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Abstract Advanced glycation end products (AGEs) are a diverse range of compounds that are formed when free amino groups of proteins, lipids, and nucleic acids are carbonylated by reactive carbonyl species or glycosylated by reducing sugars. Hyperglycemia in patients with diabetes can cause an overabundance of AGEs. Excess AGEs are generally acknowledged as major contributing factors to the development of diabetic complications because of their ability to break down the extracellular matrix directly and initiate intracellular signaling pathways by binding to the receptor for advanced glycation end products (RAGE). Inflammation and oxidative stress are the two most well-defined pathophysiological states induced by the AGE–RAGE interaction. In addition to oxidative stress, AGEs can also inhibit antioxidative systems and disturb iron homeostasis, all of which may induce ferroptosis. Ferroptosis is a newly identified contributor to diabetic complications. This review outlines the formation of AGEs in individuals with diabetes, explores the oxidative damage resulting from downstream reactions of the AGE-RAGE axis, and proposes a novel connection between AGEs and the ferroptosis pathway. This study introduces the concept of a vicious cycle involving AGEs, oxidative stress, and ferroptosis in the development of diabetic complications.

Abstract The SARS-CoV-2 Omicron variant sparked the largest wave of infections worldwide. Mainland China eased its strict COVID-19 measures in late 2022 and experienced two nationwide Omicron waves in 2023. Here, we investigated lineage distribution and virus evolution in Guangdong, China, 2022-2023 by comparing 5813 local viral genomes with the datasets from other regions of China and worldwide. Additionally, we conducted three large-scale serological surveys involving 1696 participants to measure their immune response to the BA.5 and XBB.1.9 before and after the corresponding waves. Our findings revealed the Omicron variants, mainly the BA.5.2.48 lineage, causing infections in over 90% of individuals across different age groups within a month. This rapid spread led to the establishment of widespread immunity, limiting the virus’s ability to further adaptive mutation and dissemination. While similar immune responses to BA.5 were observed across all age groups after the initial wave, children aged 3 to 11 developed a stronger cross immune response to the XBB.1.9 strain, possibly explaining their lower infection rates in the following XBB.1 wave. Reinfection with Omicron XBB.1 variant triggered a more potent neutralizing immune response among older adults. These findings highlight the impact of age-specific immune responses on viral spread in potential future waves.

Abstract Speech emotion recognition (SER) technology involves feature extraction and prediction models. However, recognition efficiency tends to decrease because of gender differences and the large number of extracted features. Consequently, this paper introduces a SER system based on gender. First, gender and emotion features are extracted from speech signals to develop gender recognition and emotion classification models. Second, according to gender differences, distinct emotion recognition models are established for male and female speakers. The gender of speakers is determined before executing the corresponding emotion model. Third, the accuracy of these emotion models is enhanced by utilizing an advanced differential evolution algorithm (ADE) to select optimal features. ADE incorporates new difference vectors, mutation operators, and position learning, which effectively balance global and local searches. A new position repairing method is proposed to address gender differences. Finally, experiments on four English datasets demonstrate that ADE is superior to comparison algorithms in recognition accuracy, recall, precision, F1-score, the number of used features and execution time. The findings highlight the significance of gender in refining emotion models, while mel-frequency cepstral coefficients are important factors in gender differences.

Abstract Seven pieces of gold foils for surface decoration of the lacquerware were excavated in the late Western Han Dynasty tomb in the area of the Jin Yang (晋阳) Ancient City site in Taiyuan (太原), Shanxi (山西), China. These gold foils portray images of the carriage, the leopard, the tigers, the ox, and the dancer with fluttering sleeves, etc., with black lines outlining the contours and red paint depicting vivid patterns. The study used Stereo Microscopes, Metallurgical Microscopy, Environmental Scanning Electron Microscopy coupled with Energy-Dispersive X-ray Spectroscopy (ESEM-EDS), and Laser Raman Spectroscopy (LRS) to analyse the thickness of the gold foils, the alloy composition, the composition of the paint and other surface attachments, and investigate the manufacturing process. As the results show, the thickness of the gold foils is about 26 μm. The composition is a gold-silver alloy with about 96% Au/(Au + Ag) (surface) and 98% Au/(Au + Ag) (cross-section). The metallurgical observation shows that the gold foils underwent heating and forging. The black lines on the front side are Chinese ink lines, with cracking and peeling phenomenon, and parallel polishing lines can be seen at the peeling places, while no polishing lines are observed on the back side. Some red paint made of cinnabar is above the black lines, and the binder is organic. Some lacquer residues are found on the back. According to the results of the study, the manufacturing process of the gold foils applied on the lacquerware is as follows: the gold foils are obtained by heating and forging, the front sides of the gold foils are polished, the shapes are carved out, and the gold foils are pasted on the lacquerware when the lacquerware’s surface is not yet dry. The gold foils are painted with black Chinese ink and red cinnabar pigment. The study’s results offer important references for understanding the manufacturing craft of the gold foils applied on the lacquerware in the late Western Han Dynasty of China and guide the conservation of the lacquerware decorated with painted gold foils.

Abstract Background Tunlametinib (HL-085) is a novel, highly selective MEK inhibitor with substantial clinical activities in patients with NRAS-mutant melanoma. This phase I study evaluated the safety and preliminary efficacy of tunlametinib plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors. Methods Patients with confirmed advanced BRAF V600-mutant solid tumors who had progressed on or shown intolerance or no available standard therapies were enrolled and received tunlametinib plus vemurafenib. This study consisted of a dose-escalation phase and a dose-expansion phase. Primary end points of this study were safety, the recommended phase II dose (RP2D), and preliminary efficacy. Results From August 17, 2018 to April 19, 2022, 72 patients were enrolled. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. The RP2D for BRAF V600-mutant non-small cell lung cancer (NSCLC) patients was tunlametinib 9 mg plus vemurafenib 720 mg, twice daily (BID, bis in die). Until the data cut-off date of December 15, 2023, of 33 NSCLC patients with evaluable disease, the objective response rate (ORR) was 60.6% (20/33; 95% confidence interval [CI], 42.1–77.1), the median progression free survival (PFS) was 10.5 months (95%CI, 5.6–14.5) and median duration of response (DoR) was 11.3 months (95%CI, 6.8-NE). At the RP2D, ORR was 60.0% (9/15; 95% CI, 32.3–83.7), the median PFS was 10.5 months (95%CI, 5.6 -NE) and median DoR was 11.3 months (95%CI, 3.9-NE). Of 24 colorectal cancer patients with evaluable disease, the ORR was 25.0% (6/24; 95% CI, 5.6-NE). All 72 patients had treatment-related adverse events (TRAEs), and the most common grade 3–4 TRAEs were anemia (n = 13, 18.1%) and blood creatine phosphokinase increased (n = 10, 13.9%). Tunlametinib was absorbed rapidly with Tmax of 0.5–1 h. Vemurafeinib did not influence the system exposure of tunlametinib and vice versa, indicating no drug-drug interaction for this combination. Conclusions Tunlametinib (HL-085) plus vemurafenib had a favorable safety profile and showed promising antitumor activity in patients with BRAF V600-mutant solid tumors. The RP2D for NSCLC was tunlametinib 9 mg BID plus vemurafeinib 720 mg BID. Trial Registration ClinicalTrials.gov, NCT03781219.

BackgroundAs individuals age, they commonly experience reduced physical activity and cognitive decline. While evidence, there is limited trajectory research on their concurrent progression and interrelation in individuals over 55 years old.MethodsThe data was collected from 5,765 individuals aged over 55 years who participated in the China Health and Retirement Longitudinal Study (CHARLS) between 2011 and 2020. Physical activity was measured by IPAQ, cognitive function by episodic memory, and mental intactness score. Separate sets of group-based trajectory models were fitted to identify physical activity trajectories and cognitive function trajectories. Multivariate logistic regression was used to estimate the association between baseline characteristics and each set of trajectories. Group-based dual trajectory modeling (GBDTM) was applied to quantify these associations.ResultsGBDTM identified three distinct trajectory groups for physical activity and cognitive outcomes. The physical activity trajectories were classified as “Persistently low physical activity” (74.2%), “Decreasing physical activity” (13.7%), and “Rising physical activity” (12.1%). Similarly, cognitive function trajectories were categorized as “Persistently low cognitive function” (22.2%), “Persistently moderate cognitive function” (37.9%), and “Persistently high cognitive function” (39.9%). Notably, 15.6% of participants followed the trajectories of “Persistently low physical activity” and “Persistently low cognitive function.” The presence of a severe decline in physical activity was associated with an increased likelihood of poor cognitive function and vice versa. Age, sex, education, residential status, BMI, and visual impairment were identified as significant predictors for physical activity and cognitive decline.ConclusionThis study found that the GBDTM can determine the consistent trajectories of physical activity and cognitive function trajectories that persistently decline in individuals over 55 years. Analyses of predictive factors can be instrumental in promoting physical activity and delaying cognitive decline.

