with Qi-yin deficiency. Our study provides a theoretical basis for the clinical development of therapeutic drugs targeting to treat lung cancer.

Bisphenol AF (BPAF) is a newly identified contaminant in the environment that has been linked to impairment of the male reproductive system. However, only a few studies have systematically studied the mechanisms underlying BPAF-induced toxicity in testicular Sertoli cells. Hence, this study primarily aims to explore the toxic mechanism of BPAF on the porcine Sertoli cell line (ST cells). The effects of various concentrations of BPAF on ST cell viability and cytotoxicity were evaluated using the Counting Kit-8 (CCK-8) assay. The results demonstrated that exposure to a high concentration of BPAF (above 50 μM) significantly inhibited ST cell viability due to marked cytotoxicity. Flow cytometry analysis further confirmed that BPAF facilitated apoptosis and induced cell cycle arrest in the G2/M phase. Moreover, BPAF exposure upregulated the expression of pro-apoptotic markers BAD and BAX while downregulating anti-apoptotic and cell proliferation markers BCL-2, PCNA, CDK2, and CDK4. BPAF exposure also resulted in elevated intracellular levels of reactive oxygen species (ROS) and malondialdehyde (MDA), alongside reduced activities of the antioxidants glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Furthermore, the ROS scavenger N-acetyl-L-cysteine (NAC) effectively blocked BPAF-triggered apoptosis and cell cycle arrest. Therefore, this study suggests that BPAF induces apoptosis and cell cycle arrest in ST cells by activating ROS-mediated pathways. These findings enhance our understanding of BPAF’s role in male reproductive toxicity and provide a foundation for future toxicological assessments.

Adjuvants are frequently incorporated into crop protection operations to modulate the droplet characteristics by diminishing the surface tension (ST) and contact angle (CA), thereby positively influencing the wetting and spreading behavior of the droplets. However, there are no quantitative conclusions on the extent to which the amount of adjuvant added affects droplet properties. Therefore, the decision to add spraying adjuvants in actual pesticide spraying operations relies on the operator’s experience. In this study, we investigated the effect of a surfactant additive (KAO A-200) on the droplet properties and deposition of prochloraz emulsion in water (PEW) solution for crop protection in unmanned aerial vehicle (UAV) aerial spraying. Three KAO A-200 additive concentrations of 0.42%, 0.83% and 1.67% and four solution concentrations of 2.5%, 3.33%, 4.17% and 5% of PEW were set to evaluate the droplet properties of PEW solution with ST and CA as assessment indicators. The results show that the average STs of adjuvant solution droplets tended to decrease as the concentration of KAO A-200 increased. According to the optimal concentration, the KAO A-200 addition concentration of 0.83% was therefore determined to be the most appropriate dosage. With the appropriate KAO A-200 dosage condition, the results show that the average STs increased as PEW solution concentration increased, while the average CAs of PEW solution droplets showed a first decreasing and then increasing trend. The “4.17% concentration PEW (22.5 g a.i./1.2 L) + 0.83% concentration KAO A-200” condition was selected as the optimized combination for crop protection UAV field aerial spraying tests. The test showed that the coverage rate of PEW solution droplets on the upper and lower layers of oilseed rape canopy increased by 71.47% and 41.55%, the deposition density increased by 71.91% and 98.45%, and the coefficient of variation in droplet deposition decreased by 44.41% and 48.13%, respectively. These results are significantly better than those obtained without the adjuvant addition.

Damage to sperm DNA was proposed to play an important role in embryonic development. Previous studies focused on outcomes after fresh embryo transfer, whereas this study investigated the influence of sperm DNA fragmentation index (DFI) on laboratory and clinical outcomes after frozen embryo transfer (FET). This retrospective study examined 381 couples using cleavage-stage FET. Sperm used for intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF) underwent density gradient centrifugation and swim up processing. Sperm DFI had a negative correlation with sperm motility (r = −0.640, P < 0.01), sperm concentration (r = −0.289, P < 0.01), and fertilization rate of IVF cycles (r = −0.247, P < 0.01). Sperm DFI examined before and after density gradient centrifugation/swim up processing was markedly decreased after processing (17.1% vs 2.4%, P < 0.01; 65 randomly picked couples). Sperm progressive motility was significantly reduced in high DFI group compared with low DFI group for both IVF and ICSI (IVF: 46.9% ± 12.4% vs 38.5% ± 12.6%, respectively; ICSI: 37.6% ± 14.1% vs 22.3% ± 17.8%, respectively; both P < 0.01). The fertilization rate was significantly lower in high (≥25%) DFI group compared with low (

