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Fubei Nan, Qingxin Tian, Shuangdong Chen Department of Anesthesiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Shuangdong Chen, Department of Anesthesiology, the First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, Zhejiang, 325035, People’s Republic of China, Tel +8613732058295, Email wfycshuangd@163.comBackground: Treating inflammatory pain (IP) continues to pose clinical challenge, because of the lack of effective pharmacological interventions. Microglial polarization serves as pivotal determinant in IP progress. Obacunone (OB), a low-molecular-weight compound with a diverse array of biological functions, having reported as an activator of nuclear factor E2-related factor 2 (Nrf2), exhibits anti-inflammatory property. However, it remains uncertain whether OB can alleviate IP by facilitating the transition of microglial polarization from the M1 to M2 state through modulating Nrf2/ heme oxygenase-1 (HO-1) pathway.Methods: We induced an mice IP model by subcutaneously administering Complete Freund’s Adjuvant (CFA) into the hind paw. Paw withdrawal latency (PWL) in seconds (s) and paw withdrawal frequency (PWF) were employed to evaluate the establishment of the IP model, while a caliper was used to measure the maximal dorsoventral thickness of the mice paw. Nerve injury was assessed by Hematoxylin-Eosin (HE) Staining. Western blot and got conducted for detection of M1/M2 microglial polarization markers, Nrf2 and HO-1 in spinal cord tissues respectively.Results: In comparison to the control cohort, PWF, M1 phenotype marker iNOS, CD86, paw thickness increased significantly within CFA cohort, while PWL, M2 phenotype marker Arg-1, interleukin-10 (IL-10) decreased in the CFA group. In comparison to model cohort, OB treatment decreased PWF, paw thickness, M1 phenotype marker iNOS, CD86 significantly, while PWL, M2 phenotype marker Arg-1, IL-10, Nrf2, HO-1 increased significantly. The morphological injuries of sciatic nerve in CFA mice were obviously improved by OB treatment. OB inhibited the release of M1-related IL-1β, CXCL1 but promoted M2-related TGF-β, IL-10 in serum in CFA mice. The intervention of the Nrf2 inhibitor ML385 mitigated analgesic effect of OB.Conclusion: We demonstrate that OB is able to attenuate inflammatory pain via promoting microglia polarization from M1 to M2 and enhancing Nrf2/HO-1 signal. OB treatment may be a potential alternative agent in the treatment of IP.Keywords: inflammatory pain, obacunone, Nrf2, HO-1

Xinran Ma,* Ling Li,* Lei Zhang, Xiaorui Fu, Xin Li, Xinhua Wang, Jingjing Wu, Zhenchang Sun, Xudong Zhang, Xiaoyan Feng, Yu Chang, Zhiyuan Zhou, Feifei Nan, Jieming Zhang, Zhaoming Li, Mingzhi Zhang Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingzhi ZhangDepartment of Oncology, The First Affiliated Hospital of Zhengzhou University, Lymphoma Diagnosis and Treatment Centre of Henan Province, Zhengzhou 450002, Henan, People’s Republic of ChinaTel +86-13838565629Email mingzhi_zhang1@163.comPurpose: Treatment options for relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL) represent an unmet medical need. Apatinib is a new oral tyrosine kinase inhibitor mainly targeting vascular endothelial growth factor receptor-2 (VEGFR-2) to inhibit tumour angiogenesis. In the present study, we evaluated the efficacy and safety of apatinib for patients with RR DLBCL.Patients and Methods: In this phase II, open-label, single-arm, prospective study, we enrolled patients aged 14– 70 years with treatment failure of at least two chemotherapeutic regimens using Simon’s two-stage design. All patients were administered apatinib at an initial dose of 500 mg on a 4-week cycle at home and visited the outpatient clinic every two cycles to evaluate efficacy and to record adverse events. We considered objective response rate (ORR) as the primary end point, and progression-free survival (PFS), and overall survival (OS) plus duration of response (DoR) as the secondary end point. (This trial was registered at ClinicalTrials.gov, identifier: NCT03376958.).Results: From January 2017 to February 2019, we screened 35 patients and enrolled 32 eligible patients. At the cutoff point (April 2019), we noted 2 (6.3%) complete responses, 12 (37.5%) partial responses, and 9 (28.1%) stable diseases, attributing to an ORR of 43.8% and a disease control rate of 71.9%. The median PFS and OS were 6.9 (95% confidence interval [CI], 5.8– 7.9) and 7.9 months (95% CI, 7.0– 8.7), respectively. The median DoR was 5.0 months (95% CI, 3.5– 6.5) for patients who achieved PR. The most common grade 3– 4 adverse events (AE) were hypertension (12.6%), hand–foot syndrome (9.4%), and leucopenia (6.3%). No apatinib-related deaths were noted.Conclusion: Home administration of apatinib shows promising efficacy and manageable AEs in patients with RR DLBCL.Keywords: apatinib, relapsed or refractory diffuse large B-cell lymphoma, VEGFR-2, efficacy, safety

Longxiang Xie,1 Qiang Wang,1 Fangmei Nan,1 Linna Ge,1 Yifang Dang,1 Xiaoxiao Sun,1 Ning Li,1 Huan Dong,1 Yali Han,1 Guosen Zhang,1 Wan Zhu,2 Xiangqian Guo1 1Bioinformatics Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Software, School of Basic Medical Sciences, Henan University, Kaifeng 475004, People’s Republic of China; 2Department of Anesthesia, Stanford University, Stanford, CA, USACorrespondence: Xiangqian GuoBioinformatics Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Software, School of Basic Medical Sciences, Henan University, Kaifeng 475004, People’s Republic of ChinaTel +86-371-23880585Email xqguo@henu.edu.cnAbstract: Gene expression profiling data with long-term clinical follow-up information are great resources to screen, develop, evaluate and validate prognostic biomarkers in translational cancer research. However, an easy-to-use interactive online tool is needed to analyze these profiling and clinical data. In the current work, we developed OSacc (Online consensus Survival analysis of ACC), a web tool that provides rapid and user-friendly survival analysis based on seven independent transcriptomic profiles with long-term clinical follow-up information of 259 ACC patients gathered from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. OSacc allows researchers and clinicians to evaluate the prognostic value of genes of interest by Kaplan–Meier (KM) survival plot with hazard ratio (HR) and log-rank test in ACC. OSacc is freely available at http://bioinfo.henu.edu.cn/ACC/ACCList.jsp.Keywords: ACC, prognostic marker, over survival, web tool, KM plot