Abstract Background The Citrus reticulata Blanco peels have been widely adopted as functional food or nutraceuticals for thousands of years. In our study, two polysaccharides from the C. reticulata Blanco peels were obtained and named as CRP-WA and CRP-02A, respectively. After characterization by monosaccharide composition, methylation and NMR, chemical structures of CRP-WA and CRP-02A were elucidated. Results As a result, CRP-WA with Mw of 32.8 kDa was an arabinogalactan polysaccharide composed of (β1 → 3) (β1 → 3,6)-D-Galp, (β1 → 4)-D-Manp and (β1 → 4)-D-Glcp units in the backbone. The CRP-02A with Mw of 70.5 kDa was an arabinogalacturonan type pectin formed by (α1 → 4) (α1 → 3,4)-D-GalpA units in the backbone. Moreover, the surface morphologies and rheological properties of CRP-WA and CRP-02A were quite different from each other. Both of these two polysaccharides possessed good antioxidant activities and immunoregulatory effects on RAW 264.7 cells, in which CRP-02A behaved remarkable antioxidant feature, whereas CRP-WA showed relatively high immunoregulatory activity. Conclusion Our study will provide fundamental information for C. reticulata Blanco-based nutritional foods development. Graphical Abstract

The development of self-powered smart biosensors has attracted great attention due to their potential applications in human motion monitoring and energy collection systems. Here, a newly designed triboelectric nanogenerator (PSP-TENG) composed of the PU sponge, polytetrafluoroethylene, and polydimethylsiloxane for monitoring rear leg rotation motion in artistic gymnastics has been developed. The PSP-TENG can monitor the buffering and stretching time of rear leg rotation and identify the angle between the hip, knee, and ankle during the stretching stage. Furthermore, the PSP-TENG has the function of converting measured signals into power signals, which can convert collected human motion mechanical energy into electrical energy to power wearable devices. The development of PSP-TENG has made contributions to the field of human motion monitoring, providing ideas for new energy and technologies to improve the environment and promote a virtuous ecological cycle.

Small interference RNA (siRNA) is a class of short double-stranded RNA molecules that cause mRNA degradation through an RNA interference mechanism and is a promising therapeutic modality. RBD1016 is a siRNA drug in clinical development for the treatment of chronic Hepatitis B Virus (HBV) infection, which contains a conjugated with N-acetylglucosamine moiety that can facilitate its hepatic delivery. We aimed to construct a semi-mechanistic model of RBD1016 in pre-clinical animals, to elucidate the pharmacokinetic/pharmacodynamic (PK/PD) profiles in mice and PK profiles in monkeys, which can lay the foundation for potential future translation of RBD1016 PK and PD from the pre-clinical stage to the clinic stage. The proposed semi-mechanistic PK/PD model fitted PK and PD data in HBV transgenic mice well and described plasma and liver concentrations in the monkeys well. The simulation results showed that our model has a reasonable predictive ability for Hepatitis B surface antigen (HBsAg) levels after multiple dosing in mice. Further PK and PD data for RBD1016, including clinical data, will assist in refining the model presented here. Our current effort focused on model building for RBD1016, we anticipate that the model could apply to other GalNAc-siRNA drugs.

The determination of compensation standards is the core of horizontal ecological compensation (HEC). However, existing studies focused on the ecological value stocks of ecosystem services (ESs) within an administrative area but ignored their spatial mobility when determining standards, so the HEC policies had difficulty in achieving the desired goals. This study takes the upper-middle reaches of the Yangtze River as the study area, adopts the gravity model to calculate the ecosystem services flow (ESF) in the eight provinces of the area, and formulates a HEC standard accounting model to determine the compensation standards. The results show that there are inhomogeneous distributions of ESs supply and demand from 2005 to 2020. The ESs supply tends to decline, then increase, whereas the demand continuously increases. The total ESF volume from the ESs-providing areas (ESPAs) to the ESs-benefiting areas (ESBAs) first increases and then decreases. In 2020, Tibet, Qinghai, Chongqing, and Hunan are the ESPAs, with Qinghai obtaining the highest compensation standard of 308.56 million CNY and accounting for more than 50% of the total. The ESBAs include Sichuan, Yunnan, Hubei, and Jiangxi, among which Sichuan is the main source of HEC funds with payments of 375.79 million CNY. This study can provide theoretical references for improving HEC rationality, as well as resolving the contradictions between environmental protection costs and benefits externalities for large-scale regions.

Abstract Introduction Kukoamine B mesylate (KB) is a mesylate chrysamine B targeting lipopolysaccharides and CpG DNA, two potential treatment targets in sepsis. Methods This first-in-human, randomized, double-blind, placebo-controlled, phase I study was conducted from July 2014 to May 2015 to explore the safety, tolerability, and pharmacokinetics of KB in healthy subjects. This study consisted of a pre-phase (four participants; KB at 0.005 mg/kg) and a dose escalation phase (eight participants/dose group, randomized 6:2 to KB or placebo; KB at 0.02, 0.04, 0.08, 0.12, 0.24, and 0.48 mg/kg). The primary endpoint was safety. Results Fifty-two participants were enrolled, including four in the pre-phase and 48 in the dose escalation phase. Among the 40 participants who received KB, 12 (30.0%) experienced adverse events (AEs), while two (16.7%) experienced AEs among 12 participants who received the placebo. The most common AEs in the KB group were headache (5.0%), influenza (5.0%) and positive white blood cell in urine (5.0%). After the administration of KB, the mean plasma elimination half was around 1.61–4.24 h. The relationship between the KB plasma exposure of KB and the administered dose was not linear. The percentage of cumulative urinary excretion of KB was similar among the different dose groups (21.7–35.2%) and the urinary excretion of KB decreased significantly about 8 h after administration. Conclusions Single-dose KB demonstrated favorable safety and tolerability in healthy subjects at the dose level of 0.005–0.48 mg/kg. KB exhibited a non-linear pharmacokinetic profile with a half-life of about 1.61–4.24 h, which mainly distributed in plasma. Trial Registration ClinicalTrials.gov identifier, NCT02219971.

Speech emotion recognition based on gender holds great importance for achieving more accurate, personalized, and empathetic interactions in technology, healthcare, psychology, and social sciences. In this paper, we present a novel gender–emotion model. First, gender and emotion features were extracted from voice signals to lay the foundation for our recognition model. Second, a genetic algorithm (GA) processed high-dimensional features, and the Fisher score was used for evaluation. Third, features were ranked by their importance, and the GA was improved through novel crossover and mutation methods based on feature importance, to improve the recognition accuracy. Finally, the proposed algorithm was compared with state-of-the-art algorithms on four common English datasets using support vector machines (SVM), and it demonstrated superior performance in accuracy, precision, recall, F1-score, the number of selected features, and running time. The proposed algorithm faced challenges in distinguishing between neutral, sad, and fearful emotions, due to subtle vocal differences, overlapping pitch and tone variability, and similar prosodic features. Notably, the primary features for gender-based differentiation mainly involved mel frequency cepstral coefficients (MFCC) and log MFCC.

Abstract Background Bioceramic cements have been widely used in endodontic treatment. This study aimed to compare the microhardness, elastic modulus, internal microstructure and chemical compositions of Biodentine, WMTA, ERRM Putty, iRoot FS and IRM after exposure to PBS, butyric acid, and butyric acid followed by PBS. Methods Specimens of each material were prepared and randomly divided into 5 subgroups (n = 5): subgroup A: PBS (pH = 7.4) for 4 days, subgroup B: PBS (pH = 7.4) for 14 days, subgroup C: butyric acid (pH = 5.4) for 4 days, subgroup D: butyric acid (pH = 5.4) for 14 days, subgroup E: butyric acid for 4 days followed by 10 days in contact with PBS. The surface microhardness, elastic modulus, internal morphologic and chemical compositions of specimens were analyzed. Results The microhardness and elastic modulus values of all materials were significantly higher in the presence of PBS compared to exposure to butyric acid, with the same setting time (P 0.05). Biodentine showed significantly higher microhardness and elastic modulus values than other materials, while IRM displayed the lowest (P

High-frequency vibratory pile driving exhibits remarkable efficiency in soft soil, with its impact on the surrounding soil to a limited range. Studying the evolution of stress and strain fields in the soil surrounding the pile during the pile driving process is of great significance for effective control of pile driving construction and accurate prediction of the pile foundation’s bearing capacity after installation. In this study, by means of numerical simulation with consideration of the large deformations of the soil and even discontinuities induced by the pile penetration into soil, the response of the soil during the high-frequency vibratory steel pipe pile driving in silt soil was investigated. The research results show that with the increase of pile driving depth, the stress concentration zones in the soil near the pile tip continuously expanded, and the plastic strain zone mainly developed downward but little horizontally. When the vibration frequency was between 33 and 38 Hz, the pile driving efficiency was higher than that of 50 Hz. High-frequency resonance free vibratory pile driving has smaller pile–soil stresses and plastic strains compared to traditional impacting pile and static pile, and it is less prone to the formation of soil plug. Therefore, high-frequency vibratory pile driving technology exhibits good adaptability in the soft soil.

