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Dan-Dan Li,1,&ast; Xue Yang,1,&ast; Yang Yang,2,&ast; Li-Hua Zhao,1 Tian-Tian Zhang,3 Yi-Nan Wang,1 Jian-Bin Su,1 Li-Hua Wang,4 Hai-Yan Shi3 1Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 2Department of General Practice, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 3Department of Hepatobiliary Surgery, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 4Department of Nursing, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-Hua Wang, Department of Nursing, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China, Email wlh512512@163.com Hai-Yan Shi, Department of Hepatobiliary Surgery, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China, Email 1198827119@qq.comBackground: Physical activity (PA) exerts an important influence on glycemic control in type 2 diabetes (T2D) patients. Alterations in body composition in patients with T2D may be involved in the overall pathophysiologic process, but PAs and alterations in body composition have been poorly studied.Methods: A total of 615 patients with T2D were selected by convenient sampling. The patients were investigated with the International Physical Activity Questionnaire (IPAQ-S). Moreover, biochemical indices were collected, and the progression of the body composition of the subjects was determined via dual-energy X-ray absorptiometry (DXA). The variables included lumbar bone mineral density (LSBMD), femoral neck bone mineral density (FNBMD), hip bone mineral density (HBMD), whole-body bone mineral density (TBMD), limb skeletal muscle mass index (ASMI), whole-body fat percentage (B-FAT) and trunk fat percentage (T-FAT). Moreover, the levels of physical activity (high level of physical activity [H-PA], medium level of physical activity [M-PA] and low level of physical activity [L-PA]) were divided into three groups to analyze the changes in patient body composition with changes in physical activity level.Results: One-way analysis of variance showed that β-CTX, TP1NP, HbA1c, B-FAT and T-FAT increased significantly (p< 0.05), while 25(OH)D, LSBMD, FNBMD, HBMD, TBMD and ASMI decreased significantly (p< 0.001) with the decrease of physical activity. However, there was no significant difference in serum lipids between lnHOMA-ir and lnHOMA-β (p> 0.05). Multiple linear regression model was established to gradually adjust for clinical confounding factors. It was found that physical activity level was independently positively correlated with LSBMD, FNBMD, HBMD, TBMD, and ASMI, and was independently negatively correlated with B-FAT and T-FAT in patients with type 2 diabetes.Conclusion: A lack of physical activity is an independent risk factor for decreased bone mineral density, decreased skeletal muscle content and increased fat content in patients with T2D.Keywords: type 2 diabetes, physical activity, body composition, correlation

Two novel phosphodiesterase 5 (PDE-5) inhibitors were detected in pressed candy using high-performance liquid chromatography (HPLC)-diode array detection. Following extraction with acetonitrile and sonication, the compounds were isolated and purified via semi-preparative liquid chromatography. Structural characterisation was achieved through high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) spectroscopy. The results indicate that both compounds possess identical UV absorption spectra. The molecular formulas of compounds 1 and 2 are C 23 H 32 N 4 O 4 and C 22 H 30 N 4 O 4 , respectively, each featuring a pyrimidinone benzene structure with a single methylene group (-CH 2 ) variation. As studies on these illicit compounds in functional foods have not been conducted, regulatory agencies must take note and incorporate them for the assessment of illicit additives in functional and healthcare foods.

Background: Increased glucagon levels are now recognized as a pathophysiological adaptation to counteract overnutrition in type 2 diabetes (T2D). This study aimed to elucidate the role of glucagon in peripheral nerve function in patients with T2D with different body mass indices (BMIs)., Methods: We consecutively enrolled 174 individuals with T2D and obesity (T2D/OB, BMI ≥ 28 kg/m 2 ), and 480 individuals with T2D and nonobesity (T2D/non-OB, BMI < 28 kg/m 2 ), all of whom underwent oral glucose tolerance tests to determine the area under the curve for glucagon (AUC gla ). Electromyography was utilized to assess overall composite Z-scores for latency, amplitude, and nerve conduction velocity (NCV) across all peripheral nerves, specifically examining the median, ulnar, common peroneal, posterior tibial, superficial peroneal, and sural nerves., Results: In the T2D/OB group, the AUC gla exhibited a significant correlation with the latency, amplitude and NCV of each peripheral nerve, as well as with the overall composite Z-scores for latency (r = -0.283, p < 0.001), amplitude (r = 0.295, p < 0.001), and NCV (r = 0.362, p < 0.001). In contrast, the T2D/non-OB group did not exhibit obvious correlations between the AUC gla and the overall composite Z-scores for latency (r = -0.088, p = 0.056), amplitude (r = 0.054, p = 0.251), and NCV (r = 0.116, p = 0.012). Furthermore, multivariate linear regression analyses indicated that elevated AUC gla was independently associated with a lower overall composite Z-score for latency (β = -0.304, t = -3.391, p = 0.001), as well as higher overall composite Z-scores for amplitude (β = 0.256, t = 2.630, p = 0.010) and NCV (β = 0.286, t = 3.503, p = 0.001), after adjusting for other clinical covariates within the T2D/OB group., Conclusion: Increased glucagon levels may be a potential protective factor against peripheral nerve compromise in patients with T2D and obesity., Competing Interests: Declarations. Ethics approval and consent to participate: This study received evaluation and approval from the Ethics Review Board of Affiliated Hospital 2 at Nantong University, under the reference number 2023KT228. All participants provided informed consent to take part in the study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