Electroacupuncture (EA) and induced pluripotent stem cell (iPSC)-derived small extracellular vesicles (iPSC-EVs) have substantial beneficial effects on ischemic stroke. However, the detailed mechanisms remain unclear. Here, we explored the mechanisms underlying the regulation of EA and iPSC-EVs in the microbiome-gut-brain axis (MGBA) after ischemic stroke. Ischemic stroke mice (C57BL/6) were subjected to middle cerebral artery occlusion (MCAO) or Sham surgery. EA and iPSC-EVs treatments significantly improved neurological function and neuronal and intestinal tract injury, downregulated the levels of IL-17 expression and upregulated IL-10 levels in brain and colon tissue after cerebral ischemia−reperfusion. EA and iPSC-EVs treatments also modulated the microbiota composition and diversity as well as the differential distribution of species in the intestines of the mice after cerebral ischemia−reperfusion. Our results demonstrated that EA and iPSC-EVs treatments regulated intestinal immunity through MGBA regulation of intestinal microbes, reducing brain and colon damage following cerebral ischemia and positively impacting the outcomes of ischemic stroke. Our findings provide new insights into the application of EA combined with iPSC-EVs as a treatment for ischemic stroke.

There is an urgent need to elucidate the pathogenesis of myocardial ischemia (MI) and potential drug treatments. Here, the anti-MI mechanism and material basis of Ginkgo biloba L. extract (GBE) were studied from the perspective of energy metabolism flux regulation. Metabolic flux analysis (MFA) was performed to investigate energy metabolism flux disorder and the regulatory nodes of GBE components in isoproterenol (ISO)-induced ischemia-like cardiomyocytes. It showed that [U–13C] glucose derived m+2 isotopologues from the upstream tricarboxylic acid (TCA) cycle metabolites were markedly accumulated in ISO-injured cardiomyocytes, but the opposite was seen for the downstream metabolites, while their total cellular concentrations were increased. This indicates a blockage of carbon flow from glycolysis and enhanced anaplerosis from other carbon sources. A Seahorse test was used to screen for GBE components with regulatory effects on mitochondrial aerobic respiratory dysfunction. It showed that bilobalide protected against impaired mitochondrial aerobic respiration. MFA also showed that bilobalide significantly modulated the TCA cycle flux, reduced abnormal metabolite accumulation, and balanced the demand of different carbon sources. Western blotting and PCR analysis showed that bilobalide decreased the enhanced expression of key metabolic enzymes in injured cells. Bilobalide's efficacy was verified by in vivo experiments in rats. This is the first report to show that bilobalide, the active ingredient of GBE, protects against MI by rescuing impaired TCA cycle flux. This provides a new mechanism and potential drug treatment for MI. It also shows the potential of MFA/Seahorse combination as a powerful strategy for pharmacological research on herbal medicine.

With the rapid development of the internet, the application of internet search data has been seen as a novel data source to offer timely infectious disease surveillance intelligence. Moreover, the advancements in internet search data, which include rich information at both space and time scales, enable investigators to sufficiently consider the spatiotemporal uncertainty, which can benefit researchers to better monitor infectious diseases and epidemics. In the present study, we present the necessary groundwork and critical appraisal of the use of internet search data and spatiotemporal analysis approaches in infectious disease surveillance by updating the current stage of knowledge on them. The study also provides future directions for researchers to investigate the combination of internet search data with the spatiotemporal analysis in infectious disease surveillance. Internet search data demonstrate a promising potential to offer timely epidemic intelligence, which can be seen as the prerequisite for improving infectious disease surveillance.