Background: Tolvaptan, a selective vasopressin V2-receptor antagonist, can elicit a diuretic effect without significant electrolyte loss. The aims were to evaluate multiple-dose pharmacokinetics, pharmacodynamics and safety of daily administration of 15 mg tolvaptan in Chinese adult patients with confirmed Child-Pugh Class B cirrhosis accompanied by ascites.Methods: This was an open-label, single-center, single- and multiple-dose study. All patients received a daily 15 mg dose of tolvaptan for 7 consecutive days. The plasma concentrations of tolvaptan and its two metabolites (DM-4103, DM-4107) were measured using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). In addition, various pharmacokinetics parameters were calculated. The pharmacodynamic outcomes evaluated changes in serum sodium and potassium concentrations, daily urine volume, daily water consumption, fluid balance and body weight. Safety profiles, including the incidence of treatment-emergent adverse events (TEAEs), were carefully recorded.Results: Eleven patients with Child-Pugh B cirrhosis were eventually enrolled in the study. Plasma concentrations of tolvaptan and DM-4107 reached steady-states after 7 days of consecutive oral administration. No accumulation of tolvaptan or DM-4107 was found, but DM-4103 accumulated 18.2-fold after multiple-dosing. The daily urine volume and daily water consumption were statistically significantly increased after administration of tolvaptan from Day 1 to Day 7 (all p < 0.05), accompanied by an increased serum sodium concentration. Of 11 patients, 9 (81.8%) reported 20 TEAEs, with the majority being mild to moderate in severity. The most commonly occurring TEAEs were thirst (45.5%), pollakiuria (36.4%) and dry mouth (27.3%).Conclusion: Tolvaptan at a daily dose of 15 mg had a diuretic effect but did not increase serum sodium excretion or lead to tolvaptan accumulation. It is therefore can be safely used for short-term treatment of Chinese adult patients with confirmed Child-Pugh B cirrhosis.Clinical Trial Registration:https://clinicaltrials.gov/search?term=NCT01359462, identifier NCT01359462.

ObjectiveDeveloping a non-invasive and reliable triage test for endometrial malignant lesions is an important goal, as it could help to reduce the number of invasive diagnostic procedures required and improve patient survival. We aimed to estimate the diagnostic value of DNA methylation levels in cervical cytological samples of endometrial cancer (EC) and endometrial atypical hyperplasia (AH).MethodsA total of 607 women who had indications for endometrial biopsy in the Department of Obstetrics and Gynecology of Cangzhou Central Hospital from October 2022 to April 2023 were enrolled in this study. The cervical exfoliated cells were collected for gene methylation before endometrial biopsy. Clinical information, tumor biomarkers, and endometrial thickness (ET) of transvaginal ultrasonography (TVS) were also collected. With endometrial histopathology as the gold standard, multivariate unconditional logistic regression was applied to analyze the risk factors of endometrial malignant lesions. The role of cysteine dioxygenase type 1 (CDO1) and CUGBP Elav-like family member 4 (CELF4) gene methylation as a triage strategy biomarker in endometrial malignant lesions was specifically explored.ResultsMultivariate logistic regression analysis showed that premenopausal ET ≥ 11 mm or postmenopausal ET ≥ 5 mm, CDO1 ΔCt ≤ 8.4, or CELF4 ΔCt ≤ 8.8 were the risk factors for AH and EC, with odds ratios (ORs) (95%CI) of 5.03 (1.83–13.82) and 6.92 (1.10–43.44), respectively (p-values < 0.05). The sensitivity and specificity of CDO1/CELF4 dual-gene methylation assay for AH and EC reached 84.9% (95%CI: 75.3%–94.5%) and 86.6% (95%CI: 83.8%–89.5%), respectively. ET combined with DNA methylation detection further improved the specificity to (94.9%, 95%CI: 93.1%–96.8%).ConclusionThe accuracy of cervical cytology DNA methylation is superior to that of other clinical indicators in the non-invasive examination of endometrial malignant lesions. DNA methylation combined with TVS can further improve the specificity and is a promising biomarker triage strategy in women with suspected endometrial lesions.

Backgrounds: Gao-Liang-Huo decoction (GLH), a traditional Chinese medicine consisting of gao liangjiang (the roots or tubers of Alpinia offinarum Hance) and guang huoxiang (the aerial parts of Pogostemon cablin (Blanco) Benth.), has been shown an effective therapeutic efficacy for ulcerative colitis (UC). However, the active compounds and underlying mechanisms involved in GLH treatment of UC remains unclear. This study aims to investigate the pharmacological mechanism of GLH on UC using an integrated strategy of metabolomics and network pharmacology. Methods: The experimental mice UC model was induced using dextran sulfate sodium (DSS). The disease activity index (DAI), colonic mucosa damage index (CMDI), biochemical assays, and histopathological analysis were used to evaluate the pharmacological effect of GLH. The LC/MS-based metabolomics was used for investigation of serum metabolites and metabolic pathways regulated by GLH. The potential targets and pathways of the active compounds in GLH were further explored using network pharmacology. Finally, the underlying mechanism of GLH on UC was verified by molecular docking and immunohistochemistry (IHC). Results: The pharmacological experiments showed that GLH significantly ameliorated the DAI, CMDI, MDA, MPO, and histopathological changes in DSS-induced UC. The 15 metabolites were identified by metabolomics, such as L-tryptophan, taurocholic acid, glycocholic acid, 3-indolebutyric acid, and tryptophol. These metabolites were found to be enriched in tryptophan metabolism, glycerophospholipid metabolism, and citrate cycle (TCA cycle). The results of network pharmacology revealed the key targets, such as PIK3CA, PIK3R1, JAK1, JAK2, and JAK3, mainly involved in the PI3K-AKT, JAK-STAT, and T-cell receptor signaling pathways. Molecular docking showed high affinity interaction of quercetin, isorhamnrtin, poriferast-5-en-3beta-ol, 1,7-diphenyl-5-hydroxy-3-heptanone, and medicarpin with PIK3CA, PIK3R1, JAK1, JAK2, and JAK3, respectively. Finally, the immunohistochemistry (IHC) results indicated that GLH regulated the PI3K-AKT pathway with decreased expression levels of PI3KCA and p-AKT in DSS-induced UC. Based on integration of pharmacological experiments, network pharmacology, and metabolomics suggested that GLH might improve DSS-induced US by modulating tryptophan metabolism, glycerophospholipid metabolism, PI3K-AKT, JAK-STAT, and T-cell receptor signaling pathways. Conclusions: This study highlights the potential of combining metabolomics and network pharmacology as a promising strategy for exploring the potential mechanism of TCMs.

Abstract Type 2 diabetes mellitus (T2DM) agent sodium‐glucose co‐transporter 2 (SGLT2) inhibitors show special benefits in reducing body weight and heart failure risks. To accelerate clinical development for novel SGLT2 inhibitors, a quantitative relationship among pharmacokinetics, pharmacodynamics, and disease end points (PK/PD/end points) in healthy subjects and patients with T2DM was developed. PK/PD/end point data in published clinical studies for three globally marketed SGLT2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) were collected according to pre‐set criteria. Overall, 80 papers with 880 PK, 27 PD, 848 fasting plasma glucose (FPG), and 1219 hemoglobin A1c (HbA1c) data were collected. A two‐compartmental model with Hill's equation was utilized to capture PK/PD profiles. A novel translational biomarker, the change of urine glucose excretion (UGE) from baseline normalized by FPG (ΔUGEc) was identified to bridge healthy subjects and patients with T2DM with different disease statuses. ΔUGEc was found to have a similar maximum increase with different half‐maximal effective concentration values of 56.6, 2310, and 841 mg/mL·h for dapagliflozin, canagliflozin, and empagliflozin respectively. ΔUGEc will change FPG based on linear function. HbA1c profiles were captured by indirect response model. Additional placebo effect was also considered for both end points. The PK/ΔUGEc/FPG/HbA1c relationship was validated internally using diagnostic plots and visual assessment and further validated externally using the fourth globally approved same‐in‐class drug (ertugliflozin). This validated quantitative PK/PD/end point relationship offers novel insight into long‐term efficacy prediction for SGLT2 inhibitors. The novelty identified ΔUGEc could make the comparison of different SGLT2 inhibitors' efficacy characteristics easier, and achieve early prediction from healthy subjects to patients.