EED (embryonic ectoderm development) is a core subunit of the polycomb repressive complex 2 (PRC2), which senses the trimethylation of histone H3 lysine 27 (H3K27). However, its biological function in cerebellar development remains unknown. Here, we show that EED deletion from neural stem cells (NSCs) or cerebellar granule cell progenitors (GCPs) leads to reduced GCPs proliferation, cell death, cerebellar hypoplasia, and motor deficits in mice. Joint profiling of transcripts and ChIP-seq analysis in cerebellar granule cells reveals that EED regulates bunches of genes involved in cerebellar development. EED ablation exhibits overactivation of a developmental repressor long non-coding RNA H19. Importantly, an obvious H3K27ac enrichment is found at Ctcf, a trans-activator of H19, and H3K27me3 enrichment at the H19 imprinting control region (ICR), suggesting that EED regulates H19 in an H3K27me3-dependent manner. Intriguingly, H19 deletion reduces EED expression and the reprogramming of EED-mediated H3K27me3 profiles, resulting in increased proliferation, differentiation, and decreased apoptosis of GCPs. Finally, molecular and genetic evidence provides that increased H19 expression is responsible for cerebellar hypoplasia and motor defects in EED mutant mice. Thus, this study demonstrates that EED, H19 forms a negative feedback loop, which plays a crucial role in cerebellar morphogenesis and controls cerebellar development., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Objective: To investigate the clinicopathological features, prognosis and the expression of HER2 and PD-L1 in invasive stratified mucin-producing carcinoma of the cervix (ISMC). Methods: The clinicopathological data of 18 ISMC cases with radical resection of the cervix diagnosed in the Daping Hospital, Army Medical University from January 2018 to December 2023 were collected and retrospectively analyzed. PD-L1 and HER2 immunohistochemical staining and HER2 FISH were conducted. Results: The patient ages ranged from 31 to 72 years, with an average of 45 years. Approximately 8% of cervical adenocarcinoma cases in our hospital during the same period. Eleven cases were pure ISMC, and 7 cases were mixed-type ISMC, with the component of squamous cell carcinoma or usual-type adenocarcinoma. One case showed concurrent small cell neuroendocrine carcinoma (SCNEC). Three cases were diagnosed through biopsy (3/18). Five cases were of Silva pattern B and 13 cases of Silva pattern C. Three cases showed regional lymph node metastasis. Thirteen patients were disease-free at the end of the follow-up, while the ISMC patient with concurrent SCNEC developed distant metastasis. Fifteen cases (15/18) had PD-L1 expression with CPS≥1, and 7 cases (7/18) had PD-L1 TPS≥1%. One case of HER2 3+ and one case of HER2 2+ were both positive for FISH amplification; two cases HER2 1+, 14 cases HER2 0. Conclusions: Cervical ISMC is rare, has a wide spectrum of morphology, and can coexist with other types of cervical cancer. PD-L1 is positive in most of the ISMC cases, while HER2 is amplified or lowly expressed in a small portion of them. Thus, it is possible to treat ISMC patients with therapies targeting PD-L1 and therapy targeting HER2.

Ten new B-ring aromatized 6/6/6-tricyclic dearomatized benzocogeijerene-based meroterpenoids with unusual methyl 1,2-shift or demethylation (2-9b), and two new geranylquinol derivatives (1 and 10), together with two known compounds (11 and 12), were isolated from the roots of Arnebia euchroma. Their structures were elucidated by extensive spectroscopic methods, X-ray diffraction crystallography, and ECD calculations. The plausible biosynthetic pathways including the unusual methyl 1,2-shfit and demethylation for B-ring aromatized 6/6/6-tricyclic meroterpenoids were discussed. Compounds 1, 2, 5, 6, 11, and 12 showed significant cardioprotective activities comparable to diltiazem against isoprenaline (ISO)-induced H9C2 cell damage in vitro. Compound 11 probably exerted heart-protective effect on ISO-induced H9C2 cells by modulating the PI3K-AKT-mTOR pathway, reducing excessive autophagy, and decreasing myocardial apoptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Prolactin-releasing peptide (PrRP) is an RF-amide neuropeptide that binds and activates its cognate G protein-coupled receptor, prolactin-releasing peptide receptor (PrRPR), also known as GPR10. PrRP and PrRPR are highly conserved across mammals and involved in regulating a range of physiological processes, including stress response, appetite regulation, pain modulation, cardiovascular function, and potentially reproductive functions. Here we present cryo-electron microscopy structures of PrRP-bound PrRPR coupled to G q or G i heterotrimer, unveiling distinct molecular determinants underlying the specific recognition of the ligand's C-terminal RF-amide motif. We identify a conserved polar pocket that accommodates the C-terminal amide shared by RF-amide peptides. Structural comparison with neuropeptide Y receptors reveals both similarities and differences in engaging the essential RF/RY-amide motifs. Our findings demonstrate the general mechanism governing RF-amide motif recognition by PrRPR and RF-amide peptide receptors, and provide a foundation for elucidating activation mechanisms and developing selective drugs targeting this important peptide-receptor system., (© 2024. The Author(s).)