Qianwen Ma,1,2,* Yu Chang,1,2,* Ling Li,1,2 Xin Li,1,2 Xinhua Wang,1,2 Jingjing Wu,1,2 Xiaorui Fu,1,2 Zhenchang Sun,1,2 Hui Yu,1,2 Xudong Zhang,1,2 Zhiyuan Zhou,1,2 Feifei Nan,1,2 Zhaoming Li,1,2 Xiyang Liu,1,2 Qian Zhao,1,2 Yang Li,1,2 Lan Zhang,2,3 Mingzhi Zhang,1,2 Lei Zhang1,2 1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China; 2Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou 450000, Henan, China; 3Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China *These authors contributed equally to this work Purpose: To compare the efficacy of rituximab, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-DA-EPOCH) with traditional rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimens in double-hit lymphoma (DHL) and gene copy number gain (CNG) lymphoma and to contrast the prognosis of these two disease types. Methods: We retrospectively examined 127 cases of newly diagnosed diffuse large B-cell lymphoma (DLBCL), and used fluorescence in situ hybridization (FISH) to detect genetic abnormalities in MYC, BCL2, and BCL6. Results: In the two schemes, the 2-year progression-free survival (PFS) was higher for R-DA-EPOCH group than for R-CHOP (79.8% vs 57.5%, P=0.002), this advantage was also reflected in 2-year overall survival (OS) (81.6% vs 58.5%, P=0.002). In double CNG patients, R-DA-EPOCH regimen was significantly better than R-CHOP (P=0.007 for PFS, P=0.010 for OS), and R-DA-EPOCH has the same advantage in DHL patients (P=0.001 for PFS, P=0.047 for OS). For the two disease types, the PFS for DHL was inferior to that for double CNG (52.9% vs 72.4%, P=0.008), while the OS was not significantly different (P=0.050). Subgroup analysis showed that the PFS for double CNG with MYC and BCL2 was superior to that for DHL with MYC and BCL2 (P=0.043), this trend is also seen in double CNG and DHL with MYC and BCL6 (P=0.036). However, the OS was not significantly different between the two subgroups. Multivariate analyses showed that in DLBCL patients with genetic abnormality detected by FISH, the treatment and disease types were independent prognostic factors. The adverse reaction rates were similar in R-DA-EPOCH and R-CHOP (P>0.05). Conclusion: Our retrospective study shows that DHL has a poorer prognosis than double CNG. Based on its improved lifetime and good tolerance, R-DA-EPOCH is a promising regimen for DHL or double CNG, which is expected to become the first-line treatment for high-risk DLBCL types based on more clinical research. Keywords: R-DA-EPOCH, R-CHOP, DHL, double CNG, efficacy and prognosis

Abstract Background Nocturnal disturbances are a common symptom experienced by People Living with Dementia (PLWD), and these often present prior to diagnosis. Whilst sleep anomalies have been frequently reported, most studies have been conducted in lab environments, which are expensive, invasive and not natural sleeping environments. In this study, we investigate the use of in-home nocturnal monitoring technologies, which enable passive data collection, at low cost, in real-world environments, and without requiring a change in routine. Methods Clustering analysis of passively collected sleep data in the natural sleep environment can help identify distinct sub-groups based on sleep patterns. The analysis uses sleep activity data from; (1) the Minder study, collecting in-home data from PLWD and (2) a general population dataset (combined n = 100, >9500 person-nights). Results Unsupervised clustering and profiling analysis identifies three distinct clusters. One cluster is predominantly PLWD relative to the two other groups (72% ± 3.22, p = 6.4 × 10−7, p = 1.2 × 10−2) and has the highest mean age (77.96 ± 0.93, p = 6.8 × 10−4 and p = 6.4 × 10−7). This cluster is defined by increases in light and wake after sleep onset (p = 1.5 × 10−22, p = 1.4 × 10−7 and p = 1.7 × 10−22, p = 1.4 × 10−23) and decreases in rapid eye movement (p = 5.5 × 10−12, p = 5.9 × 10−7) and non-rapid eye movement sleep duration (p = 1.7 × 10−4, p = 3.8 × 10−11), in comparison to the general population. Conclusions In line with current clinical knowledge, these results suggest detectable dementia sleep phenotypes, highlighting the potential for using passive digital technologies in PLWD, and for detecting architectural sleep changes more generally. This study indicates the feasibility of leveraging passive in-home technologies for disease monitoring.

Abstract UVB radiation induces oxidative stress, DNA damage, and inflammation, leading to skin wrinkling, compromised barrier function, and an increased risk of carcinogenesis. Addressing or preventing photoaging may offer a promising therapeutic avenue for these conditions. Recent research indicated that mesenchymal stem cells (MSCs) exhibit significant therapeutic potential for various skin diseases. Given that extracellular vesicles (EV) can deliver diverse cargo to recipient cells and elicit similar therapeutic effects, we investigated the roles and underlying mechanisms of both adipose-derived MSC-derived EV (AMSC-EV) and umbilical cord-derived MSC-derived EV (HUMSC-EV) in photoaging. Our findings indicated that in vivo, treatment with AMSC-EV and HUMSC-EV resulted in improvements in wrinkles and skin hydration while also mitigating skin inflammation and thickness alterations in both the epidermis and dermis. Additionally, in vitro studies using human keratinocytes (HaCaTs), human dermal fibroblast cells (HDFs), and T-Skin models revealed that AMSC-EV and HUMSC-EV attenuated senescence, reduced levels of reactive oxygen species (ROS) and DNA damage, and alleviated inflammation induced by UVB. Furthermore, EV treatment enhanced cell viability and migration capacity in the epidermis and promoted extracellular matrix (ECM) remodeling in the dermis in photoaged cell models. Mechanistically, proteomics results showed that TIMP1 was highly expressed in both AMSC-EV and HUMSC-EV and could exert similar effects as MSC-EV. In addition, we found that EV and TIMP1 could inhibit Notch1 and downstream targets Hes1, P16, P21, and P53. Collectively, our data suggests that both AMSC-EV and HUMSC-EV attenuate skin photoaging through TIMP1/Notch1.