Background: After the adjustment of COVID-19 epidemic policy, mainland China experienced two consecutive waves of Omicron variants within a seven-month period. In Guangzhou city, as one of the most populous regions, the viral infection characteristics, molecular epidemiology, and the dynamic of population immunity are still elusive. Methods: We launched a prospective cohort study in the Guangdong Provincial CDC from December 2022 to July 2023. Fifty participants who received the same vaccination regimen and had no previous infection were recruited. Results: 90% of individuals were infected with Omicron BA.5* variants within three weeks in the first wave. Thirteen cases (28.26%) experienced infection with XBB.1* variants, occurring from 14 weeks to 21 weeks after the first wave. BA.5* infections exhibited higher viral loads in nasopharyngeal sites compared to oropharyngeal sites. Compared to BA.5* infections, the XBB.1* infections had significantly milder clinical symptoms, lower viral loads, and shorter durations of virus positivity. The infection with the BA.5* variant elicited varying levels of neutralizing antibodies against XBB.1* among different individuals, even with similar levels of BA.5* antibodies. The level of neutralizing antibodies specific to XBB.1* determined the risk of reinfection. Conclusions: The rapid large-scale infections of the Omicron variants have quickly established herd immunity among the population in mainland China. In the future of the COVID-19 epidemic, a lower infection rate but a longer duration can be expected. Given the large population size and ongoing diversified herd immunity, it remains crucial to closely monitor the molecular epidemiology of SARS-CoV-2 for the emergence of new variants of concern in this region. Additionally, the timely evaluation of the immune status across different age groups is essential for informing future vaccination strategies and intervention policies.

Developing cost-effective cathode materials is conducive to accelerating the commercialization of sodium-ion batteries. Na4Fe3(PO4)2P2O7 (NFPP) has attracted extensive attention owning to its high theoretical capacity, stable structure, and low cost of raw materials. However, its inherent low conductivity hinders its further application. Herein, carbon-coated NFPP nanospheres are anchored to crumpled MXene nanosheets by an electrostatic self-assembly; this cross-linked structure induced by CTAB not only significantly expands the contact area between particles and improves the electronic conductivity, but also effectively reduces the aggregation of NFPP nanoparticles. The as-designed Na4Fe3(PO4)2(P2O7)@C/Ti3C2Tx (NFPP@MX) cathode exhibits a high discharge capacity (106.1 mAh g−1 g at 0.2 C), good rate capability (60.4 mAh g−1 at 10 C), and a long-life cyclic stability (85.2% capacity retention after 1000 cycles at 1 C). This study provides an effective strategy for the massive production of high-performance NFPP cathodes and broadens the application of MXene in the modification of other cathode materials.

State policymakers in the United States have in recent years experimented with new initiatives to change the procedures used by public institutions to assess and assign academically underprepared students to non-credit developmental education (or remedial) courses. This study explores whether the most recent developmental education reform in Floridas—Senate Bill 1720 has affected student enrollment in the Florida College System (FCS) institutions and whether the enrollment effects vary by race/ethnicity and age. Through a difference-in-differences analysis, we did not find statistically significant effects of the reform on the college enrollment in Florida, neither on the racial or age compositions of the student population, compared to non-Florida institutions in the surrounding region. These null results provide valuable implications for policy and research consideration in Florida and beyond.

Florida State University (FSU) has a long-standing commitment to promoting success for all students. FSU’s strategies for student success and equity have resulted in increased and more equitable graduation rates and record fall-to-fall retention rates. This article provides an inventory of student success and equity initiatives at FSU. The inventory covers FSU’s holistic practices designed to support students of all backgrounds, including targeted practices for students from historically underrepresented groups. The article also highlights and describes in detail salient student success programs and practices at FSU. This article aims to serve as a guide for those in higher education who seek to understand and learn from FSU’s systematic efforts to promote and sustain student success and narrow success gaps. It also offers a profile of how to effectively implement a comprehensive and interconnected network of student success initiatives that respond to the critical needs of students and deliver impactful results.

Speech emotion recognition and its precise classification are challenging tasks that heavily depend on the quality of feature extraction and selection for speech signals. Many feature selection algorithms have been proposed to achieve recognition, however, their accuracy has not reached a satisfactory level. We introduce an improved equilibrium optimizer (iEO) algorithm and utilize mel frequency cepstral coefficients (MFCCs) and pitch features for emotion recognition. The transfer function is used to complete the binarization of iEO (BiEO), and the algorithm adopts multi-swarm and transfer functions to balance global search and local search. The performance of the proposed algorithm is verified using four English speech emotion datasets, eNTERFACE05, ryerson audio-visual database of emotional speech and song (RAVDESS), surrey audio-visual expressed emotion (SAVEE) and toronto emotional speech set (TESS). The experimental results illustrate that the proposed algorithm obtains an accuracy of 0.4923, 0.5581, 0,5575 and 0.9840 in eNTERFACE05, RAVDESS, SAVEE and TESS based on K-nearest neighbors, and an accuracy of 0.5279, 0.5862, 0.6752 and 0.9941 based on random forest.

In travel recommendation systems, the most important business demand is to make adaptive route planning and navigation decision based on computational intelligence. Existing researches mostly lacked the ability to adaptively suggest route planning schemes for users, according to contextual features. To deal with the problem, this paper proposes a deep reinforcement learning-based multi-object adaptive route planning method for travel recommendation systems. In particular, the technical framework utilizes both value iterative network (VIN) module and positioning module to construct a specific DRL algorithm for this purpose. It inputs the environment map of the agent into VIN module, obtains the value distribution corresponding to the map by means of convolution iteration, and extracts features by means of self-positioning. Such a technical framework is expected to improve generalization ability of navigation strategies. Empirically, this work selects some popular scenic spots in a certain region as the research object for case analysis, and collects road network traffic data and tourist scenic spot parameter data through two public travel service platforms. The experimental results show that the suburban tourism route planning model based on deep reinforcement learning scene perception is reasonable and feasible, and can effectively improve tourist satisfaction.

Abstract Lung cancer accounts for the most cancer-related deaths in the world. Our previous study suggested the improved survival of lung cancer patients, mainly female patients, with subsequent metachronous primary breast cancer. However, whether the survival advantages of the two primaries are associated with patients’ sex and the specific breast cancer is unclear. Whether male lung cancer patients with another primary may encounter the same survival advantage as female patients is also uncertain. The uncertainty hinders these patients from the potential benefit of lung cancer clinical trial. A total of 343 male lung adenocarcinoma patients with subsequent bladder papillary transitional cell carcinoma (LCBC), 1539 lung adenocarcinoma patients with prior bladder papillary transitional cell carcinoma (BCLC), 1181 lung adenocarcinoma patients with subsequent prostate adenocarcinoma (LCPC), 7426 lung adenocarcinoma patients with prior prostate adenocarcinoma (PCLC), and patients with single bladder/prostate/lung (SLC) cancer were identified from the Surveillance, Epidemiology, and End Results. Patients were classified into simultaneous two primary cancer (sTPC), metachronous two primary cancer 1 (mTPC1), or mTPC2 groups when interval time between two cancers was within 6 months, between 7 and 60 months, or over 60 months, respectively. Propensity matching score program was executed to match the two primary cancers with single primary. Cox regression and competing risk regression were performed to identify confounders associated with all-cause and cancer-specific survival, respectively. The major cancer-related and non-cancer-related death in the two primaries were lung cancer and heart disease, respectively. Median overall survival times since lung primary of LCBC and SLC were 97 and 17 months, respectively, and incidence of all-cause and cancer-specific death in LCBC since lung malignancy was significantly lower (Coef. − 1.24, 95% CI − 1.49 to 0.99; SHR 0.42, 95% CI 0.33–0.53). Among the categorized groups, prognosis values of sTPC and mTPC2 groups were not statically different from that of the matched single lung cancer, whereas increased overall survival time and decreased incidence of all-cause and cancer-specific death relative to the matched patients were observed in mTPC1 group (H.R 0.28, 95% CI 0.19–0.41; SHR 0.33, 95% CI 0.23–0.47). Similar prognosis of LCPC relative to SLC was also observed. Furthermore, a generally improved survival relative to SLC was observed in PCLC (median survival times of PCLC and SLC were 17 and 12 months, respectively; Coef. − 0.32, 95% CI − 0.43 to 0.22; SHR 0.77, 95% CI 0.69–0.85), whereas prognosis of BCLC was similar to the matched ones. These results hinted that survival of lung cancer patients might vary with prior cancer history. Further analysis among groups with the two primaries suggested that advanced bladder cancer was not associated with prognosis of patients with LCBC and BCLC. On the contrary, advanced prostate cancer was associated with all-cause and cancer-specific death in patients with PCLC but not in patients with LCPC. Compared with patients with single lung cancer, male lung cancer patients with subsequent bladder/prostate primary over 6 months experienced generally improved survival. These results were similar to our previous study regarding female lung cancer patients with another breast primary. On the contrary, male lung cancer patients with prior primary malignancy encountered varied prognosis: improved survival relative to single lung primary was observed in lung cancer with prior prostate cancer, whereas prognosis of lung cancer with prior bladder cancer was not different. Therefore, great attention was required to characterize prognosis of lung cancer patients with another primary in advance, which was essential to eliminate the potential bias when these patients were included into the clinical trials.