Objective: To investigate the diagnostic efficacy of the clinical ultrasound imaging model, ultrasonographic radiomics model, and comprehensive model based on ultrasonographic radiomics for the differentiation of small clear cell Renal Cell Carcinoma (ccRCC) and Renal Angiomyolipoma (RAML)., Methods: The clinical, ultrasound, and contrast-enhanced CT(CECT) imaging data of 302 small renal tumors (maximum diameter ≤ 4cm) patients in Tianjin Medical University Cancer Institute and Hospital from June 2018 to June 2022 were retrospectively analyzed, with 182 patients of ccRCC and 120 patients of RAML. The ultrasound images of the largest diameter of renal tumors were manually segmented by ITK-SNAP software, and Pyradiomics (v3.0.1) module in Python 3.8.7 was applied to extract ultrasonographic radiomics features from ROI segmented images. The patients were randomly divided into training and internal validation cohorts in the ratio of 7:3. The Random Forest algorithm of the Sklearn module was applied to construct the clinical ultrasound imaging model, ultrasonographic radiomics model, and comprehensive model. The efficacy of the prediction models was verified in an independent external validation cohort consisting of 69 patients, from 230 small renal tumor patients in two different institutions. The Delong test compared the predictive ability of three models and CECT. Calibration Curve and clinical Decision Curve Analysis were applied to evaluate the model and determine the net benefit to patients., Results: 491 ultrasonographic radiomics features were extracted from 302 small renal tumor patients, and 9 ultrasonographic radiomics features were finally retained for modeling after regression and dimensionality reduction. In the internal validation cohort, the area under the curve (AUC), sensitivity, specificity, and accuracy of the clinical ultrasound imaging model, ultrasonographic radiomics model, comprehensive model, and CECT were 0.75, 76.7%, 60.0%, 70.0%; 0.80, 85.6%, 61.7%, 76.0%; 0.88, 90.6%, 76.7%, 85.0% and 0.90, 92.6%, 88.9%, 91.1%, respectively. In the external validation cohort, AUC, sensitivity, specificity, and accuracy of the three models and CECT were 0.73, 67.5%, 69.1%, 68.3%; 0.89, 86.7%, 80.0%, 83.5%; 0.90, 85.0%, 85.5%, 85.2% and 0.91, 94.6%, 88.3%, 91.3%, respectively. The DeLong test showed no significant difference between the clinical ultrasound imaging model and the ultrasonographic radiomics model (Z=-1.287, P=0.198). The comprehensive model showed superior diagnostic performance than the ultrasonographic radiomics model (Z=4. 394, P<0.001) and the clinical ultrasound imaging model (Z=4. 732, P<0.001). Moreover, there was no significant difference in AUC between the comprehensive model and CECT (Z=-0.252, P=0.801). Both in the internal and external validation cohort, the Calibration Curve and Decision Curve Analysis showed a better performance of the comprehensive model., Conclusion: It is feasible to construct an ultrasonographic radiomics model for distinguishing small ccRCC and RAML based on ultrasound images, and the diagnostic performance of the comprehensive model is superior to the clinical ultrasound imaging model and ultrasonographic radiomics model, similar to that of CECT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Zhang, Zhao, Mao, Mu, Wang, Pang, Yang, Wei and Liu.)

Somatostatin receptor 5 (SSTR5) is an important G protein-coupled receptor and drug target for neuroendocrine tumors and pituitary disorders. This study presents two high-resolution cryogenicelectron microscope structures of the SSTR5-G i complexes bound to the cyclic neuropeptide agonists, cortistatin-17 (CST17) and octreotide, with resolutions of 2.7 Å and 2.9 Å, respectively. The structures reveal that binding of these peptides causes rearrangement of a "hydrophobic lock", consisting of residues from transmembrane helices TM3 and TM6. This rearrangement triggers outward movement of TM6, enabling Gα i protein engagement and receptor activation. In addition to hydrophobic interactions, CST17 forms conserved polar contacts similar to somatostatin-14 binding to SSTR2, while further structural and functional analysis shows that extracellular loops differently recognize CST17 and octreotide. These insights elucidate agonist selectivity and activation mechanisms of SSTR5, providing valuable guidance for structure-based drug development targeting this therapeutically relevant receptor., Competing Interests: Competing interests statement:The authors declare no competing interest.

This study aimed to explore the mediating effects of ADL and depression on the relationship between sleep quality and HRQOL among older people in rural China, while also exploring the moderating impact of loneliness. The study gathered data from a household survey conducted among 1587 Chinese rural older adults (mean age = 73.63 years). The collected data was analyzed using SPSS version 23.0 software (IBM, New York, USA) and the PROCESS macro version 4.0 program. The findings indicated a significant correlation between sleep quality, ADL, depression, loneliness and HRQOL. ADL and depression exhibited a chain mediation effect on the relationship between sleep quality and HRQOL. Notably, the association between sleep quality and HRQOL was entirely mediated by ADL and depression. Additionally, loneliness acted as a moderator in the relationship between ADL and HRQOL. The findings of this study suggest that interventions focusing on sleep quality should prioritize strategies for enhancing older adults' ADL and depression as integral components of promoting older adults' HRQOL., (© 2024. The Author(s).)

Objective: To investigate the clinical, radiological, and pathological features of anaplastic gangliogliomas (AGGs) and to determine whether these tumors represent a distinct entity. Methods: Consecutive 667 cases of ganglioglioma (GG) diagnosed at the Xuanwu Hospital, Capital Medical University, Beijing, China between January 2015 and July 2023 were screened. Among these cases, 9 pathologically confirmed AGG cases were identified. Their clinical, radiological, treatment, and outcome data were analyzed retrospectively. Most of the tumor samples were subject to next-generation sequencing, while a subset of them were subject to DNA methylation profiling. Results: Among the 9 patients, there were five males and four females, with a median age of 8 years. Epileptic seizures (5/9) were the most frequently presented symptom. Radiological examinations showed three types of radiological manifestations: four cases showed abnormal MRI signals with no significant mass effects and mild enhancement; two cases demonstrated a mixed solid-cystic density lesion with peritumoral edema, which showed significant heterogeneous enhancement and obvious mass effects, and one case displayed cystic cavity formation with nodules on MRI, which showed evident enhancements. All cases exhibited mutations that were predicted to activate the MAP kinase signaling pathway, including seven with BRAF p.V600E mutation and two with NF1 mutation. Five AGGs with mutations involving the MAP kinase signaling pathway also had concurrent mutations, including three with CDKN2A homozygous deletion, one with a TERT promoter mutation, one with a H3F3A mutation, and one with a PTEN mutation. Conclusions: AGG exhibits a distinct spectrum of pathology, genetic mutations and clinical behaviors, differing from GG. Given these characteristics suggest that AGG may be a distinct tumor type, further expansion of the case series is needed. Therefore, a comprehensive integration of clinical, histological, and molecular analyses is required to correctly diagnose AGG. It will also help guide treatments and prognostication.