BackgroundNon-small cell lung cancer (NSCLC) is still of concern in differentiating it from benign disease. This study aims to validate the diagnostic efficacy of a novel seven-autoantibody (7-AAB) panel for the diagnosis of NSCLC.MethodsWe retrospectively enrolled 2650 patients who underwent both the 7-AAB panel test and CT scanning. We compared the sensitivity, specificity, and PPV of 7-AAB, CT, and PET-CT in the diagnosis of NSCLC in different subgroups. Then, we established a nomogram based on CT image features and the 7-AAB panel to further improve diagnostic efficiency. Moreover, we compared the pathological and molecular results of NSCLC patients in the 7-AABs positive group and the negative group to verify the prognostic value of the 7-AAB panel.ResultsThe strategy of a “both-positive rule” combination of 7-AABs and CT had a specificity of 95.4% and a positive predictive value (PPV) of 95.8%, significantly higher than those of CT or PET-CT used alone (P0.05) with an AUC of 0.791. Interestingly, it was found that the 7-AABs positive group was associated with higher proportion of EGFR mutations (P

The COVID-19 pandemic has seriously affected China's macroeconomy, industrial transformation, and high-quality development. Research on economic patterns and urban network systems can provide a reference for healthy development of the regional economic system. The evolution of the economic pattern and urban network system of Guangdong-Hong Kong-Macao Greater Bay Area (GBA) from 2010 to 2020 is investigated using methods (e.g., the gravity center model, the gravitational force model, social network analysis, and geographic information system). (1) The gravity center of gross domestic product (GDP) of the GBA is located in Nansha district, Guangzhou, with a skewing direction northwest-east-northwest and a movement rate of “large-small-large.” The center of import and export and the center of consumption show a “zigzagging migration” in which the center of investment shows an “irregular (random) migration”. (2) The economic connection degree of cities in the GBA exhibits a high ascending velocity, and the whole area tends to be mature, with a significant effect of spatial proximity. With the steady increase in network density, there is significant polarization of network centrality in the region. The four major cohesive subgroups have been relatively stable and consistent with the degree of geographic proximity of the cities. The center-periphery structure is more significant, in which the core area is extended to the cities on the east coast of the Pearl River Estuary, thus forming the core cluster of “Hong Kong-Shenzhen-Guangzhou-Dongguan.” In this study, the evolution of economic patterns and urban network systems in the GBA over the past decade is analyzed using multiple methods (i.e., gravity model, urban network system analysis, and geographic information system) based on urban socioeconomic data by starting from various spatial elements (e.g., “points, lines, and networks”) to gain insights into and optimize research on regional economic development after the COVID-19 pandemic.

Background: Propylthiouracil (PTU) treats hyperthyroidism and thyroid crisis in all age groups. A variety of serious adverse effects can occur during clinical use and require attention to its pharmacokinetic and pharmacodynamic characteristics in various populations.Objective: To provide information for individualized dosing and clinical evaluation of PTU in the clinical setting by developing a physiologically based pharmacokinetic (PBPK) model, predicting ADME characteristics, and extrapolating to elderly and pediatric populations.Methods: Relevant databases and literature were retrieved to collect PTU’s pharmacochemical properties and ADME parameters, etc. A PBPK model for adults was developed using PK-Sim® software to predict tissue distribution and extrapolated to elderly and pediatric populations. The mean fold error (MFE) method was used to compare the differences between predicted and observed values to assess the accuracy of the PBPK model. The model was validated using PTU pharmacokinetic data in healthy adult populations.Result: The MFE ratios of predicted to observed values of AUC0-t, Cmax, and Tmax were mainly within 0.5 and 2. PTU concentrations in various tissues are lower than venous plasma concentrations. Compared to healthy adults, the pediatric population requires quantitative adjustment to the appropriate dose to achieve the same plasma exposure levels, while the elderly do not require dose adjustments.Conclusion: The PBPK model of PTU was successfully developed, externally validated, and applied to tissue distribution prediction and special population extrapolation, which provides a reference for clinical individualized drug administration and evaluation.