Abstract Background HL-085 is a selective, orally administered MEK1/2 inhibitor. We aimed to evaluate the safety and efficacy of HL-085 in patients with advanced melanoma harboring NRAS mutations. Methods This was a multicenter phase 1 study. HL-085 was administered twice daily in a standard 3 + 3 dose-escalation design (10 dose cohorts; 0.5–18 mg twice daily), followed by dose expansion at the recommended phase II dose (RP2D). The primary endpoints included tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and RP2D. Results Between September 13, 2017, and January 18, 2021, 42 patients were enrolled (dose escalation phase: n = 30; dose expansion phase: n = 12). No DLT was reported during dose escalation and MTD was not reached with HL-085 doses up to 18 mg twice daily. The RP2D was 12 mg twice daily. The most common all-grade drug-related adverse events (AEs) across all dose levels were rash (61.9%), increased creatine phosphokinase (CK, 59.5%), face edema (50.0%), increased aspartate aminotransferase (47.6%), peripheral edema (40.5%), diarrhea (33.3%), alanine aminotransferase (33.3%), and paronychia (19.0%), most of which were grade 1 and 2. Most frequency of grade ≥ 3 AEs were CK (14.2%), asthenia (7.1%), peripheral edema (4.8%), and acneiform dermatitis (4.8%). In the cohort of 12 mg twice daily dose (15 patients), confirmed objective response rate was 26.7%; disease control rate was 86.7%; median duration of response was 2.9 months; median progression-free survival was 3.6 months. Conclusions The HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations. Trial registration Trial registration ClinicalTrials.gov number: NCT03973151.

Abstract Background Conteltinib (CT-707) is a potent second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) showing promising anti-tumor activities in preclinical studies. This study aimed to assess the safety, pharmacokinetic (PK), and efficacy of conteltinib in patients with ALK-positive non-small cell lung cancer (NSCLC). Methods In this multicenter, single-arm, open-label, first-in-human phase 1 study, conteltinib was taken orally at doses of 50 to 800 mg quaque die (QD) in a dose-escalation phase. If the response was observed in a dose cohort of the dose-escalation phase, dose expansion was started. The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and adverse events assessed by investigators. Results Between April 13, 2016, and February 8, 2020, 64 ALK-positive NSCLC patients were enrolled, including 41 (64.1%) patients with ALK TKI-naïve and 23 (35.9%) patients who received crizotinib previously. In the dose-escalation phase, 26 patients were treated with conteltinib at doses of 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, 600 mg, and 800 mg QD. One DLT event was reported at the dose of 600 mg. MTD was not reached. Overall, 58 (90.6%) patients experienced treatment-related adverse events (TRAEs) and 9 (14.1%) patients had grade ≥ 3 TRAEs. The most common TRAEs were diarrhea (46 [71.9%]), serum creatinine elevated (29 [45.3%]), aspartate aminotransferase elevated (25 [39.1%]), and nausea (24 [37.5%]). Among 39 ALK TKI-naïve patients, the overall response rate (ORR) was 64.1% (25 of 39; 95% confidence interval [CI], 47.2–78.8), median progression-free survival (PFS) was 15.9 months (95% CI, 9.26–23.3), and median duration of response (DoR) was 15.0 months (95% CI, 9.06–25.8). Among 21 patients who received crizotinib previously, the ORR was 33.3% (7 of 21; 95% CI, 14.6–57.0), median PFS was 6.73 months (95% CI, 4.73–8.54), and median DoR was 6.60 months (95% CI, 3.77–13.3). Conclusions In this study, conteltinib showed manageable safety profile, favorable PK properties, and anti-tumor activity in advanced ALK-positive NSCLC patients. The recommended phase 2 dose was determined to be 600 mg QD for ALK TKI-naïve patients and 300 mg bis in die (BID) for patients who received crizotinib previously. Trial registration ClinicalTrials.gov, NCT02695550.

Granisetron patches are a prolonged delivery transdermal system that is used to prevent Chemotherapy-induced nausea and vomiting (CINV). To date, no pharmacokinetics comparison between Chinese and Caucasian populations has been conducted for granisetron patches. This study focused on the ethnic differences in pharmacokinetics (PK) of granisetron transdermal delivery system (GTDS) between Chinese and Caucasians and the influence of demographic covariates on pharmacokinetics (age, weight, height, body mass index, sex). To achieve this, blood concentration data were collected from 112 Caucasian healthy subjects participating in four clinical trials and 24 Chinese healthy subjects from one clinical trial, after a single application of the granisetron transdermal delivery system. A nonlinear mixed-effects model method of Phoenix NLME software was used to establish a population pharmacokinetic (Pop PK) model for Caucasian subjects. Bootstrap and visual predictive check (VPC) were used to validate the model. Based on the analysis a one-compartment model with first-order absorption and a first-order elimination well described the PK characteristics of GTDS. The apparent systemic clearance was determined to be 31316.3 mL/h and the central compartment volume of distribution was 6299.03 L. None of the five covariates (age, weight, height, body mass index, and sex) included in the Pop PK were significant covariates affecting PK. The final Pop PK model was used to simulate the Caucasian blood concentration by applying the dosing regimen used for the Chinese population. Comparison of the simulated Caucasian PK data with observed clinical PK data from Chinese healthy subjects revealed no significant differences in the main parameters, AUClast and Cavg, between the two groups. These findings suggested that no dose adjustment was required when applied to the Chinese population. In conclusion, this Pop PK study comparing the transdermal patch in Chinese and Caucasian healthy subjects provided valuable insights for optimizing dosage across ethnicities.

There are a lot of multi-objective optimization problems (MOPs) in the real world, and many multi-objective evolutionary algorithms (MOEAs) have been presented to solve MOPs. However, obtaining non-dominated solutions that trade off convergence and diversity remains a major challenge for a MOEA. To solve this problem, this paper designs an efficient multi-objective sine cosine algorithm based on a competitive mechanism (CMOSCA). In the CMOSCA, the ranking relies on non-dominated sorting, and the crowding distance rank is utilized to choose the outstanding agents, which are employed to guide the evolution of the SCA. Furthermore, a competitive mechanism stemming from the shift-based density estimation approach is adopted to devise a new position updating operator for creating offspring agents. In each competition, two agents are randomly selected from the outstanding agents, and the winner of the competition is integrated into the position update scheme of the SCA. The performance of our proposed CMOSCA was first verified on three benchmark suites (i.e., DTLZ, WFG, and ZDT) with diversity characteristics and compared with several MOEAs. The experimental results indicated that the CMOSCA can obtain a Pareto-optimal front with better convergence and diversity. Finally, the CMOSCA was applied to deal with several engineering design problems taken from the literature, and the statistical results demonstrated that the CMOSCA is an efficient and effective approach for engineering design problems.

BackgroundGolidocitinib is an orally available, potent and highly selective JAK (Janus kinase)-1 inhibitor of JAK/STAT3 signaling under clinical development for the treatment of cancer and autoimmune diseases. The objectives of the two reported studies were to investigate the pharmacokinetics (PK), safety, and tolerability of golidocitinib in healthy Chinese participants as compared to those healthy Western participants, as well as the food effect exploration.MethodsTwo phase I studies (JACKPOT2 and JACKPOT3) were conducted in USA and China, respectively. In JACKPOT2 study, participants were randomized into placebo or golidocitinib arm in single-ascending dose cohorts (5 - 150 mg) and multiple-ascending dose cohorts (25 - 100 mg, once daily) for 14 days. In the food effect cohort, golidocitinib (50 mg) was administrated shortly after a high-fat meal (fed conditions) as compared to under fasting conditions. In JACKPOT3 study conducted in China, participants were randomized to placebo or golidocitinib arm in single-ascending dose cohorts (25 - 150 mg).ResultsExposure of golidocitinib generally increased in a dose-proportional manner across a dose range of 5 mg to 150 mg (single dose) and 25 mg to 100 mg (once daily). High-fat food did not alter the PK of golidocitinib with statistical significance. Low plasma clearance and extensive volume of distribution characterizes PK of golidoctinib, and long half-life across the dose levels supported once daily dosing. The inter-ethnic difference in primary PK parameters was evaluated. The result suggested slightly higher peak plasma concentrations (Cmax) but comparable area under the plasma concentration-time curve (AUC) was observed in Asian (Chinese) subjects as compared to Caucasian and/or Black subjects, while it was not considered clinically relevant. Golidocitinib was well tolerated without Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher drug-related treatment emergent adverse events (TEAE) reported.ConclusionNo noticeable inter-ethnic difference was observed among Asian, Black, and Caucasian healthy subjects in anticipation of the favorable PK properties of golidocitinib. The effect of food on the bioavailability of golidocitinib was minor following a single oral administration of 50 mg. These data guided to use the same dose and regimen for multinational clinical development.Clinical trial registrationshttps://clinicaltrials.gov/ct2/show/NCT03728023?term=NCT03728023&draw=2&rank=1, identifier (NCT03728023); http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier (CTR20191011).