During the flight of a flapping-wing flying robot, the unique flapping-wing propulsion mechanism causes periodic pitching and rolling motions of the body. In passing through different airspeeds and altitudes over different terrain, the wings cycle up-and-down through predefined stroke patterns to generate the aerodynamic force required for powered flight. However, this oscillatory flapping motion also causes the aircraft structure to pitch and roll periodically about its center of mass in an oscillatory manner. Consequently, substantial high-frequency jitter shakes aerial video footage captured by the onboard optical sensors. In particular, the rapid shaking that disrupts the image is synchronized with the characteristic wing beat rhythm. This jitter negatively affects the quality and usefulness of the acquired aerial video. Repeated up-and-down pitching and rolling displacements shake aerial footage, greatly reducing its clarity and stability. Without mitigation, the jitter severely affects imaging results, limiting the potential applications of such video. To solve this problem, this paper proposes an electronic image stabilization algorithm based on oriented fast and rotated brief (ORB) and sliding mean filtering for online debounce processing. First, because the jitter period of aerial images of a flapping-wing flying robot is consistent with the wing flapping period, we designed an estimation algorithm to estimate the wing flapping period based on image features. This algorithm enables us to more accurately capture the periodic characteristics of jitter and provides important parameters for subsequent image stabilization processing. Second, we proposed a motion filtering algorithm associated with the flapping period, which can adaptively and dynamically adjust filtering parameters adaptively according to different flight conditions. The algorithm proposed in this paper is advantageous because it can dynamically adjust parameters in real time based on the actual flight conditions of flapping-wing robots, thereby better adapting to different flight conditions and further improving the image stabilization effect. Third, to verify the feasibility and stability of the algorithm, this paper performed a flight experiment by mounting a visual imaging device on a flapping-wing flying robot. Experimental results show that the proposed algorithm shows better image stabilization effects than commonly used electronic image stabilization algorithms in flapping-wing flying robots. Finally, we summarized the advantages of the proposed algorithm and provided an outlook on the future research directions.

More and more marketplace platforms choose to use the data gathered from consumers (e.g., customer search terms, demographics) to provide a data analytics service for third-party sellers, both encouraging innovations and improving the operations of the latter. Through adopting the data analytics service, a seller can enhance its competitiveness by improving the quality of its products when there is more than one seller offering substitutes. This study develops a game-theoretic model to characterize a scenario with a marketplace platform and two competing sellers that sell substitutable products and decide whether to adopt the data analytics service provided by the platform. Then, we find that a seller's decision of whether or not to purchase the service depends on the competitor's decision and the two sellers' absorptive capacities of knowledge. Furthermore, a seller can benefit from adopting the data analytics service only if the seller has a high absorptive capacity, which can help increase product quality. When only one seller adopts, the platform and competing sellers can benefit from the adoption if this seller's absorptive capacity is high and the other's is moderate. The sellers' interests and social welfare can be aligned unless both sellers' absorptive capacities are low or high.

The 2022 MW6.7 Menyuan earthquake ruptured the western end of the Tianzhu seismic gap, providing an opportunity to study the regional seismogenic characteristics and seismic hazards. Here we use interferometric synthetic aperture radar (InSAR) and seismic data to study the mainshock rupture, early afterslip and the second largest aftershock of the 2022 Menyuan earthquake sequences. Our modeling results show that the mainshock ruptured the Lenglongling fault and the Tuolaishan fault with a maximum slip of ∼3 m. Rapid postseismic transient deformation occurred at the center of the Lenglongling fault. Our afterslip modeling reveals that the majority of afterslip occurred in the deeper part of the Lenglongling fault. A high-angle conjugated faulting event is found at the middle section of the Lenglongling fault. We use the stress inversion to investigate the possible triggering mechanism of the conjugated rupture event. The results indicate the maximum principal stress direction is in ∼222°, forming a ∼22° angle between the conjugated fault of second largest aftershock and the mainshock. The calculated normal stress changes indicate the region is within a pull-apart stress field, which favors such a conjugated rupturing event. Our study will help understand the rupture behavior of such kind of conjugated fault in other regions.

Bear bile has been a valuable and effective medicinal material in traditional Chinese medicine (TCM) for over 13 centuries. However, the current practice of obtaining it through bear farming is under scrutiny for its adverse impact on bear welfare. Here, we present a new approach for creating artificial bear bile (ABB) as a high-quality and sustainable alternative to natural bear bile. This study addresses the scientific challenges of creating bear bile alternatives through interdisciplinary collaborations across various fields, including resources, chemistry, biology, medicine, pharmacology, and TCM. A comprehensive efficacy assessment system that bridges the gap between TCM and modern medical terminology has been established, allowing for the systematic screening of therapeutic constituents. Through the utilization of chemical synthesis and enzyme engineering technologies, our research has achieved the environmentally friendly, large-scale production of bear bile therapeutic compounds, as well as the optimization and recomposition of ABB formulations. The resulting ABB not only closely resembles natural bear bile in its composition but also offers advantages such as consistent product quality, availability of raw materials, and independence from threatened or wild resources. Comprehensive preclinical efficacy evaluations have demonstrated the equivalence of the therapeutic effects from ABB and those from commercially available drained bear bile (DBB). Furthermore, preclinical toxicological assessment and phase I clinical trials show that the safety of ABB is on par with that of the currently used DBB. This innovative strategy can serve as a new research paradigm for developing alternatives for other endangered TCMs, thereby strengthening the integrity and sustainability of TCM.