Meat quality is one of the most important economic traits in pig breeding and production, and intramuscular fat (IMF) content is the major factor in improving meat quality. The IMF deposition in pigs is influenced by transcriptional regulation, which is dependent on chromatin accessibility. However, how chromatin accessibility plays a regulatory role in IMF deposition in pigs has not been reported. Xidu black is a composite pig breed with excellent meat quality, which is an ideal research object of this study. In this study, we used the assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) analysis to identify the accessible chromatin regions and key genes affecting IMF content in Xidu black pig breed with extremely high and low IMF content. First, we identified 21,960 differential accessible chromatin peaks and 297 differentially expressed genes. The motif analysis of differential peaks revealed several potential cis-regulatory elements containing binding sites for transcription factors with potential roles in fat deposition, including Mef2c, CEBP, Fra1, and AP-1. Then, by integrating the ATAC-seq and RNA-seq analysis results, we found 47 genes in the extremely high IMF (IMF_H) group compared with the extremely low IMF (IMF_L) group. For these genes, we observed a significant positive correlation between the differential gene expression and differential ATAC-seq signal (r2 = 0.42). This suggests a causative relationship between chromatin remodeling and the resulting gene expression. We identified several candidate genes (PVALB, THRSP, HOXA9, EEPD1, HOXA10, and PDE4B) that might be associated with fat deposition. Through the PPI analysis, we found that PVALB gene was the top hub gene. In addition, some pathways that might regulate fat cell differentiation and lipid metabolism, such as the PI3K-Akt signaling pathway, MAPK signaling pathway, and calcium signaling pathway, were significantly enriched in the ATAC-seq and RNA-seq analysis. To the best of our knowledge, our study is the first to use ATAC-seq and RNA-seq to examine the mechanism of IMF deposition from a new perspective. Our results provide valuable information for understanding the regulation mechanism of IMF deposition and an important foundation for improving the quality of pork.

Natural forests have the most complex structure and richest biodiversity among terrestrial ecosystems and are essential for maintaining the carbon balance and stability of the biosphere. Aboveground biomass (AGB) is a primary indicator used to evaluate forests and can directly measure forest growth and the quality of natural forests. Accurate and rapid AGB estimations can significantly improve the efficiency of forest management and deepen the understanding of the forest carbon cycle. The Ice, Cloud, and Land Elevation Satellite-2 (ICESat-2), one of the most recently launched spaceborne light detection and ranging (LiDAR) instruments, can penetrate forest canopies and obtain accurate, large-scale forest vertical parameter measurements. However, the discrete footprints offered by ICESat-2 cannot provide comprehensive spatial AGB distribution data. In this study, an optimized extreme learning machine (ELM) method was proposed to estimate the AGB of natural forests on the eastern Qinghai-Xizang Plateau, China. The synthetic Sentinel-2 images acquired from the Google Earth Engine (GEE) were synergized with ICESat-2 to realize continuous AGB mapping. To verify the effectiveness of the optimized method, support vector machine (SVM), k-nearest neighbor (kNN), and backpropagation (BP) neural network models were also established for comparison. The measured AGB data extracted from the forest management inventory (FMI) were used for model accuracy evaluation. The results show that the optimized ELM achieved the best estimation effect among all the analyzed models, with an R2 value of 0.68 and a root mean square error (RMSE) value of 25.14 mg/ha. The optimized ELM obtained the minimum RMSE and greatly improved the AGB prediction efficiency. These findings prove the ability of ICESat-2 in estimating the AGB of natural forests, which can provide a new way for large-scale forest resources investigation in high-altitude areas with a harsh environment.