Abstract We report the findings of a single‐dose, randomized, three‐period cross‐over, clinical trial in healthy Chinese individuals (n = 24) comparing the pharmacokinetics of insulin degludec/liraglutide (IDegLira) with its individual components. Furthermore, we report a population pharmacokinetic analysis of a 26‐week, phase III, treat‐to‐target, randomized trial of 720 Chinese individuals with type 2 diabetes. Participants were randomized to IDegLira, degludec or liraglutide, all once daily with metformin. The pharmacokinetic profiles of IDegLira were similar to its individual components. Dose proportionality was indicated for both IDegLira components. Although there were no relevant covariate effects on degludec exposure, liraglutide exposure was inversely correlated with bodyweight. In conclusion, for the Chinese population, the pharmacokinetics of the fixed‐ratio combination IDegLira is similar to that of its individual components.

Copper metal is a promising anode in aqueous batteries due to its low price, noble reaction potential (0.34 V), high theoretical specific capacity, abundance and chemical stability. However, only a few copper ion storage materials have been reported. Herein, layered vanadium pentoxide is chosen to store copper ions for the first time. Ex situ XRD reveals a unique two phase transition process during cycling. The V2O5 electrode shows stable copper ion storage performance. It delivers 91.9 mAh g−1 for the first cycle with a cycle life of as high as 4000 cycles at 1.0 A g−1. This work provides an intriguing copper ion storage material and expands the available options of electrode materials for copper ion storage.

Speech signals involve speakers’ emotional states and language information, which is very important for human–computer interaction that recognizes speakers’ emotions. Feature selection is a common method for improving recognition accuracy. In this paper, we propose a multi-objective optimization method based on differential evolution (MODE-NSF) that maximizes recognition accuracy and minimizes the number of selected features (NSF). First, the Mel-frequency cepstral coefficient (MFCC) features and pitch features are extracted from speech signals. Then, the proposed algorithm implements feature selection where the NSF guides the initialization, crossover, and mutation of the algorithm. We used four English speech emotion datasets, and K-nearest neighbor (KNN) and random forest (RF) classifiers to validate the performance of the proposed algorithm. The results illustrate that MODE-NSF is superior to other multi-objective algorithms in terms of the hypervolume (HV), inverted generational distance (IGD), Pareto optimal solutions, and running time. MODE-NSF achieved an accuracy of 49% using eNTERFACE05, 53% using the Ryerson audio-visual database of emotional speech and song (RAVDESS), 76% using Surrey audio-visual expressed emotion (SAVEE) database, and 98% using the Toronto emotional speech set (TESS). MODE-NSF obtained good recognition results, which provides a basis for the establishment of emotional models.

The automatic identification of emotions from speech holds significance in facilitating interactions between humans and machines. To improve the recognition accuracy of speech emotion, we extract mel-frequency cepstral coefficients (MFCCs) and pitch features from raw signals, and an improved differential evolution (DE) algorithm is utilized for feature selection based on K-nearest neighbor (KNN) and random forest (RF) classifiers. The proposed multivariate DE (MDE) adopts three mutation strategies to solve the slow convergence of the classical DE and maintain population diversity, and employs a jumping method to avoid falling into local traps. The simulations are conducted on four public English speech emotion datasets: eNTERFACE05, Ryerson Audio-Visual Database of Emotional Speech and Song (RAVDESS), Surrey Audio-Visual Expressed Emotion (SAEE), and Toronto Emotional Speech Set (TESS), and they cover a diverse range of emotions. The MDE algorithm is compared with PSO-assisted biogeography-based optimization (BBO_PSO), DE, and the sine cosine algorithm (SCA) on emotion recognition error, number of selected features, and running time. From the results obtained, MDE obtains the errors of 0.5270, 0.5044, 0.4490, and 0.0420 in eNTERFACE05, RAVDESS, SAVEE, and TESS based on the KNN classifier, and the errors of 0.4721, 0.4264, 0.3283 and 0.0114 based on the RF classifier. The proposed algorithm demonstrates excellent performance in emotion recognition accuracy, and it finds meaningful acoustic features from MFCCs and pitch.

Rice blast is a worldwide fungal disease that poses a threat to food security. Fungicide treatment is one of the most effective methods to control rice blast disease. However, the emergence of fungicide tolerance hampers the control efforts against rice blast. ATP-binding cassette (ABC) transporters have been found to be crucial in multidrug tolerance in various phytopathogenic fungi. This study investigated the association between polymorphisms in 50 ABC transporters and pyraclostrobin sensitivity in 90 strains of rice blast fungus. As a result, we identified MoABC-R1, a gene associated with fungicide tolerance. MoABC-R1 belongs to the ABCC-type transporter families. Deletion mutants of MoABC-R1, abc-r1, exhibited high sensitivity to pyraclostrobin at the concentration of 0.01 μg/mL. Furthermore, the pathogenicity of abc-r1 was significantly diminished. These findings indicate that MoABC-R1 not only plays a pivotal role in fungicide tolerance but also regulates the pathogenicity of rice blast. Interestingly, the combination of MoABC-R1 deletion with fungicide treatment resulted in a three-fold increase in control efficiency against rice blast. This discovery highlights MoABC-R1 as a potential target gene for the management of rice blast.

BackgroundWBP216 is a novel human immunoglobulin G1 (IgG1) monoclonal antibody for interleukin (IL)-6. We aimed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single ascending dose (SAD) of WBP216 in patients with rheumatoid arthritis (RA).MethodsIn this double-blind, placebo-controlled, SAD, phase Ia study, patients with RA were randomized in a 3:1 (Group A1, 10 mg) and 6:2 (Group A2, 30 mg; Group A3, 75 mg; Group A4, 150 mg; Group A5, 300 mg) ratios to receive either ascending doses of WBP216 or placebo subcutaneously. The primary endpoint was the incidence of adverse events (AEs), while the secondary endpoints were characterization of PK, PD, and immunogenicity of WBP216 and the exploratory endpoints included improvements in RA clinical metrics. All statistical analyses were performed using SAS® version 9.2.ResultsA total of 41 subjects (34 females and 7 males) were enrolled in the study. WBP216 was well tolerated in all doses (10-300 mg). Most treatment-emergent AEs (TEAEs; 97.6%) were of grade 1 severity and resolved without any treatment. No subjects experienced TEAEs leading to withdrawal or death during the study. An increase in serum concentration and total IL-6 from baseline was observed, while a substantial decrease in high-sensitivity C-reactive protein (hs-CRP) and erythrocyte sedimentation rate (ESR) was observed in all the WBP216 groups. Anti-drug antibodies were detected in only one subject after dosing, indicating an acceptable immunogenicity profile. Limited ACR20 and ACR50 response was observed in the WBP216 groups and no response in the placebo group.ConclusionWBP216 demonstrated a good safety profile and evidence of potential efficacy in the treatment of patients with RA.Clinical trial registrationhttp://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier CTR20170306.

This paper describes the construction and application of an easily assembled electrochemical probe for testing the corrosion of archaeological metals in situ. The probe tip opens a gas-guiding groove to effectively solve the problem of random diffusion of electrolyte solution onto a rusted or patinated surface. After assessing the differences in EIS curves from this probe and a conventional flat cell, a bronze coin of the Northern Song Dynasty with a diameter of 2.5 cm was successfully studied using a 28-point mapping mode. The overall corrosion state of the bronze coin was assessed by fitting the charge transfer resistance (Rct) and rust resistance (Rr) as representative parameters. This is beneficial for providing clear guidance on the protection of targeted micro-areas of metal heritage objects, with broad application prospects in the field of monitoring rusted metal corrosion.

Murine models of long-bone fracture, stress fracture, and cortical defect are used to discern the cellular and molecular mediators of intramembranous and endochondral bone healing. Previous work has shown that Osterix (Osx+) and Dentin Matrix Protein-1 (DMP1+) lineage cells and their progeny contribute to injury-induced woven bone formation during femoral fracture, ulnar stress fracture, and tibial cortical defect repair. However, the contribution of pre-existing versus newly-derived Osx+ and DMP1+ lineage cells in these murine models of bone injury is unclear. We addressed this knowledge gap by using male and female 12-week-old, tamoxifen-inducible Osx Cre_ERT2 and DMP1 Cre_ERT2 mice harboring the Ai9 TdTomato reporter allele. To trace pre-existing Osx+ and DMP1+ lineage cells, tamoxifen (TMX: 100 mg/kg gavage) was given in a pulse manner (three doses, 4 weeks before injury), while to label pre-existing and newly-derived lineage Osx+ and DMP1+ cells, TMX was first given 2 weeks before injury and continuously (twice weekly) throughout healing. TdTomato positive (TdT+) cell area and cell fraction were quantified from frozen histological sections of injured and uninjured contralateral samples at times corresponding with active woven bone formation in each model. We found that in uninjured cortical bone tissue, Osx Cre_ERT2 was more efficient than DMP1 Cre_ERT2 at labeling the periosteal and endosteal surfaces, as well as intracortical osteocytes. Pulse-labeling revealed that pre-existing Osx+ lineage and their progeny, but not pre-existing DMP1+ lineage cells and their progeny, significantly contributed to woven bone formation in all three injury models. In particular, these pre-existing Osx+ lineage cells mainly lined new woven bone surfaces and became embedded as osteocytes. In contrast, with continuous dosing, both Osx+ and DMP1+ lineage cells and their progeny contributed to intramembranous woven bone formation, with higher TdT+ tissue area and cell fraction in Osx+ lineage versus DMP1+ lineage calluses (femoral fracture and ulnar stress fracture). Similarly, Osx+ and DMP1+ lineage cells and their progeny significantly contributed to endochondral callus regions with continuous dosing only, with higher TdT+ chondrocyte fraction in Osx+versus DMP1+ cell lineages. In summary, pre-existing Osx+ but not DMP1+ lineage cells and their progeny make up a significant amount of woven bone cells (particularly osteocytes) across three preclinical models of bone injury. Therefore, Osx+ cell lineage modulation may prove to be an effective therapy to enhance bone regeneration.