In order to study the effect of temperature effect on CO2 injection and gas extraction in deep coal seams, a fluid-solid-thermal coupling model for CO2-injection enhanced coal seam extraction was established based on the basic theory of coal deformation characteristics and gas seepage characteristics, which also considered non-isothermal adsorption, binary gas competitive adsorption, gas seepage and diffusion, heat transfer and heat convection. The influence of temperature effect on coal reservoir parameters and gas production evolution law is investigated. The results show that the shrinkage of coal matrix caused by coal bed temperature decrease promotes CH4 desorption, and the fluid-solid coupling model ignoring temperature effect will underestimate gas production. When the initial permeability is 3.95×10−17 m2 and the CO2 injection pressure is 8 MPa, for the deep coal body buried 1 400 m in the No. 3 coal seam in Hancheng Mining area, compared with the fluid-solid-thermal coupling model considering the temperature effect (319.5 K), the gas extraction time of 3 650 days is higher than that of the fluid-solid coupling model. The average gas pressure of coal seam decreased by 0.69%, the permeability of A point increased by 11.02%, the gas production rate increased by 13.51%, and the cumulative gas production increased by 13.76%.

Abstract Objectives The performance of the new Respiratory Pathogen panel (fluorescent probe melting curve, FPMC) for the qualitative detection of 12 organisms (chlamydia pneumoniae, mycoplasma pneumoniae, adenovirus, influenza A virus, influenza B virus, parainfluenza virus, rhinovirus, etc.) was assessed. Methods Prospectively collected nasopharyngeal swab (NPS) and sputum specimens (n = 635) were detected by using the FPMC panel, with the Sanger sequencing method as the comparative method. Results The overall percent concordance between the FPMC analysis method and the Sanger sequencing method was 100% and 99.66% for NPS and sputum specimens, respectively. The FPMC testified an overall positive percent concordance of 100% for both NPS and sputum specimens. The FPMC analysis method also testified an overall negative percent concordance of 100% and 99.38% for NPS and sputum specimens, respectively. Conclusions The FPMC analysis method is a stable and accurate assay for rapid, comprehensive detecting for respiratory pathogens.

Cloud cover is a significant factor affecting the effectiveness of satellite-based Earth observations. Existing cloud detection algorithms primarily rely on imaging data from satellite sensors in the visible to near-infrared spectral range, making it challenging to achieve day-and-night cloud monitoring. Convolutional neural networks have shown outstanding performance in previous cloud detection algorithms due to their robust ability to extract local information. However, their inherent inductive bias limits their capacity to learn long-range semantic information. To address these challenges, we proposed SwinCloud, a U-shaped semantic segmentation network based on an enhanced Swin Transformer for cloud detection in the thermal infrared spectral range. Specifically, we augment the Swin Transformer's window attention module with a CNN-based parallel pathway to effectively model global-local information. We employ a feature fusion module before the final upsampling module in the decoder to better integrate low-level spatial information and high-level semantic information. On the Landsat-8 cloud detection dataset, our model outperforms state-of-the-art methods. When transferred to the SDGSAT-TIS cloud detection dataset, the mIOU of experiment results reaches 69.9%, demonstrating the strong transferability of SwinCloud across different sensors. We also applied SwinCloud to cloud detection in the visible bands of Landsat-8. The results demonstrated SwinCloud's generalization capability across different bands.

Background Epidemiological evidence has confirmed that periodontitis is an essential and independent risk factor of chronic obstructive pulmonary disease (COPD). Porphyromonas gingivalis, a major pathogen implicated in periodontitis, may make a vital contribution to COPD progression. However, the specific effects and molecular mechanism of the link between P. gingivalis and COPD are not clear.Methods and Results A COPD rat model was constructed by smoke exposure combined intratracheal instillation of E. coli-LPS, then P. gingivalis was introduced into the oral cavity of COPD rats. This research observed that lower lung function, more severe alveolar damage and inflammation occurred in COPD rats with P. gingivalis group. Meanwhile, P. gingivalis/gingipains could colonize the lung tissues and be enriched in bronchoalveolar lavage fluid (BALF) of COPD rats with P. gingivalis group, along with alterations in lung microbiota. Proteomic analysis suggested that Hsp90α/MLKL-meditated necroptosis pathway was up-regulated in P. gingivalis-induced COPD aggravation, the detection of Hsp90α and MLKL in serum and lung tissue verified that Hsp90α/MLKL was up-regulated.Conclusion These results indicate that P. gingivalis could emigrate into the lungs, alter lung microbiota and lead to aggravation of COPD, which Hsp90α/MLKL might participate in.