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 and MCHR2 receptors, both of which are class A G protein-coupled receptors. MCHR1 predominately couples to inhibitory G protein, G i/o , and MCHR2 can only couple to G q/11 . Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with G i and MCH-activated MCHR2 with G q at the global resolutions of 3.01 Å and 2.40 Å, respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration when bound to both receptors. A central arginine from the LGRVY core motif between the two cysteines of MCH penetrates deeply into the transmembrane pocket, triggering receptor activation. Integrated with mutational and functional insights, our findings elucidate the molecular underpinnings of ligand recognition and MCH receptor activation and offer a structural foundation for targeted drug design., (© 2024. The Author(s).)

As a continuous flow investigation of novel pesticides from natural quinolizidine alkaloids, the chemical compositions of the seeds of Sophora alopecuroides were thoroughly researched. Fifteen new aloperine-type alkaloids ( 1 - 15 ) as well as six known aloperine-type alkaloids ( 16 - 21 ) were obtained from the extract of S. alopecuroides . The structures of 1 - 21 were confirmed via HRESIMS, NMR, UV, IR, ECD calculations, and X-ray diffraction. The antiviral activities of 1 - 21 against tobacco mosaic virus (TMV) were detected following the improved method of half-leaf. Compared with ningnanmycin (protective: 69.7% and curative: 64.3%), 15 exhibited excellent protective (71.7%) and curative (64.6%) activities against TMV. Further biological studies illustrated that 15 significantly inhibited the transcription of the TMV- CP gene and increased the activities of polyphenol oxidase (PPO), peroxidase (POD), superoxide dismutase (SOD), and phenylalanine ammonia-lyase (PAL). The antifungal activities of 1 - 21 against Phytophythora capsica , Botrytis cinerea , Alternaria alternata , and Gibberella zeae were screened according to a mycelial inhibition test. Compound 13 displayed excellent antifungal activity against B. cinerea (EC 50 : 7.38 μg/mL). Moreover, in vitro antifungal mechanism studies displayed that 13 causes accumulation of reactive oxygen species and finally leads to mycelia cell membrane damage and cell death in vitro .

Background: Modifying diet is crucial for diabetes and complication management. Numerous studies have shown that adjusting eating habits to align with the circadian rhythm may positively affect metabolic health. However, eating midpoint, eating duration, and their associations with diabetic kidney disease (DKD) are poorly understood., Methods: The National Health and Nutrition Examination Survey (2013-2020) was examined for information on diabetes and dietary habits. From the beginning and ending times of each meal, we calculated the eating midpoint and eating duration. Urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g and/or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 were the specific diagnostic criteria for DKD., Results: In total, details of 2194 subjects with diabetes were collected for analysis. The overall population were divided into four subgroups based on the eating midpoint quartiles. The prevalence of DKD varied noticeably (P = 0.037) across the four categories. When comparing subjects in the second and fourth quartiles of eating midpoint to those in the first one, the odds ratios (ORs) of DKD were 1.31 (95% CI, 1.03 to 1.67) and 1.33 (95% CI, 1.05 to 1.70), respectively. And after controlling for potential confounders, the corresponding ORs of DKD in the second and fourth quartiles were 1.42 (95% CI, 1.07 to 1.90) and 1.39 (95% CI, 1.04 to 1.85), respectively., Conclusions: A strong correlation was found between an earlier eating midpoint and a reduced incidence of DKD. Eating early in the day may potentially improve renal outcomes in patients with diabetes., (© 2024. The Author(s).)

As part of our ongoing investigation of natural bioactive substances from the genus Thermopsis of the tribe Fabaceae for agricultural protection, the chemical constituents of the herb Thermopsis lupinoides were systematically investigated, which led to the isolation of 39 quinolizidine alkaloids (QAs) ( 1 - 39 ), including 14 new QAs ( 1 - 14 ) and 14 isoflavones ( 40 - 53 ). Their structures were elucidated through comprehensive spectroscopic data analysis (IR, UV, NMR, HRESIMS), ECD calculations, and X-ray crystallography. The antitomato spotted wilt virus (TSWV) and antifungal (against Botrytis cinerea , Gibberella zeae , Phytophythora capsica , and Alternaria alternata ) and insecticidal (against Aphis fabae and Tetranychus urticae ) activities of the isolated compounds were screened using the lesion counting method, mycelial inhibition assay, and spray method, respectively. The bioassay results showed that 34 exhibited excellent protective activity against TSWV, with an EC 50 value of 36.04 μg/mL, which was better than that of the positive control, ningnanmycin (86.03 μg/mL). The preliminary mechanistic exploration illustrated that 34 induced systemic acquired resistance in the host plant by acting on the salicylic acid signaling pathway. Moreover, 1 showed significant antifungal activity against B. cinerea (EC 50 value of 20.83 μg/mL), while 2 exhibited good insecticidal activity against A. fabae (LC 50 value of 24.97 μg/mL). This research is promising for the invention of novel pesticides from QAs with high efficiency and satisfactory ecological compatibility.

Root hairs are tubular-shaped outgrowths of epidermal cells essential for plants acquiring water and nutrients from the soil. Despite their importance, the growth of root hairs is finite. How this determinate growth is precisely regulated remains largely unknown. Here we identify LONG ROOT HAIR (LRH), a GYF domain-containing protein, as a unique repressor of root hair growth. We show that LRH inhibits the association of eukaryotic translation initiation factor 4Es (eIF4Es) with the mRNA of ROOT HAIR DEFECTIVE6-LIKE4 (RSL4) that encodes the master regulator of root hair growth, repressing RSL4 translation and thus root hair elongation. RSL4 in turn directly transactivates LRH expression to maintain a proper LRH gradient in the trichoblasts. Our findings reveal a previously uncharacterized LRH-RSL4 feedback regulatory loop that limits root hair growth, shedding new light on the mechanism underlying the determinate growth of root hairs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