Abstract QseC, a histidine sensor kinase of the QseBC two-component system, acts as a global regulator of bacterial stress resistance, biofilm formation, and virulence. The function of QseC in some bacteria is well understood, but not in Pasteurella multocida. We found that deleting qseC in P. multocida serotype A:L3 significantly down-regulated bacterial virulence. The mutant had significantly reduced capsule production but increased resistance to oxidative stress and osmotic pressure. Deleting qseC led to a significant increase in qseB expression. Transcriptome sequencing analysis showed that 1245 genes were regulated by qseC, primarily those genes involved in capsule and LPS biosynthesis and export, biofilm formation, and iron uptake/utilization, as well as several immuno-protection related genes including ompA, ptfA, plpB, vacJ, and sodA. In addition to presenting strong immune protection against P. multocida serotypes A:L1 and A:L3 infection, live ΔqseC also exhibited protection against P. multocida serotype B:L2 and serotype F:L3 infection in a mouse model. The results indicate that QseC regulates capsular production and virulence in P. multocida. Furthermore, the qseC mutant can be used as an attenuated vaccine against P. multocida strains of multiple serotypes.

Background: Malignant melanoma is an aggressive disease. Tunlametinib (HL-085) is a potent, selective, and orally bioavailable MEK1/2 inhibitor. The objective of this study was to determine the pharmacokinetics (PK) of tunlametinib and its main metabolite M8 in patients with NRAS-mutant melanoma following a single dose and multiple doses in a phase I safety and PK study.Methods: A multiple-center phase I study was performed in patients with melanoma including dose-escalation phase and dose-expansion phase. PK following a single oral dose and multiple doses of 0.5–18 mg twice daily was assessed.Results: A total of 30 participants were included in the dose escalation phase and then 11 patients were included in the dose-expansion phase (12 mg twice daily). Tunlametinib plasma concentration rapidly increased after dosing, with a Tmax of 0.5–1 h. Mean elimination half-life (t1/2) was dose-independent and had a range from 21.84 to 34.41 h. Mean apparent clearance (CL/F) and distribution volume (V/F) were 28.44–51.93 L/h and 1199.36–2009.26 L, respectively. The average accumulation ratios of AUC and Cmax after the multiple administration of tunlametinib were 1.64–2.73 and 0.82–2.49, respectively. Tunlametinib was rapidly transformed into the main metabolite M8 and M8 reached the peak concentration about 1 h after administration. Mean t1/2 of M8 was 6.1–33.54 h. The body exposure of M8 in plasma was 36%–67% of that of tunlametinib. There were general dose-proportional increases in maximum concentration (Cmax) and area under the curve (AUC) of tunlametinib and M8 both in the single dose phase and in the multiple doses phase.Conclusion: Tunlametinib was absorbed rapidly and eliminated at a medium speed after drug withdrawal. Pharmacokinetic body exposure increased in general dose-proportional manner from 0.5 mg up to 18 mg. Slight accumulation was found after multiple oral doses. The pharmacokinetics of tunlametinib and its metabolite suggest that twice daily dosing is appropriate for tunlametinib.

Feature selection is a widely utilized technique in educational data mining that aims to simplify and reduce the computational burden associated with data analysis. However, previous studies have overlooked the high costs involved in acquiring certain types of educational data. In this study, we investigate the application of a multi-objective gray wolf optimizer (GWO) with cost-sensitive feature selection to predict students’ academic performance in college English, while minimizing both prediction error and feature cost. To improve the performance of the multi-objective binary GWO, a novel position update method and a selection mechanism for a, b, and d are proposed. Additionally, the adaptive mutation of Pareto optimal solutions improves convergence and avoids falling into local traps. The repairing technique of duplicate solutions expands population diversity and reduces feature cost. Experiments using UCI datasets demonstrate that the proposed algorithm outperforms existing state-of-the-art algorithms in hypervolume (HV), inverted generational distance (IGD), and Pareto optimal solutions. Finally, when predicting the academic performance of students in college English, the superiority of the proposed algorithm is again confirmed, as well as its acquisition of key features that impact cost-sensitive feature selection.

The concise and highly convergent synthesis of the isodityrosine unit of seongsanamide A–D and its derivatives bearing a diaryl ether moiety is described. In this work, the synthetic strategy features palladium-catalyzed C(sp3)–H functionalization and a Cu/ligand-catalyzed coupling reaction. We report a practical protocol for the palladium-catalyzed mono-arylation of β-methyl C(sp3)–H of an alanine derivative bearing a 2-thiomethylaniline auxiliary. The reaction is compatible with a variety of functional groups, providing practical access to numerous β-aryl-α-amino acids; these acids can be converted into various tyrosine and dihydroxyphenylalanine (DOPA) derivatives. Then, a CuI/N,N-dimethylglycine-catalyzed arylation of the already synthesized DOPA derivatives with aryl iodides is described for the synthesis of isodityrosine derivatives.

AK111 is an innovative IL-17A antibody, presenting high affinity to IL-17A and showing similar pharmacokinetic (PK) characteristics to those of typical immunoglobulin (Ig) G1 antibodies. To optimize the dosage regimen for phase 2/3 clinical trials, PK and pharmacodynamics (PD) of AK111 were first characterized in Chinese moderate-to-severe plaque psoriasis patients in a phase 1b study. AK111 PK serum sample and Psoriasis Area and Severity Index (PASI) score data were collected from 48 moderate-to-severe psoriasis patients in this study. Non-linear mixed-effects modeling was used for the population PK/PD analysis. A one-compartment model with a first-order absorption and a first-order elimination best described the PK behavior of AK111. The apparent systemic clearance was 0.182 L/day, and the central volume was 6.65 L. The exposure–response relationship was characterized using an indirect response model. The pharmacological effect of AK111 was described in the form of inhibiting the formation of psoriatic plaque, whereas placebo was quantified in the form of promoting the degradation of psoriatic skin lesions. The maximum effect of drug effect (Imax) and placebo effect (PLBmax) was 1 and 0.429, respectively. The rate constant for psoriatic plaque production (Kin) was 0.474 PASI/day and psoriatic plaque loss (Kout) was 0.024 day−1. The body surface area (BSA) affected by psoriasis was identified as a significant covariate on Kout. The simulation results confirmed that all of the predicted PASI90 response rates at week 12 were higher than 60% at 150 and 300 mg dose levels with different regimens and could reach higher than 80% at week 24. We hope this first PK/PD study of AK111 in Chinese moderate-to-severe plaque psoriasis patients will be of help in the further clinical development of AK111 and provide a reference to the dosage optimization for similar antibodies with a long half-life.

Aims: The CYP2D6*41 variant is the second or third frequent reduced function allele in Chinese with a frequency of around 3–4%, while it is the major reduced function allele in Indians, Saudi Arabians and Caucasians with frequencies of around 10–20%. The present study was designed to explore the impact of CYP2D6*41 on the metabolic activity of CYP2D6 using phenotyping methods in urine, plasma, and saliva.Methods: We used dextromethorphan as the probe drug to analyze the phenotypes of 87 subjects with CYP2D6*1/*1 (n = 22), CYP2D6*1/*2 (n = 33), CYP2D6*2/*2 (n = 4), CYP2D6*1/*41 (n = 5), CYP2D6*2/*41 (n = 3), CYP2D6*10/*41 (n = 16), and CYP2D6*5/*41 (n = 4) for CYP2D6. The ratio of parent drug to metabolite in 3 h saliva, 3 h plasma, and in 0–3 h urine was considered the metabolic ratio (MR).Results: The CYP2D6*41 allele had substantial impact on the metabolic activity of CYP2D6 regardless of the urinary, plasma, or salivary phenotyping method used. In subjects with CYP2D6*1(or *2)/*1(or *2), *1 (or *2)/*41, *10/*41 and *5/*41 (all p < 0.001), the salivary, plasma, or urinary MR value increased. The MRs in saliva, plasma, and urine displayed high correlations.Conclusion: The activity score system or the consensus activity score system, instead of the traditional phenotype classification, could predict the CYP2D6 enzyme activity more accurately. CYP2D6*41 had similar or more impact on the CYP2D6 enzyme activity as compared with CYP2D6*10. Assigning *41 a score of 0.5 and assigning *10 a score of 0.25 according to the consensus AS system should be reconsidered.