Abstract Background Femoral neck system (FNS) has exhibited some drawbacks, such as non-fit of the plate with the lateral femoral cortex, postoperative pain, and the potential risk of subtrochanteric fractures. We have developed a low-profile FNS system that addresses some compatibility issues in FNS. In this study, we conducted finite element analysis on the 1-hole FNS (1 H-FNS), 2-holes FNS (2 H-FNS), and low-profile FNS (LP-FNS) and compared their biomechanical performance. Methods After the mesh convergence analysis, we established three groups of 1 H-FNS, 2 H-FNS, and LP-FNS. The interfragmentary gap, sliding distance, shear stress, and compressive stress and the bone-implant interface compression stress, stiffness, and displacement were determined under the neutral, flexion, or extension conditions of the hip joint, respectively. The stress and displacement of the femur after the implant removal were also investigated. Results (1) There were no obvious differences among the three FNS groups in terms of the IFM distance. However, the LP-FNS group showed less rotational angle compared with conventional FNS (neutral: 1 H-FNS, -61.64%; 2 H-FNS, -45.40%). Also, the maximum bone-implant interface compression stress was obviously decreased under the neutral, flexion, or extension conditions of the hip joint (1 H-FNS: -6.47%, -20.59%, or -4.49%; 2 H-FNS: -3.11%, 16.70%, or -7.03%; respectively). (2) After the implant removal, there was no notable difference in the maximum displacement between the three groups, but the maximum von Mises stress displayed a notable difference between LP-FNS and 1 H-FNS groups (-15.27%) except for the difference between LP-FNS and 2 H-FNS groups (-4.57%). Conclusions The LP-FNS may not only provide the same biomechanical stabilities as the 1 H-FNS and 2 H-FNS, but also have more advantages in rotational resistance especially under the neutral condition of the hip joint, in the bone-implant interface compression stress, and after the implant removal. In addition, the 1 H-FNS and 2 H-FNS have similar biomechanical stabilities except for the maximum von Mises stress after the implant removal. The femur after the LP-FNS removal not only is subjected to relatively little stress but also minimizes stress concentration areas.

In order to explore the influence of thermal effect and strain on gas drainage, a fluid solid thermal coupling model considering coal deformation, gas adsorption and thermal effect was established to simulate the influence of thermal effect and strain on gas drainage. The results show that the gas production rate is 11.48% higher and the gas production rate is 11.45% higher when the thermal effect is considered than when the thermal effect is not considered. The stronger the thermal effect, the greater the permeability, and the higher the gas production. This shows that the influence of thermal effect on gas drainage cannot be ignored; the influence of different strains on gas extraction is different, adsorption strain > temperature strain > pressure strain.

Binomials have been relatively understudied compared to other types of multiword expressions (MWEs) in second language research, such as collocations and idioms. This study investigated English as a Foreign Language (EFL) learners’ processing of English binomials and how it is influenced by interlexical factors (L1-L2 congruency and L1-lexicalization) and intralexical factors (word and binomial frequency, binomial reversibility, and binomial predictability). Forty Chinese EFL learners participated in a phrase acceptability judgment task of 64 target binomials (16 congruent L1-lexicalized, 16 congruent L1-nonlexicalized, and 32 incongruent) and 64 non-binomial controls. Results revealed that learners experienced difficulty judging the formulaicity of binomials. They processed binomial stimuli significantly faster than non-binomial baselines, demonstrating a binomial phrase effect. They also processed L1-L2 congruent items faster and more accurately than incongruent items, showing a robust congruency effect. The congruent items which are lexicalized in the L1 showed further processing advantage than the non-lexicalized items, indicating a graded congruency effect. Moreover, binomial reversibility and binomial predictability (measured with cloze probability) also showed significant effects. These findings highlight the need to distinguish and investigate different types of congruency, explore appropriate measures for MWE predictability, and to examine binomials focusing on their unique features.

The technology of CO2-enhanced coalbed methane (CO2-ECBM) can reduce greenhouse gas emissions, and has the function of clean energy production and environmental protection. In order to study the drainage and production laws of CH4 production by CO2 injection in water-bearing coal seams under gas-water two-phase flow conditions, as well as the effects of different initial water saturation and CO2 injection conditions on CH4 production, CO2 storage, and reservoir permeability. A coupled fluid-solid-thermal model for competitive adsorption, temperature changes, coal deformation, and water transport was constructed. The high accuracy of the model was demonstrated by comparing with the field data, existing experiments and numerical solutions of existing model, and the advantages of the model were specified. CO2-ECBM numerical simulation were subsequently carried out using COMSOL. The results shown that, CO2 injection can enhance the rate and amount of CH4 production, which indicated the feasibility of CO2 injection to increase production. With the continuous CO2 injection, the CH4 concentration in the reservoir decreased, the CO2 concentration increased, the temperature near the gas injection well increased, the temperature near the production well decreased and the temperature from the gas injection well to the production well slowly decreased. Water phase relative permeability gradually decreased and gas phase relative permeability gradually increased during gas injection and extraction period. Due to the combined effect of effective stress and matrix shrinkage/expansion, the reservoir permeability exhibited a trend of “decrease-increase-decrease”. The higher the initial water saturation of the coal seam, the lower the CH4 production and the lower the permeability decrease. The maximum decrease in cumulative CH4 production was 15.19%. Ignoring the impact of water in coal seams can overestimate CH4 production, and the impact of coal seam water should be considered in numerical simulation. The higher the CO2 injection temperature and pressure, the greater the CH4 production and the greater the permeability decrease. The cumulative CH4 production increased by 13.27% and 39.77%, and permeability decreased by 20.4% and 46.14%, respectively. Increasing the CO2 injection temperature and pressure was conducive to increase CH4 production.

Stress and illness connection is complex and involves multiple physiological systems. Panax ginsengs, reputed for their broad-spectrum “cure-all” effect, are widely prescribed to treat stress and related illnesses. However, the identity of ginseng's “cure-all” medicinal compounds that relieve stress remains unresolved. Here, we identify ginsentides as the principal bioactives that coordinate multiple systems to restore homeostasis in response to stress. Ginsentides are disulfide-rich, cell-penetrating and proteolytic-stable microproteins. Using affinity-enrichment mass spectrometry target identification together with in vitro, ex vivo and in vivo validations, we show that highly purified or synthetic ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells via intracellular PI3K/Akt signaling pathway, alleviate α1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of aorta, decrease monocyte adhesion to endothelial cells via CD166/ESAM/CD40 and inhibit P2Y12 receptors to reduce platelet aggregation. Orally administered ginsentides were effective in animal models to reduce ADP-induced platelet aggregation, to prevent collagen and adrenaline-induced pulmonary thrombosis as well as anti-stress behavior of tail suspension and forced swimming tests in mice. Together, these results strongly suggest that ginsentides are the principal panacea compounds of ginsengs because of their ability to target multiple extra- and intra-cellular proteins to reverse stress-induced damages.