To date, the benefit of intravenous thrombolysis is confined to within 4.5 h of onset for acute ischemic stroke (AIS) without advanced neuroimaging selection. The current trial aimed to investigate the safety and efficacy of intravenous tenecteplase (TNK) plus Dl-3-n-Butylphthalide (NBP) in AIS within 4.5 to 6 h of onset. In this randomized, multicenter trial, eligible AIS patients were randomly assigned to receive intravenous TNK (0.25 mg/kg) plus NBP or NBP within 4.5 to 6 h of onset. The primary endpoint was symptomatic intracranial hemorrhage (sICH). Secondary endpoints included excellent functional outcome defined as a modified Rankin Scale score of 0 to 1 at 90 days. 100 patients diagnosed by non-contrast CT (NCCT) were enrolled, including 50 in TNK group and 50 in control group. sICH occurred in 2.0% (1/50) in TNK group and 0.0% (0/49) in control group with no difference (unadjusted P = 0.998). The proportion of excellent functional outcome was 77.6% (38/49) in TNK group and 69.4% (34/49) in control group with non-significance (absolute difference 8.2%, P = 0.36). A significant decrease in NIHSS score at 24 h (P = 0.004) and more early neurological improvement (20.4% vs 4.1%; P = 0.026) was observed in TNK vs control group, but there was no difference in other secondary outcomes. This phase 2 study suggests that intravenous TNK with adjuvant NBP seems safe, feasible and may improve early neurological function in AIS patients within 4.5 to 6 h of symptom onset selected using NCCT.Clinical Trials Registration: This trial was registered with ClinicalTrials.gov (NCT05189509)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Thermally conductive materials (TCMs) are highly desirable for thermal management applications to tackle the "overheating" concerns in the electronics industry. Despite recent progress, the development of high performance TCMs integrated with an in-plane thermal conductivity (TC) higher than 50.0 W (m K) -1 and a through-plane TC greater than 10.0 W (m K) -1 is still challenging. Herein, self-standing liquid metal@boron nitride (LM@BN) bulks with ultrahigh in-plane TC and through-plane TC were reported for the first time. In the LM@BN bulks, LM could serve as a bonding and thermal linker among the oriented BN platelets, thus remarkably accelerating heat transfer across the whole system. Benefiting from the formation of a unique structure, the LM@BN bulk achieved an ultrahigh in-plane TC of 82.2 W (m K) -1 and a through-plane TC of 20.6 W (m K) -1 , which were among the highest values ever reported for TCMs. Furthermore, the LM@BN bulks exhibited superior compressive and leakage-free performances, with a high compressive strength (5.2 MPa) and without any LM leakage even after being crushed. It was also demonstrated that the excellent TCs of the LM@BN bulks made them effectively cool high-power light emitting diode modules. This work opens up one promising pathway for the development of high-performance TCMs for thermal management in the electronics industry.

This article focuses on the robust H ∞ synchronization of two types of coupled reaction-diffusion neural networks with multiple state and spatial diffusion couplings by utilizing pinning adaptive control strategies. First, based on the Lyapunov functional combined with inequality techniques, several sufficient conditions are formulated to ensure H ∞ synchronization for these two networks with parameter uncertainties. Moreover, node-based pinning adaptive control strategies are devised to address the robust H ∞ synchronization problem. In addition, some criteria of H ∞ synchronization for these two networks under parameter uncertainties are developed via edge-based pinning adaptive controllers. Finally, two numerical examples are presented to verify our results.