The Rafflesia Optimization Algorithm (ROA) is a new swarm intelligence optimization algorithm inspired by Rafflesia’s biological laws. It has the advantages of high efficiency and fast convergence speed, and it effectively avoids falling into local optimum. It has been used in logistics distribution center location problems, and its superiority has been demonstrated. It is applied to solve the problem of continuity, but there are many binary problems to be solved in the actual situation. Thus, we designed a binary version of ROA. We used transfer functions to change continuous values into binary values, and binary values are used to symmetrically represent the meaning of physical problems. In this paper, four transfer functions are implemented to binarize ROA so as to improve the original transfer function for the overall performance of the algorithm. In addition, on the basis of the algorithm, we further improve the algorithm by adopting a parallel strategy, which improves the convergence speed and global exploration ability of the algorithm. The algorithm is verified on 23 benchmark functions, and the parallel binary ROA has a better performance than some other existing algorithms. In the aspect of the application, this paper adopts the datasets on UCI for feature selection. The improved algorithm has higher accuracy and selects fewer features.

The mobile node location method can find unknown nodes in real time and capture the movement trajectory of unknown nodes in time, which has attracted more and more attention from researchers. Due to their advantages of simplicity and efficiency, intelligent optimization algorithms are receiving increasing attention. Compared with other algorithms, the black hole algorithm has fewer parameters and a simple structure, which is more suitable for node location in wireless sensor networks. To address the problems of weak merit-seeking ability and slow convergence of the black hole algorithm, this paper proposed an opposition-based learning black hole (OBH) algorithm and utilized it to improve the accuracy of the mobile wireless sensor network (MWSN) localization. To verify the performance of the proposed algorithm, this paper tests it on the CEC2013 test function set. The results indicate that among the several algorithms tested, the OBH algorithm performed the best. In this paper, several optimization algorithms are applied to the Monte Carlo localization algorithm, and the experimental results show that the OBH algorithm can achieve the best optimization effect in advance.

Ancient iron artifacts need to be protected with a rust layer, often stabilized by tannic acid corrosion inhibition. In humid environments, water vapor could slowly penetrate and trigger galvanic corrosion of metal artefacts. Sealing treatments are generally applied to the artefact surface to isolate water and enhance its corrosion resistance. Superhydrophobic modifications could effectively block the penetration of moisture into the interior of the artefact and provide a nice water barrier. Stearic acid with tannic acid inhibition treatment creates a superhydrophobic protective layer on the surface of rusted iron artifacts and enhances corrosion resistance effectively. Various scientific analyses and testing methods are used in this paper to evaluate the corrosion resistance of rusted surfaces after superhydrophobic modification and investigate the reaction mechanisms. The results indicate that the contact angle of the rusted surface after corrosion inhibition by tannic acid and modified by stearic acid is increased to 152.2°, which means the superhydrophobic protective layer has been successfully constructed. The C/Fe ratio of the rusted surface is increased from 0.21 to 2.10, and the characteristic diffraction peaks of O1s and Fe 2p3/2 shift toward higher binding energy. Stearic acid is combined with the corrosion product layer by chemical bonding. Chelation between rust products, tannic acid, and steric acid is effective, and the chelate is chemically stable. The superhydrophobic surface forms a lamellar wax-like layer as an air barrier to isolate liquid water, resulting in a significant decrease in corrosion current and an increase in Warburg impedance to 217.9 times the original state, with a protection efficiency of 88.3%. Tannic acid corrosion inhibition and stearic acid superhydrophobic modification have an excellent synergistic protective effect on improving the corrosion resistance of iron artifacts, resulting in better corrosion resistance of iron artifact materials. The research provides new ideas and references for the protection of ancient iron artifacts sealing.

Abstract Background Lanreotide autogel is a somatostatin analog (SSA) approved for the treatment of acromegaly in 73 countries worldwide; however, it is not yet approved in China. The aim of this study was to evaluate the efficacy and safety of lanreotide autogel compared with lanreotide 40 mg prolonged release (PR) in Chinese patients with active acromegaly. Methods LANTERN was a phase 3, randomized, open-label, non-inferiority study. Patients with active acromegaly who had undergone surgery ≥3 months prior, or were unlikely or unable to undergo surgery, were treated with lanreotide autogel 60/90/120 mg (monthly deep subcutaneous injection) or lanreotide 40 mg PR (intramuscular injection every 7, 10, or 14 days) for 32 weeks. Primary endpoint was mean change-from-baseline in age-adjusted insulin-like growth factor-1 (IGF-1) standard deviation scores (SDS) at the end-of-study. Secondary endpoints included: growth hormone (GH) levels ≤2.5 μg/L or ≤ 1.0 μg/L, ≥20% reduction in tumor volume (TV) and safety. Results In total, 128 patients were randomized and received study treatment. Lanreotide autogel was non-inferior to lanreotide 40 mg PR: treatment difference (95% CI) for IGF-1 SDS between groups was − 0.32 (− 0.74, 0.11; per protocol population) and − 0.27 (− 0.63, 0.09; intention-to-treat [ITT] population), respectively. Reductions in IGF-1 (− 6.453 vs − 7.003) and GH levels (− 9.548 μg/L vs − 13.182 μg/L), and the proportion of patients with ≥1 acromegaly symptom (− 20.3% vs − 32.5%) were observed from baseline to end-of-study in lanreotide autogel and lanreotide 40 mg PR groups, respectively. In the lanreotide autogel group, 45.5% (25/55) patients achieved ≥20% reduction in TV compared with 50.9% (25/53) in lanreotide 40 mg PR group (ITT). Safety profiles were similar in both treatment groups. Conclusions Lanreotide autogel was non-inferior to lanreotide 40 mg PR in Chinese patients with active acromegaly after 32 weeks of treatment. Trial registration Retrospectively registered on ClinicalTrials.gov: NCT02493517 (9 July 2015); prospectively registered on chinadrugtrials.org.cn: CTR20140698 (24 October 2014).

Abstract Wireless sensor network (WSN) can effectively help us monitor the surrounding environment and prevent the occurrence of some natural disasters earlier, but we can only get the information of the surrounding environment correctly if we know the locations of nodes. How to know the exact positions of nodes is a strict challenge in WSN. Intelligent computing algorithms have been developed in recent years. They easily solve complex optimization problems, especially for those that cannot be modeled mathematically. This paper proposes a novel algorithm, named parallel whale optimization algorithm (PWOA). It contains two information exchange strategies between groups, and it significantly enhances global search ability and population diversity of the original whale optimization algorithm (WOA). Also, the algorithm is adopted to optimize the localization of WSN. Twenty-three mathematical optimization functions are accustomed to verifying the efficiency and effectiveness of the novel approach. Compared with some existing intelligent computing algorithms, the proposed PWOA may reach better results.

Abstract Background BPI-9016M is a novel small-molecule inhibitor that simultaneously targets both c-Met and AXL tyrosine kinases. This phase I study aimed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of BPI-9016M in Chinese patients with advanced non-small cell lung cancer (NSCLC). Methods Over the dose range of 100 mg to 800 mg, eligible patients were administered with a single dose of 9016M tablet and received 7 days of pharmacokinetics evaluation, followed by continuous dose administration (QD dosing, 28 days). Standard “3 + 3” dose escalations were performed. Results Twenty NSCLC patients were treated. All patients experienced at least one adverse event (AE), of which treatment-related adverse events (TRAEs) were reported in 17 (85.0%) patients. The most common TRAEs were alanine transaminase (ALT) elevation (60%), bilirubin increased (40%), dysgeusia (40%), constipation (30%), hypertension (25%), and palmar-plantar erythrodysesthesia syndrome (15%). The TRAEs of grade 3 or higher during treatment were hypertension (15%), pulmonary embolism (5%), and laryngeal pain (5%). No dose-limiting toxicity (DLT) was observed, and the MTD was not reached. The median time to C max ranged from 2.0 to 3.5 h, and the plasma concentration of BPI-9016M declined rapidly after T max fitting a single-compartment model. The mean AUC0–72 h of M1 and M2-2, main metabolites of BPI-9016M, were 4.8–6.6 folds and 4.1–9.8 folds higher than that of BPI-9016M, respectively. Exposure to BPI-9016M, M1, and M2-2 reached moderate saturation at 600 mg. Among 19 evaluable patients, 1 had a partial response and 10 patients had stable disease. Conclusion BPI-9016M showed favorable safety and pharmacokinetic profiles, and no DLT was observed at doses up to 800 mg once daily. The promising antitumor activity in Chinese NSCLC patients supports further development of this tyrosine kinase inhibitor. Trial registration Clinical Trial ID: NCT02478866, registered May 21, 2015.