Abstract Urinary Tract Infections (UTIs) are one of the most prevalent bacterial infections in older adults and a significant contributor to unplanned hospital admissions in People Living with Dementia (PLWD), with early detection being crucial due to the predicament of reporting symptoms and limited help-seeking behaviour. The most common diagnostic tool is urine sample analysis, which can be time-consuming and is only employed where UTI clinical suspicion exists. In this method development and proof-of-concept study, participants living with dementia were monitored via low-cost devices in the home that passively measure activity, sleep, and nocturnal physiology. Using 27828 person-days of remote monitoring data (from 117 participants), we engineered features representing symptoms used for diagnosing a UTI. We then evaluate explainable machine learning techniques in passively calculating UTI risk and perform stratification on scores to support clinical translation and allow control over the balance between alert rate and sensitivity and specificity. The proposed UTI algorithm achieves a sensitivity of 65.3% (95% Confidence Interval (CI) = 64.3–66.2) and specificity of 70.9% (68.6–73.1) when predicting UTIs on unseen participants and after risk stratification, a sensitivity of 74.7% (67.9–81.5) and specificity of 87.9% (85.0–90.9). In addition, feature importance methods reveal that the largest contributions to the predictions were bathroom visit statistics, night-time respiratory rate, and the number of previous UTI events, aligning with the literature. Our machine learning method alerts clinicians of UTI risk in subjects, enabling earlier detection and enhanced screening when considering treatment.

Alismatis Rhizoma (AR) is a crucial substance for discovering new triterpenoids to address hyperlipidemia and obesity. Currently, approximately 120 triterpenoids have been identified in AR, making the discovery of new triterpenoids increasingly challenging. Thus, based on the advantages of HPLC-HRMS, it was utilized to identify both reported and new triterpenoids, and then in-silico analysis was employed to predict the functions of these new triterpenoids. Twenty reported triterpenoids and four new triterpenoids (25-methoxy-16-oxo-11-anhydroalisol A, 25-methoxy-16-oxo-alisol A, 25-methoxy-16-oxo-alisol A 23-acetate, and 25-methoxy-16-oxo-alisol A 24-acetate) from AR were identified using HPLC-HRMS, and then KEGG analysis suggested four new triterpenoids might be activated the PPAR signaling pathway to relieve hyperlipemia. The results of PPI and molecular docking indicated PPARA might be the key targets for anti-hyperlipidemia of four new triterpenoids, of which 25-methoxy-16-oxo-11-anhydroalisol A has better binding activity with PPARA. Additionally, 25-methoxy-16-oxo-11-anhydroalisol A has more potential as a candidate drug because of its better absorption, distribution, metabolism, excretion, and lower toxicity. Hence, our findings proved there are new triterpenoids with anti-hyperlipidemia medicinal potential in AR, thereby guiding the direction of future works and reducing the consumption of time and financial resources.

A trajectory-based guidance strategy is proposed for the three-dimensional terminal return task of an uncrewed space vehicle (USV). The overall guidance scheme consists of reference trajectory planning and robust trajectory tracking modules. The trajectory planning algorithm involves determining the motion of the USV to achieve a prescribed target under multiple constraints. The altitude-domain-based USV model is firstly proven to be differentially flat utilizing the dynamic pressure and position of the USV as flat outputs. The original trajectory planning problem is reformulated in a lower-dimensional flat output space. The discretization of the planning problem is then achieved using the pseudospectral method, based on which an initial guess technique is designed in order to accelerate the solving speed of the planning algorithm. Subsequently, a feedforward linearization-based trajectory tracking guidance law is designed using the differential flatness property of the altitude-domain model. Simulation results in different scenarios show that the proposed guidance strategy provides a satisfactory guidance solution.

Sentinel-1A/B data are crucial for retrieving numerical information about surface phenomena and processes. Coregistration of terrain observation by progressive scans (TOPS) data is a critical step in its application. TOPS data must be fundamentally co-registered with an accuracy of 0.001 pixels. However, various decorrelation factors due to natural vegetation and seasonal effects affect the coregistration accuracy of TOPS data. This paper proposed an enhanced spectral diversity coregistration method for dual-polarimetric (PolESD) Sentinel-1A/B TOPS data. The PolESD method suppresses speckle noise based on a unified non-local framework in dual-pol Synthetic Aperture Radar (SAR), and extracts the phase of the optimal polarization channel from the denoised polarimetric interferometric coherency matrix. Compared with the traditional ESD method developed for single-polarization data, the PolESD method can obtain more accurate coherence and phase and get more pixels for azimuth-offset estimation. In bare areas covered with low vegetation, the number of pixels selected by PolESD is more than the Boxcar method. It can also correct misregistration more effectively and eliminate phase jumps in the burst edge. Therefore, PolESD will help improve the application of TOPS data in low-coherence scenarios.

Abstract Dementia is a progressive condition that affects cognitive and functional abilities. There is a need for reliable and continuous health monitoring of People Living with Dementia (PLWD) to improve their quality of life and support their independent living. Healthcare services often focus on addressing and treating already established health conditions that affect PLWD. Managing these conditions continuously can inform better decision-making earlier for higher-quality care management for PLWD. The Technology Integrated Health Management (TIHM) project developed a new digital platform to routinely collect longitudinal, observational, and measurement data, within the home and apply machine learning and analytical models for the detection and prediction of adverse health events affecting the well-being of PLWD. This work describes the TIHM dataset collected during the second phase (i.e., feasibility study) of the TIHM project. The data was collected from homes of 56 PLWD and associated with events and clinical observations (daily activity, physiological monitoring, and labels for health-related conditions). The study recorded an average of 50 days of data per participant, totalling 2803 days.