Background: Hepatocellular carcinoma (HCC) is one of the most frequent cancers and the main cause of cancer-related death worldwide. Ectopic HCC, an extremely rare type of HCC, exhibits a wide range of clinical signs and radiographic features, making preoperative identification challenging., Case Summary: A 47-year-old man underwent routine abdominal color ultrasonography, which identified an asymptomatic tumor in the left upper abdomen. The patient had no history of hepatitis, did not drink alcohol, and had no family history of cancer. Abdominal contrast-enhanced computed tomography (CT) revealed a heterogeneously enhanced lesion between the spleen and stomach that had invaded the diaphragm, with blood supplied by the left inferior phrenic artery. The patient underwent laparoscopic surgery, and HCC was identified by postoperative pathology. Additionally, specific immunohistochemical staining was performed to assess the molecular biological characteristics of the HCC. The patient underwent two rounds of hepatic arterial interventional chemotherapy after surgery. Abdominal plain and enhanced magnetic resonance imaging and lung CT 3 mo postoperatively revealed no signs of local recurrence or distant metastasis., Conclusion: This asymptomatic ectopic HCC case described achieved an excellent result due to early detection, radical resection, and systematic surveillance., Competing Interests: Conflict-of-interest statement: All the authors declare that they have no conflict of interest to disclose., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets 1-5 . Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development 6,7 . Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (G s ) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with G s . The PCO371-binding site is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. The residues that make up the PCO371-binding pocket are conserved in class B GPCRs, and a single alteration in PTH2R and two residue alterations in GLP1R convert these receptors to respond to PCO371. Functional assays reveal that PCO371 is a G-protein-biased agonist that is defective in promoting PTH1R-mediated arrestin signalling. Together, these results uncover a distinct binding site for designing small-molecule agonists for PTH1R and possibly other members of the class B GPCRs and define a receptor conformation that is specific only for G-protein activation but not arrestin signalling. These insights should facilitate the design of distinct types of class B GPCR small-molecule agonist for various therapeutic indications., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The microbiomes of cesarean-born infants differ from vaginally delivered infants and are associated with increased disease risks. Vaginal microbiota transfer (VMT) to newborns may reverse C-section-related microbiome disturbances. Here, we evaluated the effect of VMT by exposing newborns to maternal vaginal fluids and assessing neurodevelopment, as well as the fecal microbiota and metabolome. Sixty-eight cesarean-delivered infants were randomly assigned a VMT or saline gauze intervention immediately after delivery in a triple-blind manner (ChiCTR2000031326). Adverse events were not significantly different between the two groups. Infant neurodevelopment, as measured by the Ages and Stages Questionnaire (ASQ-3) score at 6 months, was significantly higher with VMT than saline. VMT significantly accelerated gut microbiota maturation and regulated levels of certain fecal metabolites and metabolic functions, including carbohydrate, energy, and amino acid metabolisms, within 42 days after birth. Overall, VMT is likely safe and may partially normalize neurodevelopment and the fecal microbiome in cesarean-delivered infants., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To explore the characteristics of orthokeratology lenses designed for small correction zones and their effectiveness and safety in long-term prevention and control of myopia in children and adolescents. Methods: It was a prospective cohort study that included myopic children and adolescents who received corneal reshaping treatment at the Qingdao Eye Hospital of Shandong First Medical University between January 2019 and May 2020. The patients were randomly divided into two groups using computer-generated randomization, and were fitted with corneal reshaping lenses with small treatment zones and conventional designs, respectively. The uncorrected visual acuity, best-corrected visual acuity, refractive error, and axial length were measured before and after 6, 12, and 18 months of wearing the lenses. Corneal topography with the Pentacam was also performed, and the area and diameter of the corneal treatment zone were calculated using the Matlab software. Results: A total of 60 myopic patients (60 eyes) were enrolled, including 29 males and 31 females, with an age of (10.40±1.01) years and a spherical equivalent of (-2.88±0.42) D. There were 30 cases in the small correction zone group and 30 cases in the conventional group. There was no significant difference in uncorrected visual acuity and spherical equivalent between the two groups at each time point after treatment. The axial growth in the conventional group was (0.16±0.09) mm at 6 months after treatment, (0.28±0.17) mm at 12 months, and (0.37±0.20) mm at 18 months, whereas in the small treatment zone group it was (0.06±0.05) mm, (0.12±0.10) mm, and (0.18±0.14) mm, respectively. The myopia progression rate in the small treatment zone group was only 37.50%, 42.86%, and 48.64% of the conventional group at 6, 12, and 18 months, respectively. Corneal topography showed that the treatment area in the conventional group was (6.98±0.89) mm², while in the small treatment zone group it decreased by 23.2% [(5.36±0.73) mm²] ( P <0.05). Correlation analysis revealed that the axial increase after 18 months of lens wearing was negatively correlated with the age before lens wearing ( P <0.05), positively correlated with the corneal surface treatment zone size ( P <0.05), and not correlated with the pupil diameter and spherical equivalent (all P >0.05). After the shaping treatment, the rate of adverse reaction, which was mild, in both groups was 10%, and the symptoms disappeared. Conclusion: Orthokeratology lenses with smaller treatment zones can significantly reduce the rate of axial length growth in children and adolescents compared to lenses with conventional treatment zones, without compromising treatment safety.

Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are two endogenous hormones recognized by PTH receptor-1 (PTH1R), a member of class B G protein- coupled receptors (GPCRs). Both PTH and PTHrP analogs including teriparatide and abaloparatide are approved drugs for osteoporosis, but they exhibit distinct pharmacology. Here we report two cryo-EM structures of human PTH1R bound to PTH and PTHrP in the G protein-bound state at resolutions of 2.62 Å and 3.25 Å, respectively. Detailed analysis of these structures uncovers both common and unique features for the agonism of PTH and PTHrP. Molecular dynamics (MD) simulation together with site-directed mutagenesis studies reveal the molecular basis of endogenous hormones recognition specificity and selectivity to PTH1R. These results provide a rational template for the clinical use of PTH and PTHrP analogs as an anabolic therapy for osteoporosis and other disorders., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: To establish a novel model using radiomics analysis of pre-treatment and post-treatment magnetic resonance (MR) images for prediction of progression-free survival in the patients with stage II-IVA nasopharyngeal carcinoma (NPC) in South China., Methods: One hundred and twenty NPC patients who underwent chemoradiotherapy were enrolled (80 in the training cohort and 40 in the validation cohort). Acquiring data and screening features were performed successively. Totally 1133 radiomics features were extracted from the T2-weight images before and after treatment. Least absolute shrinkage and selection operator regression, recursive feature elimination algorithm, random forest, and minimum-redundancy maximum-relevancy (mRMR) method were used for feature selection. Nomogram discrimination and calibration were evaluated. Harrell's concordance index (C-index) and receiver operating characteristic (ROC) analyses were applied to appraise the prognostic performance of nomograms. Survival curves were plotted using Kaplan-Meier method., Results: Integrating independent clinical predictors with pre-treatment and post-treatment radiomics signatures which were calculated in conformity with radiomics features, we established a clinical-and-radiomics nomogram by multivariable Cox regression. Nomogram consisting of 14 pre-treatment and 7 post-treatment selected features has been proved to yield a reliable predictive performance in both training and validation groups. The C-index of clinical-and-radiomics nomogram was 0.953 (all P < 0.05), which was higher than that of clinical (0.861) or radiomics nomograms alone (based on pre-treatment statistics: 0.942; based on post-treatment statistics: 0.944). Moreover, we received Rad-score of pre-treatment named RS1 and post-treatment named RS2 and all were used as independent predictors to divide patients into high-risk and low-risk groups. Kaplan-Meier analysis showed that lower RS1 (less than cutoff value, - 1.488) and RS2 (less than cutoff value, - 0.180) were easier to avoid disease progression (all P < 0.01). It showed clinical benefit with decision curve analysis., Conclusions: MR-based radiomics measured the burden on primary tumor before treatment and the tumor regression after chemoradiotherapy, and was used to build a model to predict progression-free survival (PFS) in the stage II-IVA NPC patients. It can also help to distinguish high-risk patients from low-risk patients, thus guiding personalized treatment decisions effectively., (© 2023. The Author(s).)