Airborne laser scanning (ALS) and terrestrial laser scanning (TLS) are two ways to obtain forest three-dimensional (3D) spatial information. Due to canopy occlusion and the features of different scanning methods, some of the forest point clouds acquired by a single scanning platform may be missing, resulting in an inaccurate estimation of forest structure parameters. Hence, the registration of ALS and TLS point clouds is an alternative for improving the estimation accuracy of forest structure parameters. Currently, forest point cloud registration is mainly conducted based on individual tree attributes (e.g., location, diameter at breast height, and tree height), but the registration is affected by individual tree segmentation and is inefficient. In this study, we proposed a method to automatically fuse ALS and TLS point clouds by using feature points of canopy gap shapes. First, the ALS and TLS canopy gap boundary vectors were extracted by the canopy point cloud density model, and the turning or feature points were obtained from the canopy gap vectors using the weighted effective area (WEA) algorithm. The feature points were then aligned, the transformation parameters were solved using the coherent point drift (CPD) algorithm, and the TLS point clouds were further aligned using the recovery transformation matrix and refined by utilizing the iterative closest point (ICP) algorithm. Finally, individual tree segmentations were performed to estimate tree parameters using the TLS and fusion point clouds, respectively. The results show that the proposed method achieved more accurate registration of ALS and TLS point clouds in four plots, with the average distance residuals of coarse and fine registration of 194.83 cm and 2.14 cm being much smaller compared with those from the widely used crown feature point-based method. Using the fused point cloud data led to more accurate estimates of tree height than using the TLS point cloud data alone. Thus, the proposed method has the potential to improve the registration of ALS and TLS point cloud data and the accuracy of tree height estimation.

Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.

Background: Acetaminophen (APAP) overdose can cause liver injury and liver failure, which is one of the most common causes of drug-induced liver injury in the United States. Pharmacological activation of autophagy by inhibiting mechanistic target of rapamycin (mTOR) protects against APAP-induced liver injury likely via autophagic removal of APAP-adducts and damaged mitochondria. In the present study, we aimed to investigate the role of genetic ablation of mTOR pathways in mouse liver in APAP-induced liver injury and liver repair/regeneration. Methods: Albumin-Cre (Alb-Cre) mice, mTORf/f and Raptorf/f mice (C57BL/6J background) were crossbred to produce liver-specific mTOR knockout (L-mTOR KO, Alb Cre+/-, mTORf/f) and liver-specific Raptor KO (L-Raptor, Alb Cre+/-, Raptor f/f) mice. Alb-Cre littermates were used as wild-type (WT) mice. These mice were treated with APAP for various time points for up to 48 h. Liver injury, cell proliferation, autophagy and mTOR activation were determined. Results: We found that genetic deletion of neither Raptor, an important adaptor protein in mTOR complex 1, nor mTOR, in the mouse liver significantly protected against APAP-induced liver injury despite increased hepatic autophagic flux. Genetic deletion of Raptor or mTOR in mouse livers did not affect APAP metabolism and APAP-induced c-Jun N-terminal kinase (JNK) activation, but slightly improved mouse survival likely due to increased hepatocyte proliferation. Conclusions: Our results indicate that genetic ablation of mTOR in mouse livers does not protect against APAP-induced liver injury but may slightly improve liver regeneration and mouse survival after APAP overdose.

Due to the changes in the domestic and international economic situation in the post-pandemic era, the economic development of the Guangdong-Hong Kong-Macao Greater Bay Area has become unstable in many aspects. The paper adopted the Pressure-State-Response (PSR) model to build a regional economic resilience evaluation system from the perspective of public health emergencies. Then, the spatial and temporal evolution of the economic resilience of the Guangdong-Hong Kong-Macao Greater Bay Area and the influencing factors were explored by using entropy weight method, GIS and gray correlation method. The conclusions show that: (1) Temporally, the economic resilience of the Guangdong-Hong Kong-Macao Greater Bay Area has generally increased from 2010 to 2021, and is divided into three main stages: rapid development, adjustment to fluctuations and stable development. (2) Spatially, the overall pattern of economic resilience in the Guangdong-Hong Kong-Macao Greater Bay Area is high in the middle and south and low in the northwest, and shows a “stochastic—equalized—polarized” pattern of transformation. (3) In terms of influencing factors, economic status and economic response are the main dimensions affecting the resilience level of the economic system in the Guangdong-Hong Kong-Macao region. The level of scientific research and innovation, medical governance, government regulation and the rationalization of the industrial system are the key factors.