To infer product fitness information, consumers often consult digital influencers who exert effort to learn and evaluate product features and then propagate information to their followers. However, influencers' recommendations are not limited to products that exactly match their expertise, which may lead followers to unfollow them. This study investigates which product (high or low congruence) an influencer should endorse and how much endorsement effort should be exerted. Using a theoretical model, we obtain several interesting results. First, endorsing a low-congruence product can surprisingly benefit the influencer if the penalty per lost follower is moderate or if the influencer has sufficiently high efficiency in reducing the perception error of this product. Second, although the influencer has high expertise in the high-congruence product, she will lose more followers when endorsing it than when endorsing the low-congruence product if a particularly small or large proportion of her followers are potential consumers of the low-congruence product. Third, when the influencer endorses the low-congruence product, the number of new followers increases with the size of the influencer's follower base only when the follower base is small and a large proportion of followers are potential consumers of the low-congruence product. Interestingly, as the size of the follower base increases, the influencer always exerts more effort when endorsing the high-congruence product but will exert less effort in learning about the low-congruence product if a sufficiently small proportion of followers are potential consumers. Finally, after taking consumers' knowledge about product features into account, the main results still hold, and when considering the competition between influencers, we uncover the conditions under which both influencers will choose to endorse the high-congruence product.

Objectives This study aims to explore the incidence of, and risk factors for medical adhesive-related skin injury (MARSI) at peripherally inserted central venous catheter (PICC) sites in patients with cancer.Design A prospective observational cohort study was conducted at a tertiary hospital in Shenzhen, China.Setting This was a single-centre study conducted in a tertiary hospital in Shenzhen, China.Participants A total of 340 patients with cancer and PICC placement from January 2022 to June 2023 were selected using a convenience sampling method.Methods Factors potentially associated with PICC-related MARSI (PICC-MARSI) were recorded, including patient demographics, and catheter placement and maintenance. Patients were divided into MARSI and non-MARSI groups. Univariate analysis was performed to screen for associated variables, and logistic regression analysis was used to identify independent risk factors for PICC-MARSI.Results Of all 340 patients enrolled, 33 (9.7%) developed PICC-MARSI, including skin tear (8, 24.2%), tension injury (5, 15.2%), irritant contact dermatitis (10, 30.3%), allergic dermatitis (7, 21.2%) and maceration (3, 9.1%). Multivariable analysis showed that age (OR=1.058, p=0.001, 95% CI 1.023–1.094), wet skin (OR=4.873, p=0.003, 95% CI 1.728–13.742), dry skin (OR=6.247, p

A modified algorithm is proposed in this study to correct time-varying mesh stiffness (TVMS) and transmission error (TE) in helical gears considering tooth root transition curve. The parametric model of helical gear is established by using the meshing principle of helical gear and hob in order to obtain the accurate tooth root transition curve. Moreover, a TE test rig is set up to compare the theoretical and experimental results. The results of the improved algorithm are very similar to the experimental results compared to the traditional model, and the relative error of TE is also small. In this study, the effect of multi-parameters (e.g. pressure angle, meshing position, transverse contact ratio, and overlap ratio) on TE are investigated by comparing theory with experimental analysis. Through the analysis of parameters, it has been established that an elevation in pressure angle leads to a decrease in TE, followed by an increase. In the event that the meshing position is situated closer to the nodal point, the TE slightly decreases. Moreover, as the transverse contact ratio and overlap ratio increase, the TVMS increases, while the TE decreases. When the overlap ratio approaches an odd multiple of 0.5, the TE displays a significant peak.

BackgroundThere are various therapeutic methods for treating stage IA (T1N0M0) non-small cell lung cancer (NSCLC), but no studies have systematically assessed multiple treatments to determine the most effective therapy.MethodsStage IA NSCLC patient data collected between 2004 and 2018 were gathered from the Surveillance, Epidemiology, and End Results (SEER) database. Treatment modalities included observation, chemotherapy alone (CA), radiation alone (RA), radiation+chemotherapy (RC), surgery alone (SA), surgery+chemotherapy (SC), surgery+radiation (SR) and surgery+radiation+chemotherapy (SRC). Comparisons were made of overall survival (OS) and lung cancer-specific survival (LCSS) among patients based on different therapeutic methods by survival analysis.ResultsUltimately, 89147 patients with stage IA NSCLC between 2004 and 2018 were enrolled in this study. The order of multiple treatment modalities based on the hazard ratio (HR) for OS for the entire cohort revealed the following results: SA (HR: 0.20), SC (HR: 0.25), SR (HR: 0.42), SRC (HR: 0.46), RA (HR: 0.56), RC (HR: 0.72), CA (HR: 0.91) (PConclusionSA appeared to be the optimal treatment modality for patients with stage IA NSCLC, and lobectomy was associated with the best prognosis. There may be some indication and selection bias in our study, and the results of this study should be confirmed in a prospective study.

Let $ k, l, m_1 $ and $ m_2 $ be positive integers and let both $ p $ and $ q $ be odd primes such that $ p^k = 2^{m_1}-a^{m_2} $ and $ q^l = 2^{m_1}+a^{m_2} $ where $ a $ is a positive integer with $ a\equiv {\pm 3}\pmod 8 $. In this paper, using only the elementary methods of factorization, congruence methods and the quadratic reciprocity law, we show that Je$ \acute{s} $manowicz' a conjecture holds for the following set of primitive Pythagorean numbers: $ \frac{q^{2l}-p^{2k}}{2}, p^kq^l, \frac{q^{2l}+p^{2k}}{2}. $ We also prove that Je$ \acute{s} $manowicz' conjecture holds for non-primitive Pythagorean numbers: $ n\frac{q^{2l}-p^{2k}}{2}, np^kq^l, n\frac{q^{2l}+p^{2k}}{2}, $ for any positive integer $ n $ if for $ a = a_1a_2 $ with $ a_1\equiv 1 \pmod 8 $ not a square and $ \gcd(a_1, a_2) = 1 $, then there exists a prime divisor $ P $ of $ a_2 $ such that $ \left(\frac{a_1}{P}\right) = -1 $ and $ 2|m_1, a\equiv 5 \pmod 8 $ or $ 2\not|m_2, a\equiv 3\pmod 8 $.