Background: Papillary thyroid cancer (PTC) is life-threatening due to its malignant progression. Considerable evidence demonstrates that circular RNA (circRNA) regulates PTC development. This study aims to explore the mechanism of circ&#95;0000644 modulating PTC malignant progression., Methods: The RNA levels of circ&#95;0000644, microRNA-671-5p (miR-671-5p) and annexin A2 (ANXA2) were detected by quantitative real-time polymerase chain reaction. Western blot was performed to check protein expression. Cell proliferation and cell apoptosis were investigated by 5-ethynyl-29-deoxyuridine and flow cytometry. Angiogenic capacity, migration and invasion were analyzed by tube formation assay and transwell assay. The interaction between miR-671-5p and circ&#95;0000644 or ANXA2 was identified by dual-luciferase reporter assay. Xenograft mouse model assay was performed to analyze the effect of circ&#95;0000644 on tumor formation in vivo., Results: Circ&#95;0000644 and ANXA2 expression was significantly upregulated, while miR-671-5p was downregulated in PTC tissues and cells when compared with control groups. Circ&#95;0000644 knockdown inhibited PTC cell proliferation, tube formation, migration, and invasion, but induced apoptosis in vitro. Moreover, circ&#95;0000644 knockdown led to delayed tumorigenesis in vivo. In addition, circ&#95;0000644 acted as a miR-671-5p sponge and mediated PTC cell tumor properties through miR-671-5p. ANXA2 was identified as a target gene of miR-671-5p, and its overexpression relieved miR-671-5p-induced effects in PTC cells. Furthermore, circ&#95;0000644 depletion inhibited ANXA2 production by combining with miR-671-5p., Conclusion: Circ&#95;0000644 depletion repressed PTC cell tumor properties through the miR-671-5p/ANXA2 axis., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

As a continuation of our research on the development of pesticide active quinolizidine alkaloids (QAs) from the family Fabaceae, the chemical constituents of the root of Sophora tonkinensis Gagnep. were systematically investigated. Seventeen new matrine-type alkaloids ( 1 - 17 ), including one new naturally occurring compound ( 17 ), along with 20 known ones were isolated from the EtOH extract of S. tonkinensis . Notably, compound 5 possessed an unprecedented 6/6/5/4/6/6 hexacyclic system. Their structures were confirmed via comprehensive spectroscopic data analysis (IR, UV, NMR, HRESIMS), ECD calculation, and X-ray crystallography. Biological tests indicated that compounds 1 , 4 , 10 , 12 , 13 , and 30 displayed significant anti-tomato spotted wilt virus (TSWV) activities compared with the positive control ningnanmycin. Moreover, compound 12 strongly inhibited the expression of the TSWV N , NSs , and NSm genes and TSWV NSs protein in plant host. Furthermore, compounds 4 , 10 , 12 , 20 , and 22 exhibited moderate insecticidal activities against TSWV thrip vector ( Frankliniella occidentalis ).

Huoluo Xiaoling Dan is a classical prescription commonly used for blood circulation and pain relief in clinic with obvious effects. To make it directly treat lesion and improve the effect, this research optimized the preparation process of Huoluo Xiaoling gel paste and further evaluated its in vitro transdermal absorption performance, so as to provide a scientific basis for its development and utilization. Using primary viscosity, holding viscosity, and sensory score as evaluation indexes, the matrix amount of gel paste was determined by the single factor test and Box-Behnken response surface method. The ultra-performance liquid chromatography(UPLC) method was established to determine the content of eight active ingredients, including Danshensu, ferulic acid, salvianolic acid B, salvianolic acid A, ligustilide, tanshinone Ⅱ&#95;A, 11-keto-β-boswellic(KBA), and 3-acetyl-11-keto-β-boswellic acid(AKBA). A mo-dified Franz diffusion cell method was used to evaluate and compare the absorption properties of the gel paste without volatile oil and with volatile oil microemulsion. The results showed that the optimal prescription for Huoluo Xiaoling gel paste matrix was NP700(1.35 g), glycerol(7.00 g), micropowder silica gel(1.25 g), sodium carboxymethyl cellulose(0.20 g), tartaric acid(0.06 g), and glyceryl aluminum(0.04 g). The mass fractions of eight active ingredients in the paste were successively 0.48, 0.014, 0.95, 0.39, 0.57, 0.055, 0.35, and 0.97 mg·g~(-1). The results of the in vitro transdermal absorption test showed that the addition of the volatile oil or the volatile oil microemulsion promoted the transdermal absorption of the active ingredients, and the law of drug penetration conformed to the zero equation or the Higuchi equation. The gel paste prepared by the optimal prescription has good appearance and adhesion, with no residue, and has the characteristics of skeletal slow-release preparation, which is easy to reduce the number of administration, la-ying a foundation for the development of new external dosage forms of Huoluo Xiaoling Dan.

Purposes: To explore the relationship between frailty and community-acquired pneumonia (CAP) in older patients., Methods: A prospective observational study included 109 older patients(≥ 65 years) hospitalized with CAP in respiratory department of Fuxing hospital, Capital Medical University from June 2018 to December 2020. Frailty scores(Frail Scale, range 0-5) and pneumonia severity CURB-65 scale(mild = 1, modest = 2, and severe ≥ 3) were measured. We extracted clinical variables including white blood cell(WBC), neutrophil-to-lymphocyte ratio (NLR), C-reactive protein(CRP), hemoglobin, and albumin. Charlson Comorbidity Index(CCI) was calculated as well. The correlations between the variables and frailty scores were investigated, respectively. After adjusting for covariates, binomial logistic regression analysis was used to assess independent effect of frailty scores on the outcome(discharge or death/progression) in older CAP patients., Results: The subjects had a median age 87(interquartile range,8.5) years, 60.6% male, 45.9% pre-frail, and 32.1% frail. There were positive correlations between frailty scores and CURB-65 scale (p = 0.000, r = 0.542), CCI(p = 0.000, r = 0.359) and NLR(p = 0.005, r = 0.268). Negative correlations were observed between frailty scores and hemoglobin (p = 0.002, r = - 0.298), albumin (p = 0.000, r = - 0.465). In multivariable logistic regression analysis, the factors associated with discharge or death/progression of CAP were frailty scores (OR = 1.623, p = 0.037), NLR (OR = 1.086, p = 0.008) and albumin (OR = 0.869, p = 0.034)., Conclusions: Frailty is correlated with CURB-65 scale, CCI and hemoglobin, and albumin in older patients with CAP. Frailty is also a correlate of increased risk for death or progression in these older people., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Two new isoflavones ( 1 and 2 ), as well as eight known ones were isolated from the roots of Sophora tonkinensis Gagnep. Compound 1 represents an unprecedented polymerization pattern constructed by isoflavone and cytisine. Their structures were elucidated by comprehensive spectroscopic data analysis, combined with ECD calculations. Compound 1 displayed significant anti-tobacco mosaic virus (TMV) activity compared with the positive control ningnanmycin. Moreover, compound 6 exhibited potent α -glucosidase inhibitory activity with IC 50 value of 47.4 mg/L.

Objectives: Clinically, it is very difficult to prevent pathological fracture caused by high recurrence rate of osteolytic disease of proximal femur in children. At present, there is no consensus in clinical studies of which internal fixation method can significantly reduce the probability of recurrence of pathological fracture. The study aims to research the mechanical properties of different internal fixations in the treatment of osteolytic lesions of proximal femur in children by finite element analysis, and to find out the optimal treatment., Methods: Based on finite element analysis, the osteolytic disease models of the femoral neck and intertrochanter in a child (8-year-old, boy) were established respectively, and different internal fixation models (plate and titanium elastic intramedullary nails, TENs) were assembled. For the osteolytic lesion of the femoral neck: model A1 was assembled with a plate; model A2 with two TENs crossing the physis; model A3 with two TENs without crossing the physis. And for pertrochanteric osteolytic lesion: model B1 was assembled with a plate, model B2 with two TENs crossing the physis and model B3 with two TENs without crossing the physis. The Eccentric bearing load, torsional restraintal restraint of calcar femorale and composite load were analyzed for each models., Results: When the yield strain of each model is reached, the stress concentration points are located in the proximal and distal femoral calcar. In the model of femoral neck lesions, the failure load of model A1 and model A2 are the same (1250 N), and the failure load of model A3 (980 N) is significantly lower than that of the former two; in the model of intertrochanteric lesions, the failure load of model B2 is the largest (1350 N), and the failure load of model B1 (1220 N) is lower than that of model B3 (1260 N), but both are smaller than that of model B2., Conclusion: Through finite element analysis, TENs through the epiphyseal plate, is found to be the better internal fixation method for femoral neck lesions and intertrochanteric lesions under two different working conditions. The results of clinical correlation study provide new biomechanical information for orthopedic doctors to consider different treatment options for osteolytic lesions of proximal femur., (© 2023 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Background: To assess the effectiveness of the nurse-led individualised self-care model on myocardial infarction (MI) patients with diabetes., Methods: A total of 120 MI patients were enrolled from May 2020 to December 2021. The intervention group received the nurse-led individualised self-care model (n = 60), whereas the control group only received routine health education (n = 60). The Myocardial Infarction Dimensional Assessment Scale (MIDAS), Coronary Heart Disease Self-Management Behavior Scale (CSMS), Self-Rated Abilities for Health Practices (SRAHP) scale, General Self-Efficacy Scale (GSES), Hospital Anxiety and Depression Scale (HADS), blood glucose and nursing satisfaction in both groups were observed and recorded., Results: The six MIDAS subscales except for insecurity, and all dimensions of the CSMS, SRAHP, GSES and HADS scores, of the intervention group were significantly improved compared to those of the control group ( p < 0.05). Compared with the control group (5.69 ± 1.43 mmol/L), the intervention group showed a decrease in the serum levels of fasting blood glucose (4.83 ± 1.57 mmol/L; p < 0.01)., Conclusions: Our pilot study provides preliminary evidence supporting the feasibility of implementing nurse-led individualised self-care, suggesting its preliminary effects in improving health-related quality of life, self-care ability, health behaviours, self-efficacy, social support and nursing satisfaction among MI patients with diabetes. However, considering the unblinded and pilot nature of this study, these positive results should be interpreted with caution., Clinical Trial Registration: OSF Registration number: DOI 10.17605/OSF.IO/DVW95 (https://archive.org/details/osf-registrations-dvw95-v1)., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 The Author(s). Published by IMR Press.)

Introduction: Bear bile powder (BBP) is widely used in the clinic and has a hypoglycemic effect, but its mechanism is not clear. Methods: In this study, type 2 diabetes mellitus (T2DM) rats induced by a high-sugar and high-fat diet combined with streptozotocin were given BBP, and biochemical indexes, pathological sections, metabonomics, intestinal microbiota (IM) and short-chain fatty acids (SCFAs) were determined. Results: The results showed that BBP could reduce blood glucose, relieve inflammation, insulin resistance, and lipid metabolism disorder, and alleviate tissue damage of the liver, spleen, kidney, and pancreas in T2DM rats. It is worth noting that BBP can reverse the changes in blood and urine metabolites in T2DM rats, which are mainly related to tryptophan metabolism, pentose and glucuronate interconversions, starch and sucrose metabolism, and glycerophospholipid metabolism. In addition, BBP restored IM disorder in T2DM rats, decreased the abundance of Allobaculum , Blautia , Dubosiella , and Anaerostipes , enriched the abundance of Lactobacillus , Romboutsia , UCG-005 , and norank&#95;f&#95;&#95;Eggerthellaceae , and increased the concentration of SCFAs in intestinal contents. Discussion: These findings suggest that BBP may improve T2DM by regulating multiple metabolic pathways, IM composition, and SCFAs levels., Competing Interests: Author L-PQ was employed by the company Fujian Guizhentang Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Cai, Zhang, Su, Zhao, Qiu and Duan.)