The C+L band elastic optical networks (C+L-EONs) increase the network capacity significantly. However, the introduction of an L band enhances the inter-channel stimulated Raman scattering effect (ISRS), consequently deteriorating the quality of transmission (QoT) of the signal. Furthermore, spectrum allocation leads to spectrum fragmentation inevitably, which escalates the bandwidth blocking rate. In addition, in C+L-EONs, a single fiber carries more services, and once one of the links fails, a huge number of requests will be interrupted, resulting in huge economic losses. Therefore, this paper proposes a survivability routing, band, modulation, and spectrum allocation (RBMSA) algorithm that effectively guarantees service survivability and reduces the impact of ISRS and spectrum fragmentation. The algorithm employs shared backup path protection and a band partitioning method, whereby the spectrum resource of the primary path is assigned in the L band and the backup path is assigned in the C band in order to minimize the impact of ISRS on the QoT of the request while ensuring the survivability of the network. Furthermore, a fragmentation metric accounting for both the free and shared spectrum resource is proposed to mitigate both free and shared spectrum fragmentation. The simulation results reveal that the proposed RBMSA algorithm reduces the bandwidth blocking probability (BBP) and the fragmentation rate (FR) by 47.7% and 21.3%, respectively, and improves the optical signal-to-noise ratio (OSNR) by 4.17 dB in NSFNET. In COST239, the BBP, FR, and OSNR are 22.1%, 21.5%, and 4.71 dB, respectively.

Objective To retrospectively evaluate the clinical efficacy and safety of brentuximab vedotin(BV) combined with chemotherapy in the treatment of malignant lymphoma. Methods We collected the data of 32 lymphoma patients with CD30-positive status, including 14 cases of Hodgkin's lymphomas, 2 cases of diffuse large B-cell lymphomas, and 16 cases of mature T/NK cell lymphomas. Chemotherapy combined with BV was administered to all patients for a minimum of two cycles. The efficacy of the treatment was evaluated according to Lugano criteria every two cycles. Results Complete response rate and overall response rate after four cycles of treatment were 22% and 50%, respectively. Sixteen cases (50.0%) had grades 1 and 2 toxicity, and 16 cases (50.0%) had grade 3 toxicity or higher. The most common adverse events were neutropenia (50.0%), pneumonia (46.9%), and anemia (43.8%). The most common grade 3 or higher adverse events were pneumonia (18.8%) and febrile neutropenia (12.5%). Four patients discontinued brentuximab vedotin because of severe adverse events. Conclusion BV is effective in treating relapsed and refractory CD30- positive Hodgkin's lymphoma and peripheral T-cell lymphoma, and its overall safety is acceptable.

Abstract The tumor microenvironment (TME) has been extensively investigated; however, it is complex and remains unclear, especially in elderly patients. Senescence is a cellular response to a variety of stress signals, which is characterized by stable arrest of the cell cycle and major changes in cell morphology and physiology. To the best of our knowledge, senescence leads to consistent arrest of tumor cells and remodeling of the tumor-immune microenvironment (TIME) by activating a set of pleiotropic cytokines, chemokines, growth factors, and proteinases, which constitute the senescence-associated secretory phenotype (SASP). On the one hand, the SASP promotes antitumor immunity, which enhances treatment efficacy; on the other hand, the SASP increases immunosuppressive cell infiltration, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), M2 macrophages, and N2 neutrophils, contributing to TIME suppression. Therefore, a deeper understanding of the regulation of the SASP and components contributing to robust antitumor immunity in elderly individuals with different cancer types and the available therapies is necessary to control tumor cell senescence and provide greater clinical benefits to patients. In this review, we summarize the key biological functions mediated by cytokines and intercellular interactions and significant components of the TME landscape, which influence the immunotherapy response in geriatric oncology. Furthermore, we summarize recent advances in clinical practices targeting TME components and discuss potential senescent TME targets.

The use of single-molecule optical tweezers shows that complexin-1 shapes the assembly of the Synaptic-soluble N-ethylmaleimide-sensitive factor Attachment Receptor by multiple domains’ coordination.

Abstract Metformin, the first line pharmacotherapy for type 2 diabetes has demonstrated favourable effects in prostate cancer (PCa) across a range of studies evaluating PCa patient outcomes amongst metformin users. However, a lack of rigorously conducted prospective studies has stalled clinical use in this setting. Despite multiple studies evaluating the mechanisms underpinning antitumour effects of metformin in PCa, to date, no reviews have compared these findings. This systematic review and meta‐analysis consolidates the mechanisms accounting for the antitumour effect of metformin in PCa and evaluates the antitumour efficacy of metformin in preclinical PCa studies. Data were obtained through Medline and EMBASE, extracted by two independent assessors. Risk of bias was assessed using the TOXR tool. Meta‐analysis compared in vivo reductions of PCa tumour volume with metformin. In total, 447 articles were identified with 80 duplicates, and 261 articles excluded based on eligibility criteria. The remaining 106 articles were assessed and 71 excluded, with 35 articles included for systematic review, and eight included for meta‐analysis. The mechanisms of action of metformin regarding tumour growth, viability, migration, invasion, cell metabolism, and activation of signalling cascades are individually discussed. The mechanisms by which metformin inhibits PCa cell growth are multimodal. Metformin regulates expression of multiple proteins/genes to inhibit cellular proliferation, cell cycle progression, and cellular invasion and migration. Published in vivo studies also conclusively demonstrate that metformin inhibits PCa growth. This highlights the potential of metformin to be repurposed as an anticancer agent, warranting further investigation of metformin in the setting of PCa.